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Pulmonol. 2019;xxx(xx):xxx---xxx

www.journalpulmonology.org

ORIGINAL ARTICLE

Preventive therapy compliance in pediatric

tuberculosis --- A single center experience
J.C. Santos a,∗ , J.B. Silva a , M.A. Rangel a , L. Barbosa a,b , I. Carvalho a,b,c

a
Pediatrics Department, Vila Nova de Gaia/Espinho Hospital Center, Rua Dr. Francisco Sá Carneiro, 4400-129 Vila Nova de Gaia,
Portugal
b
Pediatric Tuberculosis, Pneumologic Diagnosis Center, Rua do Conselheiro Veloso da Cruz 383, 4400-088 Vila Nova de Gaia,
Portugal
c
Allergy and Pulmonology Pediatrics Unit of Pediatrics Department, Vila Nova de Gaia/Espinho Hospital Center, Rua Dr. Francisco
Sá Carneiro, 4400-129 Vila Nova de Gaia, Portugal

Received 12 April 2019; accepted 10 June 2019

KEYWORDS Abstract
Tuberculosis; Introduction: Despite its importance, there are some barriers to patient compliance in preven-
Chemoprophylaxis; tive therapy (PT) of tuberculosis (TB). The purpose of this study was to evaluate the compliance
Children; to appointments, PT and follow-up in a pediatric population after TB exposure, followed in a
Compliance; single TB outpatient center, and the subsequent identification of compliance determinants.
Latent tuberculosis Methods: Retrospective analysis of all pediatric patients who underwent PT in Gaia TB outpa-
infection; tient center from January 2015 to June 2016. Patients were divided into two groups: compliant
Isoniazid and non-compliant, according to adherence to screening, visits and medication. The data col-
lection was based on review of medical records.
Results: A total of 72 patients were enrolled, 33 (45.8%) on chemoprophylaxis and 39 (54.2%) on
latent tuberculosis infection (LTBI) treatment. The majority of patients were compliant (63.9%,
n = 46). Non-compliance was found in 36.1% (n = 26): in 12 patients to contact screening, in 11
patients to PT and 22 patients did not attend medical appointments in the first place. In 10
patients, non-compliance was related to social problems/family dysfunction (low socioeconomic
status and parent’s unemployment). After putting in place several strategies, such as telephone
contact, activating social services and direct observation of therapy, a compliance of 98.6% was
achieved. Isoniazid was the main drug used (91.7%), during 9 months for LBTI.

∗ Corresponding author.
E-mail address: [email protected] (J.C. Santos).

https://doi.org/10.1016/j.pulmoe.2019.06.002
2531-0437/© 2019 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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PULMOE-1384; No. of Pages 6 ARTICLE IN PRESS
2 J.C. Santos et al.

Conclusion: PT compliance in TB can be challenging, probably related to the lack of risk percep-
tion and caregiver’s reluctance to undergo a prolonged treatment to an asymptomatic condition.
We conclude that implementing interventions can considerably improve treatment compli-
ance and reduce the risk of future tuberculosis development. We emphasize the success in
compliance to a 9 month regimen of isoniazid in the vast majority of patients with LTBI.
© 2019 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction 2015 to June 2016 at Gaia outpatient TB center, a TB refe-

rence center at the north region of Portugal. This center
Tuberculosis (TB) remains an important infectious disease in is a community referral center for tuberculosis in the city
pediatric age group.1---3 Although a low incidence threshold of Gaia, Portugal, where all children/adolescents of this
for tuberculosis was achieved in 2015 in Portugal (incidence region who have been exposed to someone with tubercu-
of tuberculosis < 20/100,000 habitants),4 children remain at losis or with suspected tuberculosis disease are screened,
higher risk for developing tuberculosis. investigated and treated, including patients with Mt sensi-
After Mycobacterium tuberculosis (Mt) infection, chil- tive to antitubercular drugs and multidrug-resistant cases.
dren, especially those under 6 years old, have a higher Chemoprophylaxis was prescribed after TB contact with a
probability of developing the disease, usually in the first smear-positive patient for children younger than 6 years,
two years following infection.1,5 TB contact screening and after exclusion of active tuberculosis and discontinued 8---12
implementation of preventive therapy (PT) remain as impor- weeks later, after a second negative screening. The drug
tant measures to reduce the risk of progression to TB.5 TB of choice was isoniazid, unless index case was resistant to
contact screening is carried out in TB outpatient centers isoniazid, in which case rifampicin was chosen. LTBI diag-
after TB exposure and in candidates to immunosuppressive nosis was made in case of positive IGRA/TST in children
therapies.6 younger than 6 years of age or both positive TST and IGRA
PT is indicated when latent tuberculosis infection (LTBI) in children ≥6 years old, asymptomatic and with normal
is diagnosed and as chemoprophylaxis (CP) in children under chest X-ray. LTBI treatment consisted of a 9-month regi-
6 years old after TB exposure. men of isoniazid monotherapy or, in case of resistance to
LTBI diagnose is based on a positive immunological test, isoniazid of index case or intolerance/side effects to isoni-
and PT is continued with isoniazid for 6---9 months. Alter- azid, 4-months regimen of rifampicin. Medication was given
native regimens, such as 4 months rifampicin, may be an to parents/caregivers once a week, free of charge, daily
option in cases of resistance to isoniazid, or adverse events. dosing was indicated and administered by parents at home.
Efficacy is described in the literature as 90% with 9-months All patients on PT were seen monthly until the treatment
of isoniazid, 69% with 6-months of isoniazid and 59% with was complete both to improve compliance and to check
3---4 months of rifampicin.6,7 Most recently, another regimen for symptoms or adverse effects. Demographic character-
has emerged, with twelve doses of weekly rifapentine plus istics, clinical findings at admission, side effects to the
and isoniazid for 3 months. This last regimen has shown to regimens, workup and strategies to improve compliance,
be equivalent to isoniazid in children aged 2 years and older, were collected from patient medical record. Patients were
but with higher compliance.6,8 divided into two groups: (a) compliant --- those patients who
There has been some controversy about the best PT,9,10 attended all the scheduled appointments/screening proce-
with some authors defending shorter anti-TB drugs regimens dures and completed the proposed PT; (b) non-compliant ---
in order to improve compliance.8,11 Compliance to a long- considered to be failure on medication regimen or presence
term daily treatment is crucial to TB control. The primary of other factors that raised the suspicion of non-compliance
objective of this study was to determine the compliance rate (missing to one or more medical appointment or screen-
to TB PT in a cohort of children and adolescents receiving ing). Reasons for non-compliance were classified from the
TB drugs as primary chemoprophylaxis, or as LTBI treatment, perspective of the patient’s medical doctor through review
identifying failure compliance determinants. The evaluation of clinical records. Social problems/family dysfunction were
of implementation of strategies to improve PT compliance defined by the presence of any of the following criteria: (1)
was a secondary objective of this study. families in which conflict and child neglect occurred and was
noticed during medical appointments; (2) families shown to
be at risk by the protection commission for children and
adolescents; (3) alcohol or drug abuse of any of the parents;
Methods
(4) low socioeconomic status and parental unemployment.
All data analyses were performed using the SPSS, version
We carried out a retrospective cohort study, based on
24.0. Statistical significance was determined at the level
medical records review, on the compliance to PT (CP or
of p < 0.05. Confidence intervals were set at 95%. Categori-
LTBI treatment) and to scheduled appointments in pedi-
cal variables are described as frequencies and percentages,
atric patients (<18 years of age) followed-up from January

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Preventive therapy compliance in pediatric tuberculosis 3

and continuous variables as means and standard deviation related with medication such as nausea, vomiting or other
or medians and interquartile ranges, respectively. Differ- gastrointestinal symptoms, side effects and intolerance to
ences between compliant and non-compliant were tested treatment. Non-compliance to contact screening was found
using 2 test or Fisher exact test for categorical variables in 12 patients and in 11 patients (15.3%) to PT. In 10 patients,
and Student’s t-test or Mann---Whitney test for independent non-compliance was related to family dysfunction/social
samples, as appropriate. problems. Medication side effects were seen in 3 patients
(4.2%), with one patient needing to change isoniazid to
rifampicin (9.1%), with subsequent compliance to treat-
Results ment. Oral intolerance to medication was seen in 1 patient
(9.1%). For 2 patients there was no explanation found to non-
A total of 72 patients were enrolled, 33 (45.8%) on CP and 39 compliance to treatment. Follow-up of patients was monthly
(54.2%) on LTBI. The overall results are synthesized in Fig. 1. until treatment was complete.
Sociodemographic data are described in Table 1. The When non-compliance of any kind was noticed, some
median age was 5.5 years, and it was significantly lower in strategies were implemented (Fig 2): all parents/caregivers
the CP group comparing with LTBI group (2.9 vs. 7.7 years, were contacted by phone and encouraged to return to
respectively; p < 0.001). Globally there was a male predomi- the appointments and take the medication, rescheduling
nance. Patients were referred to our center mostly by public a new appointment (n = 26; 100%); social service was acti-
health services, especially after exposure to tuberculosis vated in order to help the return of these families to the
(n = 63). The index case was intrafamilial in the majority appointments (n = 2; 7.7%); directly observed treatment was
of patients (79.2%), with a predominance of grandparents implemented (n = 1; 3.8%); change in medication (3.8%) and
(n = 20); with a daily contact (n = 35). Mt of the index case shortening of the time of prescription ensuring regular and
was susceptible to all drugs in 90% of cases. There were 4 closer monitoring of drug supply (7.7%). With the implemen-
patients referred to screening for immune mediated inflam- tation of these strategies, a final compliance rate of 98.6%
matory diseases candidates for biologic therapy or other was achieved (n = 71). There was 1 case of loss of follow-up.
immunosuppressive agents. Patients were vaccinated with Isoniazid was the main drug used (n = 66; 91.7%), in 31 cases
BCG-vaccine (100%, n = 68; 4 missing values), according to of CP with a median duration of 9 (IQR 8:12) weeks and in 35
the universal BCG vaccination standard in practice at that cases of LTBI for 9 months, with a compliance of 97.1% to 9-
time. At the time of the first medical consultation, 17 month regimen with isoniazid. Rifampicin was used for four
patients (23.6%) had symptoms (cough and/or fever). Ison- months in 8.3% (n = 6), one for side effects to isoniazid and
azid was started in 67 patients (93.1%) and rifampicin in 5 for resistance to isoniazid in the index case. There was no
5 patients (6.9%, for isoniazid-resistant Mt of the index statistical significant difference in PT compliance between
case). In case of CP, treatment was continued for a mean rifampicin and isoniazid (83.3% vs 62.7%; p = 0.658).
of 9.7 ± 3.1 weeks and till a second screening ruled out
LTBI. The second screening was preformed 9.7 weeks after
the first one and included TST and IGRA. Complete blood Discussion
count and liver function tests were performed in 33.4% of
patients (n = 24) after the initiation of treatment, with nor- Tuberculosis in childhood represents a missed opportunity
mal results. for TB screening and establishment of PT.12 PT has the aim of
There was compliance to screening, visits and treatment precluding occurrence of disease in those already infected
in 63.9% (n = 46) and non-compliance in 36.1% (n = 26; Fig or exposed to TB. Despite its importance, there are some
1). A stratified analysis of the results according to the type barriers, usually related with long PT courses and the lack
of treatment (CP vs. LTBI) revealed a compliance of 75.8% of perception of the risk of TB development by the par-
(n = 25) in CP group and 53.8% (n = 21) in LTBI, p = 0.054. ents/caregivers in the asymptomatic child.2 The compliance
Patient age was significantly higher in non-compliant group to prolonged regimens is another difficult issue. In our study,
(6.9 ± 4.7 years-old vs. to 4.8 ± 3.8 in compliance group, initial compliance to PT was 63.9%, which was slightly infe-
p = 0.046). Social problems/family dysfunction were present rior to another study that reported 72.8% of compliance
in 38.5% (n = 10) patients, all non-compliant ones. to CP ant LTBI treatment in pediatric age.13 There was
Missing appointments were registered in 30.6% (n = 22) no statistical significant differences in the PT compliance
and were related with age ≥6 years old (46.2% vs. between CP and LTBI patients (75.8% vs 53.8%, p = 0.054),
21.9% in children <6 years old; p = 0.031). Of those who as also reported by Guix-Comellas et al.,13 which described
missed appointments, 36.4% (n = 8) failed to complete an adherence of 24.3% by CP patients and 35.1% by LTBI
the treatment. There was an association between missing patients, p = 0.08, although with shorter regimens, young
appointments and failure in treatment (p = 0.002). A group children on CP usually depend on their parents and are
of 14 patients maintained treatment despite missing medi- likely to adhere better to medical therapies. Older age was
cal appointments (19.4%) and this group was significantly associated with non-compliance (p = 0.046), consistent with
older (mean age 8.9 ± 4.0 vs. 4.8 ± 3.8 years old; p = 0.003) another study that reported adolescence as a risk factor for
and mostly on LTBI treatment (n = 12; 85.7%). Patients in CP non-compliance.13 Another study about treatment comple-
had a median of 4 (IQR 3---6) medical appointments and LTBI tion for LTBI reported 65.7% of treatment compliance, with
patients a median of 7 (IQR 4:8). significant higher adherence with 4-month rifampicin (85%)
The reasons found for non-compliance are described in compared to isoniazid (52%).8 However, in our study no sig-
Fig. 2, and included social problems/family dysfunction nificant differences were found in the compliance between
and medication problems, which consisted of symptoms isoniazid and rifampicin (83.3% vs 62.7%; p = 0.658), although

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4 J.C. Santos et al.

Screening
n= 60 (83.3%)

COMPLIANCE
n=46
n= (63.9%)
12
(1
6.7
%

appointments
n= 50 )

Medical
(69.4%)
COMPLIANCE
n=71
(98.6%)
n= 2 Strategies
2 (3
0.6% implemented to
)
improve
compliance
4.7%)
Treatment

n= 61 (8
NON-
COMPLIANCE NON-
n=26 (36.1%) COMPLIANCE
n= 11 (15.3%) n=1 (1.4%)

Figure 1 Results overview.

Directly observed treatment 1 (3.8%)

Treatment modification 1 (3.8%)

n=11 (42.3%) n=10 (38.5%)
Family disfunction Every 2 weeks prescription of
Medication problems 2 (7.7%)
medication
No reason identified
Social service activation 2 (7.7%)
n=10 (38.5%)
Phone contact 26 (100%)

0% 20% 40% 60% 80% 100%

Figure 2 Reasons to non-compliance and strategies implemented to improve compliance.

the small number of patients on rifampicin may have limited Drug-related adverse effects were low, with just one
the conclusions. In our population, isoniazid for 9 months patient needing to change medication. Routine liver func-
was the chosen regimen, with 90% efficacy described in the tion monitoring is not necessary for children unless they have
literature.6,7,14 In cases in which Mt strains of the index liver disease10 and in our population they were performed in
case were resistant to isoniazid or intolerance to isoniazid 33.4% of cases once during the treatment course. Household
was observed, a 4-month regimen with rifampicin was used, contacts were the most frequent source of infection, as also
as described in the literature.6 Some studies suggest other described by others.8,13
shorter regimens with higher completion rates, such as 6- The implementation of several strategies was successful
month therapy with isoniazid, with an efficacy of 69%,5 3---4 in the compliance improvement, achieving a final compli-
month of daily isoniazid plus rifampicin6 or twelve doses ance of 98.6%. To the best of our knowledge, this is the first
once-weekly with isoniazid and rifapentine, although this study in Portugal about PT compliance.
last regimen is not recommended for children younger than 2 Our study has some limitations. First, its retrospective
years of age but has an estimated efficacy of 90%, equivalent design and sample size limit the strength of the conclu-
to 9-months of isoniazid.6 sions. Second, although this study considers a recruitment of
The main barriers to PT implementation identified in participants at a community center, we cannot exclude the
different studies16,17 are, lack of awareness, lack of risk possibility of a selection bias. This may occur because some
perception among parents, inadequate knowledge among patients may not have been identified by public health ser-
healthcare providers and poor programmatic monitoring. vices as tuberculosis contact patients and therefore were
However, in our study, social problems/family dysfunction not included in our sample. Considering that this should
and medication problems were the main reasons identified represent a small number of patients, this bias is expected
for non-compliance. We believe that our community-based to have a minimal effect on the results. Finally, some fac-
approach with collaboration of pediatricians with expe- tors found in other studies as determinants of compliance,
rience in tuberculosis, with closer contact with families such as parents’ education15 and cultural beliefs were not
and regular scheduled appointments was responsible for assessed in this study.
an increased awareness of the health care providers to TB
PT importance, reducing this non-compliance determinant
reported in other studies. Another study in Ethiopia17 about Conclusions
compliance to isonazid CP reported poor compliance (12%)
with the main reason being the perception that drugs were PT compliance was largely increased after implemen-
not necessary when the child was healthy. tation of improvement strategies. Non-compliance was

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Preventive therapy compliance in pediatric tuberculosis 5

Table 1 Sociodemographic and clinical characteristics.

Variable Total group Compliance Non- p-Value
n = 72 n = 46 compliance
n = 26
Age, years, mean ± SD 5.5 ± 4.2 4.8 ± 3.8 6.9 ± 4.7 0.046
Male, No. (%) 40 (55.6) 29 (63.0) 11 (42.3) 0.089
Index case
Mother, No. (%) 12 (16.7) 7 (15.2) 5 (19.2) 0.746
Father, No. (%) 9 (12.5) 7 (15.2) 2 (7.7) 0.473
Brother/sister, No. (%) 2 (2.8) 0 (0) 2 (7.7) 0.127
Grandparents, No. (%) 20 (27.8) 14 (30.4) 6 (23.1) 0.503
Uncle/aunt, No. (%) 14 (19.4) 8 (17.4) 6 (23.1) 0.558
Other, No. (%) 10 (13.9) 7 (15.2) 3 (11.5) 0.739
No index case identified, No. (%) 5 (6.9) 3 (6.5) 2 (7.7) 0.999
Contact with index case*
Daily, No. (%) 35 (63.6) 22 (61.1) 13 (68.4) 0.592
Weekly, No. (%) 11 (20.0) 8 (22.2) 3 (15.8) 0.730
Sporadic, No. (%) 9 (16.4) 6 (16.7) 3 (15.8) 0.999
Tuberculosis of the index case†
Pulmonar, No. (%) 59 (92.2) 36 (87.8) 23 (100) 0.150
Pleuropulmonar, No. (%) 3 (4.7) 3 (7.3) 0 (0) 0.547
Miliar, No. (%) 2 (3.1) 2 (4.9) 0 (0) 0.532
M. tuberculosis of the index case‡
Susceptible to all drugs, No. (%) 54 (90.0) 33 (86.8) 21 (95.5) 0.400
Resistant to isoniazid, No. (%) 5 (8.3) 4 (10.5) 1 (4.5) 0.643
Multidrug resistant, No. (%) 1 (1.7) 1 (2.6) 0 (0) 0.999
Drug of choice, No. (%)
Isoniazid 67 (93.1) 42 (91.3) 25 (96.2) 0.647
Rifampicin 5 (6.9) 4 (8.7) 1 (3.8) 0.647
Origin of the patient, No. (%)
Public health 61 (84.7) 39 (84.8) 22 (84.6) 0.999
Family doctor 4 (5.6) 3 (6.5) 1 (3.8) 0.999
Emergency department 1 (1.4) 1 (2.2) 0 (0) 0.999
Oncology department 1 (1.4) 0 (0) 1 (3.8) 0.361
Pediatrician appointment 4 (5.6) 3 (6.5) 1 (3.8) 0.999
Inpatient department 1 (1.4) 0 (0) 1 (3.8) 0.361
Reason for referral, No. (%)
Exposure to TB 63 (87.5) 39 (84.8) 24 (92.3) 0.473
Suspicion of active TB 5 (6.9) 4 (8.7) 1 (3.8) 0.647
Candidate to immunosuppressive treatment 4 (5.6) 3 (6.5) 1 (3.8) 0.999
Type of preventive therapy, No. (%)
CP 33 (45.8) 25 (75.8) 8 (24.2) 0.054
LTBI treatment 39 (54.2) 21 (53.8) 18 (46.2) 0.054
§
Family disfunction, No. (%) 10 (13.9) 0 (0) 10 (38.5)
§
Medication problems, No. (%) 10 (13.9) 0 (0) 10 (38.5)
SD: standard deviation; CP: chemoprophylaxis; LTBI: latent tuberculosis infection.
* 17 missing values (10 in the compliance group; 7 in the non-compliance group).
† 8 missing values (5 in the compliance group; 3 in the non-compliance group).
‡ 12 missing values (8 in the compliance group; 4 in the non-compliance group).
§ Not possible to compute.

associated with older age of patients. There was no treatment. Compliance can be greatly improved by close
significant difference in treatment compliance between monitoring and strategies to reconnect families with
rifampicin and isoniazid. A 9-month regimen with iso- the PT, rather than shortening of treatment regimens.
niazid continues to be the preferred modality for LTBI We emphasize the importance of health facilities inside

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the community, with experience in tuberculosis in chil- 9. Sterling TR, Villarino E, Borisov AS, Shang N, Gordin F, Bliven-
dren. sizemore E, et al. Three months of rifapentine and isoniazid for
latent tuberculosis infection. N Engl J Med. 2011:2155---66.
10. Lamb GS, Starke JR. Tuberculosis in infants and children. Micro-
Conflict of interest biol Spectr. 2017;5(2):422---33.
11. Spyridis NP, Spyridis PG, Gelesme A, Sypsa V, Valianatou M,
The authors declare that they have no conflict of interest. Metsou F, et al. The effectiveness of a 9-month regimen of iso-
niazid alone versus 3- and 4-month regimens of isoniazid plus
rifampin for treatment of latent tuberculosis infection in chil-
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