Study Protocol Clinical Trial Medicine ® OPEN Tuberculosis infection in children visiting friends and relatives in countries with high incidence of tuberculosis A study protocol Antoni Soriano-Arandes, MD, PhDa, Joan A. Caylà, MD, PhDb, Alessandra Queiroga Gonçalves, PhDc,d, Àngels Orcau, MDe,f, Antoni Noguera-Julian, MD, PhDf,g,h,i, Emma Padilla, MD, PhDj, Elisabet Solà-Segura, MDk, Neus Rius Gordillo, MD, MScl, María Espiau, MD, PhDa, Mónica G. García-Lerín, MDm, Maria Àngels Rifà-Pujol, MDn, Jordi Gómez i Prat, MD, MSco, Esperança Macia-Rieradevall, MD, MScp, Andrea Martin-Nalda, MDa,q,r, Maria Eril-Rius, MDs, José Santos Santiago, MD, MSct, Lídia Busquets-Poblet, MDu, Raisa Morales Martínez, MDt, ∗ Tomàs Maria Pérez-Porcuna, MD, PhDm,v, Abstract Introduction: Tuberculosis (TB) is a global infectious disease. In low-incidence countries, paediatric TB affects mostly immigrant children and children of immigrants. We hypothesize that these children are at risk of exposure to Mycobacterium tuberculosis when they travel to the country of origin of their parents to visit friends and relatives (VFR). In this study, we aim to estimate the incidence rate and risk factors associated to latent tuberculosis infection (LTBI) and TB in VFR children. Methods and analysis: A prospective study will be carried out in collaboration with 21 primary health care centres (PCC) and 5 hospitals in Catalonia, Spain. The study participants are children under 15 years of age, either immigrant themselves or born to immigrant parents, who travel to countries with high incidence of TB (≥ 40 cases/100,000 inhabitants). A sample size of 492 children was calculated. Participants will be recruited before traveling, either during a visit to a travel clinic or to their PCC, where a questionnaire including sociodemographic, epidemiological and clinical data will be completed, and a tuberculin skin test (TST) will be performed and read after 48 to 72 hours; patients with a positive TST at baseline will be excluded. A visit will be scheduled eight to This work was supported by a research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded on the 2016 call under the Health Strategy Action 2013–2016, within the National Research Program oriented to Societal Challenges, within the Technical, Scientific and Innovation Research National Plan 2013–2016, with reference PI16/00314, co-funded with European Union ERDF funds (European Regional Development Fund); by the Departament de Salut of the Generalitat de Catalunya, in the call for the year 2017 of granting grants of the Strategic Plan for Research and Innovation in Health (PERIS) 2016–2020, modalitat Intensificació de Facultatius Especialistes, with the file code SLT006/17/144; by the Spanish Society of Pneumology and Thoracic Surgery (grant number 90/ 2015). The funders will not have any authority over any of the activities of the project. The authors have no conflicts of interest to disclose. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. a Unitat de Patologia Infecciosa i Immunodeficiències Pediàtriques, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron, b Fundació de la Unitat d’Investigació en Tuberculosi de Barcelona, Barcelona, c Unitat de Suport a la Recerca Terres de l’Ebre, Fundació Institut Universitari per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), d Unitat Docent de Medicina de Familia i Comunitària, Tortosa-Terres de l’Ebre, Institut Català de la Salut, Tortosa, Tarragona, e Servei d’epidemiologia, Agència de Salut Pu blica de Barcelona, Barcelona, f Centro de Investigación Biomédica en Red de Epidemiología y Salud Pu blica g (CIBERESP), Madrid, Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d’Infeccions, Servei de Pediatria, Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, h Departament de Pediatria, Universitat de Barcelona, Barcelona, i Red de Investigación Translacional en Infectología Pediátrica (RITIP), Madrid, j Àrea de Microbiologia de Catlab, Terrassa, k Equip d’Atenció Primària Vic Nord, Institut Català de la Salut, Vic, l Servei de Pediatria Hospital Universitari Sant Joan de Reus, Reus, m Atenció Primària, Fundació Assistencial Mu tua Terrassa, Terrassa, n Equip d’Atenció Primària Tona, Institut Català de la Salut, Tona, o Equip de Salut Pu blica i Comunitària de la Unitat de Salut Internacional Drassanes-Hospital Universitari Vall d’Hebron, Servei de Medicina Preventiva de Vall d’Hebron, Barcelona, p Equip d’atenció primària Manlleu, Institut Català de la Salut, Manlleu, q Grup de recerca infecció en el pacient pediàtric immunodeprimit, Vall d’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d’Hebron, Barcelona, r Centre de Diagnòstic i Investigació per a Immunodeficiències Primàries Jeffrey Modell, Barcelona, s Equip d’atenció primària La Vall del Ges, Institut Català de la Salut, Torelló, t Centre de Salut Internacional i Malalties Transmissibles Drassanes/Vall d’Hebron. Programa de Salut Internacional de l’ICS (PROSICS), Barcelona, u Servei de pediatría, CAP El Remei, L’Equip d’Assistència Primària de Vic, Vic, v Unitat clínica de Tuberculosi i Salut Internacional, Fundació de Docència i Recerca Mu tua Terrassa, Servei de Pediatria, Hospital Universitari Mutua Terrassa, Terrassa, Spain. ∗ tua Terrassa, Terrassa, Spain (e-mail: tomas.perez.porcuna@gmail.com). Correspondence: Tomàs Maria Pérez-Porcuna, Atenció Primària, Fundació Assistencial Mu Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Soriano-Arandes A, Caylà JA, Gonçalves AQ, Orcau À, Noguera-Julian A, Padilla E, Solà-Segura E, Gordillo NR, Espiau M, García-Lerín MG, Rifà-Pujol MÀ, Jordi Gómez i Prat, Macia-Rieradevall E, Martin-Nalda A, Eril-Rius M, Santos Santiago J, Busquets-Poblet L, Martínez RM, Pérez-Porcuna TM. Tuberculosis infection in children visiting friends and relatives in countries with high incidence of tuberculosis: a study protocol. Medicine 2020;99:36(e22015). Received: 25 July 2020 / Accepted: 31 July 2020 http://dx.doi.org/10.1097/MD.0000000000022015 1 Soriano-Arandes et al. Medicine (2020) 99:36 Medicine twelve-weeks after their return to perform a TST and a QuantiFERON-TB Gold Plus test. The incidence rate of LTBI will be estimated per individual/month and person/year per country visited, and also by age-group. Ethics and dissemination: The study protocol was approved by the Clinical Research Ethics Committee of the Hospital tua Terrassa (code 02/16) and the Clinical Research Ethics Committee of the Fundació Institut Universitari per a la Universitari Mu Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (code P16/094). Articles will be published in indexed scientific journals. Trial registration: Clinical-Trials.gov: NCT04236765 Abbreviations: LTBI = latent infection by M. tuberculosis, PCC = primary health care centres, QFT-Plus = QuantiFERON-TB Gold Plus, TB = Tuberculosis, TST = tuberculin skin test, VFR = visit friends and relatives. Keywords: children, incidence, interferon-gamma release assay, latent tuberculosis, travel-related infection, tuberculin test, tuberculosis 1. Introduction 2. Methods and design It is estimated that one third of the world population is infected An interventional, single group assignment, multicentre study will with Mycobacterium tuberculosis and that 5% to 10% of those be carried out from June 2017 to December 2020 in Catalonia. The infected will develop tuberculosis (TB) during their lifetime.[1] incidence rate of LTBI/TB in Catalonia is 12.6 cases/100,000 Current global figures indicate that 10 million people develop TB inhabitants and 36.3 cases/100,000 inhabitants among the general every year, of which 1.1 million are children.[2] and the immigrant population, respectively.[20] BCG vaccination is It is important to underscore that children have a greater risk of not included in the national programme of immunization. developing active TB after primary infection, especially before their fifth birthday.[3] Significantly, children infected with M 2.1. Setting and participants tuberculosis that do not develop the disease and that do not receive preventive treatment will constitute a reservoir of TB in Participants of the study are children that meet the inclusion the future.[4] Consequently, the identification and administration criteria, attended at any of the 5 pre-travel health clinics or at any of preventive treatment to children with latent tuberculosis of the 21 primary health centres (PCC) involved in the study. infection (LTBI) are critical to the global TB control and 2.1.1. Inclusion criteria (all criteria must be met). eradication efforts.[5–7] In countries with low TB incidence, the burden of disease is  Children less than 15 years of age, either immigrants or notably higher in the immigrant than in the autochthonous children born in Spain to immigrant parents. population.[8–10] Importantly, this higher incidence of tuberculo-  Children with at least one of the parents from a high TB sis persists beyond the first years after arrival to the host incidence country. We define “high TB incidence country” as a country.[11,12] In fact, most new paediatric TB cases in western country with a TB incidence rate 3 times higher than in countries occur in immigrant children and autochthonous Catalonia, namely 40 cases/100,000 inhabitants or great- children born to immigrant parents.[5,8,9] er.[6,20] Countries with official reports describing an incidence In Europe, TB and hepatitis C are the main imported infections less than the value proposed but with some regions with among the immigrant population.[13] The recent increase in ≥40 cases /100,000 inhabitants will also be considered of high international travel of immigrants to their countries of origin to incidence (Fig. 1 and Table 1). visit friends and relatives (VFR)[14–16] and subsequent exposure to  Children travelling and accompanying at least one of the M tuberculosis in countries with incidences of TB higher than in the parents to their country of origin. host countries could partially explain the differences in incidence  The duration of the trip must last a minimum of 21 days. between children of immigrant families and children from the  Informed consent must be obtained from the parents or legal autochthonous population.[17] It seems plausible to associate guardian. travel-related factors with risk of contagion, including the intensity of transmission (proportional to the local TB incidence), the 2.1.2. Exclusion criteria. relationship and contact with the local population, the duration of  Children with previous TB or LTBI. the stay, and individual host factors.[18]  Tourist travel staying in hotels and/or resorts with scarce However, the risk of LTBI is difficult to estimate, firstly because contact with the autochthonous population. of the lack of a gold standard for the diagnosis, and secondly due  Children with primary or secondary immunodeficiency due to to the long incubation period before the development of the TB treatment with corticosteroids, transplantation, treatment with disease, specially in people over 5 years of age.[18] anti-tumour necrosis factor, or chronic renal insufficiency. Due to the little evidence on the risk factors associated to LTBI  Children with congenital heart disease. and TB in VFR children, it is crucial to elucidate the epidemiology  Children with cystic fibrosis and other congenital pulmonary of TB in the immigrant population and their children to better diseases. inform public health policies aimed at reducing the number of TB cases.[19] The objectives of this study are (1) to estimate the incidence 2.2. Sample size rate of LTBI and TB in paediatric VFR travellers when returning from the countries of origin of their parents and (2) to identify The sample size was calculated using the GRANMO v7.2, 2012 risk factors associated with LTBI and TB. program for the study of paired proportions, accepting an alpha 2 Soriano-Arandes et al. Medicine (2020) 99:36 www.md-journal.com Figure 1. Countries considered in the study for having regions with an incidence of tuberculosis of 40 cases/100,000 inhabitants or greater. risk of 0.05 and a beta risk of 0.2 in a two-sided test. It was software platform designed to support data capture for research estimated that 492 subjects are necessary to obtain a statistically studies.[21,22] significant difference considering an initial LTBI proportion of 0% and a final proportion of 2%. A drop-out rate of 20% is 2.4. Outcomes anticipated. 2.4.1. Primary outcome. The primary outcome is the diagnosis of LTBI and/or TB after travelling to a high TB incidence country 2.3. Data collection in accordance with World Health Organization (WHO) guide- lines.[1] At the end of the study, patients will be classified as: “not Baseline data collection: Eligible children will be offered to infected; LTBI/TB disease; unknown/lost to follow-up”. Table 2 participate in the study during a programmed visit in a pre-travel shows study variables and timing of data collection. health clinic or in a PCC. In the first visit, the parents or legal guardians will be interviewed to complete a questionnaire 2.4.2. Secondary outcomes. including socio-demographic, epidemiological, and clinical data. A tuberculin skin test (TST) will be performed and read 48 to 72 1. Sociodemographic data: sex, age, country of birth, country of hours later. Figure 2 shows the study flowchart. birth of mother and father. The TST will be made within 30 days prior to the trip. In BCG 2. Clinical data: weight and height (before and after travel), BCG vaccinated children, TST will be performed and if the result is vaccination, presence of BCG scar. positive, a QuantiFERON-Plus© (QFT-Plus) test will be carried 3. Epidemiological data: pre-travel visit date, travel date, post- travel visit date, return date of the travel, trip duration, travel out to confirm the infection. Subsequently, if the QFT-Plus test is positive, the child will be excluded from the study and treated for country, number of people that lived in host home, travel LTBI. environment (rural / urban / mixed), smokers in host home, Follow-up: A visit will be scheduled 8 to 12 weeks after contact with a person suspected of having TB. returning from the trip. Here, a questionnaire with epidemiologi- cal and clinical data about the trip will be completed and a TST 2.5. TST and QFT-Plus test procedures and QFT-Plus test will be simultaneously performed. Children diagnosed with LTBI or TB, either at baseline or at Tuberculin Skin Test (TST): TST will be performed by follow-up, will receive treatment as per national guidelines, and intradermal injection of 2 UT of PPD RT23 (Statens Serum relatives will be referred for contact tracing. Similarly, the Institut, Copenhagen, Denmark) and read after 48 to 72 hours. A investigators will verify the need for other preventive measures positive test is defined as an induration greater than or equal to (malaria chemoprophylaxis, helminthiasis study, other immuni- 10 mm according to recommendations from the Agència de Salut zations, etc). Publica de Catalunya[23] and WHO guidelines.[1] Data registration: The information collected in the question- QuantiFERON-TB Plus (QFT-Plus) (Cellestis, Victoria, naires will be registered and managed in REDCap (Research Australia; QIAGEN, Dusseldorf, Germany): We will draw four Electronic Data Capture) tools hosted at Fundació de Docència I ml of blood per child and interpret the QFT-Plus test according to Recerca M utua Terrassa. REDCap is a secure, web-based manufacturer’s instructions. Values ≥ 0.35 IU/ml in either TB1 3 Soriano-Arandes et al. Medicine (2020) 99:36 Medicine Table 1 Table 1 High and low tuberculosis incidence countries. (continued). Estimated rate Estimated rate per 100,000 Number per 100,000 Number Country/Territory population of cases Country/Territory population of cases ∗ High tuberculosis incidence Micronesia (Federated States of) 108 120 Afghanistan 189 70,000 Mongolia 428 14,000 Algeria 69 29,000 Morocco 99 36,000 Angola 355 109,000 Mozambique 551 162,000 Azerbaijan 63 6300 Myanmar 338 181,000 Bangladesh 221 357,000 Namibia 524 13,000 Benin 56 6500 Nauru 54 6 Bhutan 149 1100 Nepal 151 42,000 Bolivia (Plurinational State of) 108 12,000 Nicaragua 41 2600 Botswana 275 6200 Niger 87 19,000 Brazil 45 95,000 Nigeria 219 429,000 Brunei Darussalam 68 290 Niue 71 1 Burkina Faso 48 9500 Northern Mariana Islands 95 54 Burundi 111 12,000 Pakistan 265 562,000 Cabo Verde 46 250 Palau 109 20 Cambodia 302 49,000 Panama 52 2200 Cameroon 186 47,000 Papua New Guinea 432 37,000 Central African Republic 540 25,000 Paraguay 43 3000 Chad 142 22,000 Peru 123 39,000 China 61 866,000 Philippines 554 591,000 China, Hong Kong SAR 67 4900 Republic of Korea 66 34,000 China, Macao SAR 60 380 Republic of Moldova 86 3500 Congo 375 20,000 Romania 68 13,000 Côte d’Ivoire 142 36,000 Russian Federation 54 79,000 Democratic People’s Republic of Korea 513 131,000 Rwanda 59 7300 Democratic Republic of the Congo 321 270,000 Sao Tome and Principe 124 260 Djibouti 260 2500 Senegal 118 19,000 Dominican Republic 45 4800 Sierra Leone 298 23,000 Ecuador 44 7400 Singapore 47 2700 El Salvador 70 4500 Solomon Islands 74 480 Equatorial Guinea 201 2600 Somalia 262 39,000 Eritrea 89 3100 South Africa 520 301,000 Eswatini 329 3700 South Sudan 146 16,000 Ethiopia 151 165,000 Sri Lanka 64 14,000 Fiji 54 480 Sudan 71 30,000 Gabon 525 11,000 Tajikistan 84 7600 Gambia 174 4000 Thailand 153 106,000 Georgia 80 3200 Timor-Leste 498 6300 Ghana 148 44,000 Turkmenistan 46 2700 Greenland 100 56 Tuvalu 270 31 Guam 49 82 Uganda 200 86,000 Guinea 176 22,000 Ukraine 80 36,000 Guinea-Bissau 361 6800 United Republic of Tanzania 253 142,000 Guyana 83 640 Uzbekistan 70 23,000 Haiti 176 20,000 Vanuatu 46 130 India 199 2,690,000 Venezuela (Bolivarian Republic of) 48 14,000 Indonesia 316 845,000 Viet Nam 182 174,000 Iraq 42 16,000 Yemen 48 14,000 Kazakhstan 68 12,000 Zambia 346 60,000 Kenya 292 150,000 Zimbabwe 210 30,000 Kiribati 349 400 Low tuberculosis incidence † Kyrgyzstan 116 7300 Argentina 27 12,000 Lao People’s Democratic Republic 162 11,000 Belize 30 110 Lesotho 611 13,000 Colombia 33 16,000 Liberia 308 15,000 Egypt 12 12,000 Libya 40 2700 Guatemala 26 4500 Lithuania 44 1200 Honduras 37 3500 Madagascar 233 61,000 Suriname 38 220 Malawi 181 33,000 Togo 36 2800 Malaysia 92 29,000 Tunisia 35 4000 Mali 53 10,000 Turkey 16 13,000 Marshall Islands 434 250 ∗ Mauritania 93 4100 estimated incidence rate of 40 per 100,000 population or greater. † estimated incidence rate of less than 40 per 100,000 population. Source: World Health Organization (continued ) (WHO) Tuberculosis burden estimates. https://www.who.int/tb/publications/global_report/en/. 4 Soriano-Arandes et al. Medicine (2020) 99:36 www.md-journal.com Figure 2. Timeline of study visits and procedures. and/or TB2 antigen tubes will be considered positive.[24] In the 2.6. Statistical analysis case of QFT-Plus values ≥0.2 and <0.35 (gray zone), the test will Qualitative variables will be described using frequency tables, be repeated 4 to 8 weeks later. QFT-Plus can have a positive, and quantitative variables will be determined using median, mean negative or indeterminate result. and interquartile range (IQR). We will use paired proportions for If TST and QFT-Plus results are discordant, the test with a comparisons. The incidence rate of LTBI and TB will be estimated negative result will be repeated 4 to 8 weeks later. per individual/month and person/year per country visited and by Table 2 Study variables and timing of data collection. Data collection Characteristics Type of response Baseline Follow-up Sociodemographic data Sex; age Nominal; Quantitative (years) ▪ Country of birth of the child Nominal ▪ Mother’s country of origin Nominal ▪ Father’s country of origin Nominal ▪ Clinical data Weight; height Quantitative (Kg); (cm) ▪ ▪ BCG Vaccination Nominal (Yes/No type) ▪ Presence of BCG scar Nominal (Yes/No type) ▪ Infection study Tuberculin test date Date (yyyy-mm-dd) ▪ ▪ Tuberculin test result Quantitative (mm) ▪ ▪ QFT-Plus date Date (yyyy-mm-dd) ▪ QFT-Plus result Quantitative (UI/ml)) ▪ Final diagnosis Nominal ▪ Epidemiological data Date of visits Date (yyyy-mm-dd) ▪ ▪ Age at visits Quantitative (years) ▪ ▪ Travel country Nominal ▪ Travel date (probablea/trueb) Date (yyyy-mm-dd) ▪a ▪b Return date of the travel (probablea/trueb) Date (yyyy-mm-dd) ▪a ▪b Time between tuberculin test and travel date (probablea/trueb) Time in days ▪a ▪b Trip duration Quantitative (days) ▪ Time between tuberculin test and return date Time in days ▪ Number of people that lived in host home Quantitative (number of people) ▪ Travel environment Nominal (rural, urban, mixed) ▪ Smokers in host home Nominal (Yes/No type) ▪ Contact with a person suspected of having TB Nominal (Yes/No type) ▪ BCG = Bacillus Calmette–Guérin vaccine, QFT-Plus = QuantiFERON-plus test, TB = tuberculosis. 5 Soriano-Arandes et al. Medicine (2020) 99:36 Medicine age group. To identify factors associated with presence of LTBI or be prioritized to prevent new cases of TB in the paediatric and the TB, the Fisher exact test or Chi-square test and the Mann- adult population.[33] Whitney test will be used for bivariate analyses, followed by Since state-level data are those usually published in official analysis of logistic regression calculating odds ratios and 95% reports and regional incidence could vary significantly within the confidence intervals. A 5% type I error will be estimated. Data same country, a limitation of the study is the unavailability of will be exported from the REDCap database to PASW Statistics data on regional incidence, which may hinder the assessment on 25 (SPSS Inc., Chicago, IL) for statistical analyses. the intensity of exposure to M tuberculosis.[17] In addition, due to the specific immigration patterns of Catalonia, some countries of origin will be overrepresented in our sample. 2.7. Ethics The lack of gold standard for LTBI diagnosis responds to its This study protocol (version 2, 01/02/2016) has been approved paucibacillary nature, the quiescent state of M tuberculosis and by the Clinical Research Ethics Committee of the Hospital the localization in the mediastinal lymph nodes.[34] However, this Universitari M utua Terrassa on 24/02/2016 (code 02/16) and by is a universal limitation in all studies on this issue. the Clinical Research Ethics Committee of the Fundació Institut The low positive predictive value of the screening tests of LTBI Universitari per a la recerca a l’Atenció Primària de Salut Jordi in the general population constitutes another limitation. Gol i Gurina (IDIAPJGol) on 25/04/2016 (code P16/094), in However, in low burden countries and among high risk groups agreement with the Declaration of Helsinki/Tokyo. All parents such as immigrants and VFR travellers, tests may be useful for or legal guardians of the participants will receive oral and LTBI screening.[35] written information about the study and Informed Consent will Similarly, the TST and interferon-g release assays have well be obtained. Any amendment to the study protocol will be described limitations, which can hinder the interpretation of submitted to the ethical committees for approval. results and the calculation of incidence rates, especially in the case The REDCap© database will be exclusively used by the team of of discordant results.[36,37] Again, this is a universal limitation in researchers. The data included in the database used for statistical all studies on this issue. analyses will be anonymized and identified with internal codes of The study will implement and evaluate a new detection strategy the project to avoid identification by the investigative team to and management of LTBI in VFR children in a country with a guarantee confidentiality. low incidence of TB. This strategy may prove useful to design The results of the study will be published in scientific journals public health policies in regions with low incidence of TB with and will be presented in national and international meetings. The significant numbers of VFR travellers. results will be communicated to participants in a meeting and via local and national media, and will also be disseminated to the Acknowledgments general population. The authors thank the tuberculosis prevention and control program from the Agència de Salut P ublica de Catalunya for 3. Discussion study support. This study aims to evaluate the risk of LTBI and TB in paediatric VFR travellers that live in Catalonia, a low incidence TB Author contributions region.[20] The study will be conducted in primary care centres, specialized travel clinics and hospital paediatric departments of Conceptualization: Antoni Soriano-Arandes, Joan A. Caylà, the public health-care system. The joint role of primary care and Àngels Orcau, Antoni Noguera-Julian, Tomàs Maria Pérez- infectious disease specialists is crucial in the implementation of Porcuna. strategies aimed at the eradication of TB in this population.[25] To Data curation: Alessandra Queiroga Gonçalves, Emma Padilla, our knowledge, this is the first study to prospectively analyse Elisabet Solà-Segura, Neus Rius Gordillo, María Espiau, collected data from VFR children. Mónica G. García-Lerín, Maria Àngels Rifà-Pujol, Jordi The few studies published with adults to date suggest that in Gómez i Prat, Esperança Macia-Rieradevall, Andrea Martin- non-VFR travellers, the risk of infection is similar to the local Nalda, Maria Eril-Rius, José Santos Santiago, Lídia Busquets- annual risk of TB infection.[26] In contrast, studies conducted Poblet, Raisa Morales Martínez. with the immigrant population suggest that a significant Funding acquisition: Antoni Soriano-Arandes, Tomàs Maria percentage of TB cases are related to recent travel to the Pérez-Porcuna. country of origin.[27] In the case of children, a population Investigation: Alessandra Queiroga Gonçalves, Emma Padilla, group with higher susceptibility to develop TB after primary Elisabet Solà-Segura, Neus Rius Gordillo, María Espiau, infection, a case-control study from California reported an Mónica G. García-Lerín, Maria Àngels Rifà-Pujol, Jordi increased risk of LTBI in young paediatric VFR travellers and Gómez i Prat, Esperança Macia-Rieradevall, Andrea Martin- children of families that hosted visitors from countries with high Nalda, Maria Eril-Rius, José Santos Santiago, Lídia Busquets- TB incidence.[28] Poblet, Raisa Morales Martínez, Tomàs Maria Pérez- Awareness of travel-associated risk of disease in VFR remains Porcuna. low, which might explain the scarce use of pre-travel health-care Methodology: Joan A. Caylà, Alessandra Queiroga Gonçalves, services by the immigrant population.[29] Moreover, the diversity Àngels Orcau, Antoni Noguera-Julian. of recommendations for different regions and countries demon- Project administration: Antoni Soriano-Arandes, Tomàs Maria strates the limited information available on this topic.[30,31] Pérez-Porcuna. Knowledge about the effectiveness of LTBI screening or BCG Supervision: Antoni Soriano-Arandes, Joan A. Caylà, Àngels vaccination strategies also remains poor.[32] The implementation Orcau, Antoni Noguera-Julian, Elisabet Solà-Segura, Neus of strategies for the detection and treatment of LTBI cases should Rius Gordillo, María Espiau, Mónica G. García-Lerín, Maria 6 Soriano-Arandes et al. Medicine (2020) 99:36 www.md-journal.com Àngels Rifà-Pujol, Jordi Gómez i Prat, Esperança Macia- [17] Elfrink F, van den Hoek A, Mensen ME, et al. Screening travellers to high-endemic countries for infection with Mycobacterium tuberculosis Rieradevall, Andrea Martin-Nalda, Maria Eril-Rius, José using interferon gamma release assay; a prospective study. BMC Infect Santos Santiago, Lídia Busquets-Poblet, Raisa Morales Dis 2014;14:515. Martínez, Tomàs Maria Pérez-Porcuna. [18] Denholm JT, Thevarajan I. Tuberculosis and the traveller: evaluating and Visualization: Antoni Soriano-Arandes, Joan A. Caylà, Àngels reducing risk through travel consultation. 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