ORIGINAL RESEARCH published: 11 June 2019 doi: 10.3389/fped.2019.00238 Clinical Presentations and Outcomes Related to Tuberculosis in Children Younger Than 2 Years of Age in Catalonia Antoni Soriano-Arandes 1 , Silvia Brugueras 2,3,4*, Alejandro Rodríguez Chitiva 1 , Antoni Noguera-Julian 3,5,6,7 , Àngels Orcau 2,3 , Andrea Martín-Nalda 1 , Joan P. Millet 2,3 , Teresa Vallmanya 8 , Maria Méndez 9 , Maite Coll-Sibina 10 , Luis Mayol 11 , Asumpció Clopés 12 , Valentí Pineda 13 , Lourdes García 14 , Nuria López 15 , Olga Calavia 16 , Neus Rius 17 , Tomas M. Pérez-Porcuna 18 , Pere Soler-Palacín 1 and Joan A. Caylà 19 1 Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 2 Servei Epidemiologia, Agència de Salut Pública de Barcelona, Barcelona, Spain, 3 Centre for Biomedical Research in Epidemiology & Public Health (CIBER Epidemiología y Salud Pública - CIBERESP), Barcelona, Spain, 4 Departament de Pediatria, Edited by: d’Obstetrícia i Ginecologia i de Medicina Preventiva, Universitat Autònoma de Barcelona, Barcelona, Spain, 5 Hospital Dimitri Van der Linden, Universitari Sant Joan de Déu, Pediatrics, Esplugues de Llobregat, Spain, 6 Departament de Pediatria, Universitat de Cliniques Universitaires Barcelona, Barcelona, Spain, 7 Red de Investigación Translacional en Infectología Pediátrica, Madrid, Spain, 8 Pediatrics, Saint-Luc, Belgium Hospital Universitari Arnau de Vilanova, Lleida, Spain, 9 Pediatrics, Hospital Universitari Germans Trias i Pujol, Badalona, Reviewed by: Spain, 10 Pediatrics, Hospital General de Granollers, Granollers, Spain, 11 Pediatrics, Hospital Universitari Josep Trueta, Casper Roed, Girona, Spain, 12 Pediatrics, Hospital Pius, Valls, Spain, 13 Pediatrics, Hospital Universitari Parc Taulí, Sabadell, Spain, Copenhagen Municipal 14 Pediatrics, Consorci Sanitari del Maresme, Mataró, Spain, 15 Pediatrics, Hospital Universitari del Mar, Barcelona, Spain, Hospital, Denmark 16 Pediatrics, Hospital Universitari Joan XXIII, Tarragona, Spain, 17 Pediatrics, Hospital Universitari Sant Joan de Reus, Reus, Teresa Del Rosal, Spain, 18 Unitat clínica de Tuberculosi i Salut Internacional, Fundació Recerca Mútua Terrassa, Servei de Pediatria, Hospital University Hospital La Paz, Spain Universitari Mútua de Terrassa, Terrassa, Spain, 19 Foundation of TB Research Unit of Barcelona, Barcelona, Spain *Correspondence: Silvia Brugueras Introduction: Children younger than 2 years have an increased risk of complications silviabruguerastorrella@gmail.com associated with tuberculosis (TB) due to the immaturity of the innate and adaptive Specialty section: immune response. We aimed to identify TB clinical presentations and outcomes as well This article was submitted to as risk factors for complications in this age group. Pediatric Infectious Diseases, a section of the journal Materials and Methods: Multicenter, retrospective, cross-sectional study of TB cases Frontiers in Pediatrics in children aged <2 years in Catalonia (2005–2013). Epidemiological and clinical data Received: 28 September 2018 were collected from the hospital medical records. TB complications, sequelae included, Accepted: 24 May 2019 Published: 11 June 2019 were defined as any tissue damage generating functional or anatomical impairment Citation: after being diagnosed or after TB treatment being completed. Statistical analyses were Soriano-Arandes A, Brugueras S, based on bivariate chi-square and multivariate logistic regression, and it was carried Rodríguez Chitiva A, Noguera-Julian A, Orcau À, out with Stata® version 13.1. Odds ratios (OR) and its 95% confidence intervals were Martín-Nalda A, Millet JP, Vallmanya T, calculated (CI). Méndez M, Coll-Sibina M, Mayol L, Clopés A, Pineda V, García L, Results: A total of 134 patients were included, 50.7% were male, the median [IQR] López N, Calavia O, Rius N, age was 13[8-18] months, and 18.7% (25/134) showed TB-associated complications. Pérez-Porcuna TM, Soler-Palacín P and Caylà JA (2019) Clinical Pulmonary TB was diagnosed in 94.0% (126/134) of children, and the most Presentations and Outcomes Related common complications were lobar collapse (6/126). TB meningitis was diagnosed to Tuberculosis in Children Younger in 14/134 (10.4%), and hydrocephalus and mental impairment occurred in 1 and 2 Than 2 Years of Age in Catalonia. Front. Pediatr. 7:238. patients, respectively. Two patients with spinal TB developed vertebral destruction and doi: 10.3389/fped.2019.00238 paraplegia, respectively. Only one of the patients died. At multivariate level, tachypnea Frontiers in Pediatrics | www.frontiersin.org 1 June 2019 | Volume 7 | Article 238 Soriano-Arandes et al. Tuberculosis Complications in Children (OR = 4.24; 95% CI 1.17–15.35) and meningeal (OR = 52.21; 95% CI 10.05–271.2) or combined/extrapulmonary forms (OR = 11.3; 95% CI 2.85–45.1) were associated with the development of TB complications. Discussion: TB complications are common in children under 2 years old. Extrapulmonary TB forms in this pediatric age remain a challenge and require prompt diagnosis and treatment in order to prevent them. The presence of tachypnea at the time of TB diagnosis is an independent associated factor to the development of TB complications in infants. This clinical sign should be closely monitored in patients in this age group. It is necessary to perform further studies in this age group in a prospective design in order to understand whether there are other factors associated to TB complications. Keywords: tuberculosis, infants, low-incidence country, complications, sequelae, risk factors INTRODUCTION active disease, and their sensitivity is lower in this age group than in older children, making it more difficult to establish diagnosis An estimated one million children were diagnosed with of infection (4). The contribution of all these factors leads to delay tuberculosis (TB) in 2016, according to World Health in diagnosis that can be crucial for the patient’s clinical outcome Organization (WHO) data (1). In the European WHO region, and complication occurrence (6, 7). the European Centre for Disease Prevention and Control Literature is scarce on treatment outcome, complications and (ECDC) estimated that Spain, the United Kingdom, Romania, sequelae occurring in TB diagnosed in children under two. and France contributed 62% of pediatric TB cases occurring in Wiseman et al. (6) described complications as any infiltration the European Union/European Economic Area countries (2). or compression of anatomical structures adjacent to the affected However, the true global incidence and prevalence of site (i.e., neurologic, vascular, bronchial, cardiac, and bone childhood TB remains uncertain due to lack of microbiological complications), with the potential to cause a functional deficit. confirmation of active TB in the majority of children (3). The aims of this study were: 1/ to determine the prevalence Children typically have a paucibacillary disease, which hinders rate of TB clinical presentations, outcomes and complications the detection of Mycobacterium tuberculosis in biological occurring in a large cohort of children with TB under samples. Also, respiratory specimens (i.e., sputum) are difficult two, and 2/ to investigate the factors associated with these to obtain in young children and, consequently most children complications. Knowledge of these factors will help in applying with active TB worldwide are started on treatment based solely preventive measures. on clinical history, clinical symptoms, and radiological signs (3). Microscopic examination of sputum smears is the key to diagnosis in most countries, but its usefulness is limited in MATERIALS AND METHODS young children with paucibacillary disease who are also unable Design and Setting to expectorate (4). This was a multicentric cross-sectional study of pediatric TB cases Children in whom M. tuberculosis infection is detected, diagnosed in children under 2 years of age from January 2005 young children and those with recent exposure are at increased to December 2013 in 10 hospitals which are part of the public risk for progression to disease (4). Knowledge of the child’s Healthcare Network of Catalonia, Spain. status regarding exposure intensity to the index case modifies During 2013, the last year of our period of inclusion in the the pre-test probability of disease and the positive predictive study, a total of 1,135 TB cases were registered in Catalonia, value of subsequent investigations (4). In fact, children under which represents a rate of 15.1 cases per 100,000 population; two account for the major part of the elevated morbidity and pediatric patients, aged under 15 years old accounted for 8.5% of mortality associated with TB (5). Moreover, the diversity of the total1 . In Barcelona, capital city of Catalonia, 1.2% (92 cases) the clinical presentation in infants and young children and the of the total TB registered during the period of 2000-2017 affected non-specific nature of most signs and symptoms complicate TB children under 2 years of age, and incidence of TB showed a diagnosis at this age. Constitutional symptoms often include progressive and declining trend from 45 to 11 cases per 100,000 failure to thrive and reduced playfulness (4). Non-specific population (Dr. A Orcau, TB Control Program Barcelona—as yet clinical manifestations, particularly in meningeal forms, further unpublished data). complicate early recognition of the disease in these infants (6, 7). Data were retrospectively collected from the patient’s medical Finally, the recognition of cellular immune response against history at the time of TB diagnosis (in hospital or healthcare M. tuberculosis is based on two main tests, the tuberculin skin test (TST) and the interferon-γ release assays (IGRAs). However, 1 http://salutpublica.gencat.cat/ca/detalls/Article/Publicacio-informe-TBC-2015 these tests fail to differentiate M. tuberculosis infection from (accessed September 13, 2018). Frontiers in Pediatrics | www.frontiersin.org 2 June 2019 | Volume 7 | Article 238 Soriano-Arandes et al. Tuberculosis Complications in Children center). Data related to subsequent clinical evolution at follow- thrombosis, bronchial artery dilatations, aneurysms of the up visits in the Primary Healthcare Centers was collected through bronchial arteries, pulmonary hypertension compromise the ECAP system (“Estació clínica d’atenció primària”), which secondary to destruction of the pulmonary vascular bed is the computerized clinical history used by all professionals in and chronic pulmonary heart; mediastinal lesions, with the primary care network of Catalonia, and the shared clinical displacement, mediastinal fibrosis, hilar, and mediastinal history of Catalonia. Any health professional working in any lymph node calcifications, esophageal fistulas, chronic of the Catalonian health-care centers can obtain information pneumothorax, with or without fluid effusion; and lesions on patient follow-up regardless of contact with the hospital of the thoracic walls, with costal retractions or alterations where the patient was diagnosed or treated for TB. Patients were produced by surgical procedures (10). TB meningitis identified at each center by the local participating physician and complications were included when any of the following monitored at least until the end of TB treatment. They were was present: tuberculoma, cavernous sinus syndrome, also monitored until the end of 2015 through data obtained cranial nerve palsy, stroke, cerebral edema/hydrocephalus, from patients’ clinical records. Data were collected at the time mental impairment/memory loss, spinal involvement, of TB diagnosis, at completion of TB treatment again, and at audiologic/visual impairment, epilepsy, and hypothalamic completion of follow-up procedure (December 31, 2015). syndrome (11). - Low weight gain was defined as the inability to maintain an Variables adequate weight curve, established by a percentile drop during Demographical, epidemiological, and clinical data was collected. the period prior to TB diagnosis on standardized age and sex Variables collected for the study were the following: chart (12). Demographical: Sex, date of birth, country of birth, and date - Tachypnea was defined according to WHO (13) as following: of arrival to Europe in the case of immigrant children. respiratory rate (RR) of > 60 per minute in children under Epidemiological: Household with TB cases, Bacillus Calmette- 2 months, > 50 per minute in children between 2 and Guérin (BCG) vaccination, contact tracing, and resistance test for 12 months, and > 40 per minute in children older than the index case. 12 months. Clinical: Duration of symptoms prior to diagnosis, poor - Household contact: when the index case lives in the same weight gain, respiratory distress, tachypnea, intensive flat/apartment/house as diagnosed child. care admission, fever, hepatomegaly, splenomegaly, poor - TST was used to screen the subject under study with bacillary nutrition, irritability, neurological symptoms, lymph nodes, antigens, which causes a delayed cellular immune response in gastrointestinal symptoms, and vomiting. the infected individual. We used a dose of 2UT (0.1 ml) of Complementary exams: Chest X-ray (CXR), chest computed PPD RT 23 with Tween 80. The injection was given on the tomography (CT), human immunodeficiency virus (HIV) test, inside forearm, and the test reading was carried out within 48– clinical TB form, microbiological diagnosis, diagnostic tests for 72 h. The transverse diameter of the induration produced in microbiological diagnosis, and tuberculin skin test (TST or the infected children marked the result of this test measured Mantoux test). in millimeters. Treatment: type of TB treatment and date commenced, length of therapy (months), and completion of treatment. Analysis Outcome: Complications secondary to TB (yes/no), and site A descriptive analysis of the variables was carried out. Categorical of complications. variables were expressed in number and percentage. Continuous variables were expressed as the median and interquartile range Definitions (IQR). The distribution of the main variable was compared with - Case of tuberculosis was defined as patient meeting following the remaining variables using the Fisher exact test (dichotomous two criteria: (1) Presence of clinical or radiological signs variables) or Mann-Whitney U-test (continuous variables). and/or symptoms compatible with TB disease of any location, Comparison between patients with and without complications as long as there is no evidence of another disease to explain took place. At the bivariate level, associations were examined their existence. (2) Prescription of standard anti-tuberculosis using the odds ratio (OR) with its 95% confidence interval (CI). treatment, generally using three or more drugs. This definition The associated variables were analyzed at the multivariate level includes confirmed and suspected cases (8, 9). by logistic regression following the Bayesian multiple imputation - TB complication was defined as any tissue injury leading methods. Significance was set at a p-value of ≤ 0.05. The to functional or anatomical impairment after completion of statistical analysis was performed with the Stata R (version 13.1) TB treatment or after TB diagnosis (7). TB sequelae were software package (College Station, Texas, USA). also included as a specific type of complication and defined as any anatomic lesion produced and maintained during a Ethics long-term period (at least 2 years) after completion of TB Confidentiality of data was maintained at all times in treatment. This includes cavitation, focal secondary fibrosis, accordance with the guidelines of Organic Law 15/1999 bronchiectasis, starchy or linear fibrous healing of a cured (Ley Orgánica 15/1999), “Protection of Personal Data.” cavity, destroyed lung on finalizing treatment, airway lesions This study was evaluated and approved by the Clinical including bronchiectasis, bronchial stenosis, and even tracheal Research Ethics Committee of the Hospital Universitari deformities; In the vascular system: bronchial arteritis, Vall d’Hebron (CEIC—HUVH, project PR(AMI)349/2015), Frontiers in Pediatrics | www.frontiersin.org 3 June 2019 | Volume 7 | Article 238 Soriano-Arandes et al. Tuberculosis Complications in Children as the coordination center. In order to participate each TABLE 1 | Epidemiological and clinical characteristics of 134 children with center obtained approval from the corresponding Ethics tuberculosis under 2 years old during the 2005-2013 period in Catalonia. Committee. As this was a retrospective study that did not Variable Frequency/total Frequency/only involve interventions other than usual clinical practice and TB cases (%) pulmonary TB cases (%) in accordance with national legislation informed consent was not required. Female 66/134 (49.3) 48/101 (47.5) Age in months (median, IQR) 13 (8–18) 13 (9–18) Age 0–12 months 56/134 (41.8) 42/101 (41.6) RESULTS Spanish born 127/134 (94.8) 94/101 (93.1) Country of exposition (VFR) 10/134 (7.5) 4/101 (4.0) A total of 134 patients was included and follow-up information BCG vaccination 3/134 (2.2) 3/101 (3.0) was collected until the end of 2015. The median duration TST positive 122/134 (91.0) 94/101 (93.1) of follow-up was 86 months (range: 61–106 months). Chest XR or CT consistent with TB 113/134 (84.3) 89/101 (88.1) Epidemiological and microbiological characteristics of the Microbiological confirmation 44/134 (32.8) 27/101 (26.7) study are described in Table 1. It was relevant that almost all of DST of index case (known) 60/134 (44.8) 47/101 (46.5) them were Spanish-born, had a positive TST and the CXR or Sensitive to first line drugs 58/60 (96.7) 47/47 (100.0) thoracic CT were compatible with TB. Regarding CT, the test MDR-TB 2/60 (3.3) 0/47 (0.0) was performed in 63 children, of which: 59 were compatible with Contact investigation completed 98/130 (75.4) 79/98 (80.6) TB, 2 abnormal but unlikely TB and 2 were normal. All patients Active TB case at home* 75/121 (62.0) 62/92 (67.4) except one completed TB treatment, and the BCG vaccination Treatment completion 132/133 (99.3) 100/100 (100.0) coverage was low. Most of the children had an active TB case at TB, tuberculosis; IQR, interquartile range; VFR, visiting friends and relatives; BCG, bacillus home (household adult TB contact). The cases in which there Calmette-Guérin vaccine; TST, tuberculin skin test; XR, X-ray; CT, computed tomography; were other TB cases in the home had more exclusively pulmonary MDR-TB, multi-drug resistant tuberculosis; DST, drug susceptibility testing. forms than those with no active TB cases in the home (p = 0.03). * It is statistically significant the association between the presence of active TB case at Moreover, those with no TB cases in the home were older (>12 home and the exclusively pulmonary TB forms (p = 0.03), the younger age (p = 0.002), less symptomatology (p < 0.001), and less TB related complications (p = 0.003) when months of age: 73.9 vs. 45.3% p-value = 0.002), presented more compared to the cases with no active TB case at home. symptoms before diagnosis (87 vs. 44% p-value < 0.001) and suffered more TB related complications (32.6 vs. 10.7% p-value = 0.003). Microbiological investigation was performed in 110/134 Concerning TB-associated complications (Table 4), 18.7% of (82.1%) of the TB cases. Throughout all TB cases included in the children had complications, but the highest percentage was the study, less than one third were confirmed by microbiology among TB meningitis cases followed by other TB cases and diagnostic tests (44/134), 4/106 (3.8%) by acid-fast bacilli (AFB) pulmonary TB cases. Lung lobar collapse was the most common strain, 13/47 (27.7%) by GenXpert R MTB/RIF (Cepheid R ) and pulmonary TB-related complication among the pulmonary TB 27/110 (24.5%) by culture. Among those with microbiological forms but also among all the TB cases. Bronchospasm was study, 44/110 (40%) were confirmed with any of the tests (AFB considered a TB related complication as the episodes of wheezing or GenXpert R MTB/RIF or culture). Two cases of multi-drug were temporarily correlated after TB diagnosis and none of resistance TB (MDR-TB) were detected. None of the children them had experienced any prior bronchiolitis or wheezing. tested positive for HIV co-infection. One patient died (case No paradoxical reactions have been reported among the 134 fatality rate of 0.7%) due to neurological complications after TB cases. TB meningitis. At the bivariate analysis level, to be symptomatic at diagnosis, Table 2 shows a description of all TB-related clinical having extrapulmonary TB, including meningeal and mixed manifestations of study subjects. Over one-third of the children forms, and tachypnea and fever >38◦ C at diagnosis were were asymptomatic (37.3%; 50/134) at the moment of TB associated with the development of TB complications (see diagnosis. In pulmonary TB, this percentage was even higher Table 5). In contrast, to have a household TB contact was a representing nearly half the cases. On the contrary, cases of TB protective factor for TB complications. meningitis were almost uniformly symptomatic on TB diagnosis. In the multivariate analysis, only extrapulmonary and The most common clinical signs and symptoms on diagnosis combined clinical TB forms, and the presence of tachypnea were fever >38◦ C, tachypnea, poor feeding, poor weight gain, at diagnosis remained risk factors for the development of and irritability. TB complications. Pulmonary TB was the most common clinical form, but nearly In the case of children suffering pulmonary TB, tachypnea 20% of the cases (25/126) had other organ or system involvement. was found to be associated with complications in the bivariate The most frequent extrapulmonary TB cases were meningeal, analysis (Table 6). lymphatic, pleural, miliary, osseous, and genitourinary (Table 3). Among the 14 cases with TB meningitis, 12 were investigated DISCUSSION using AFB stain, GenXpert R , and culture, and 2 using only AFB stain and culture. Ten (71.4%) of them were The presence of TB complications in this study carried out in microbiologically confirmed. children under two in a low incidence country was relevant, Frontiers in Pediatrics | www.frontiersin.org 4 June 2019 | Volume 7 | Article 238 Soriano-Arandes et al. Tuberculosis Complications in Children TABLE 2 | Clinical characteristics at tuberculosis diagnosis in 134 children under 2 years old during the 2005-2013 period in Catalonia according to the clinical form. Variable Pulmonary TB (N = 101) TB meningitis (N = 14) Total TB (N = 134) N (%) N (%) N (%) Clinical manifestations (signs or symptoms) 56 55.4 13 92.9 84 62.7 Symptoms duration 39 38.6 9 64.3 58 43.3 < 2 weeks Duration 17 16.8 4 28.6 26 19.4 > 2 weeks Respiratory distress 6 5.9 3 21.4 12 9.0 Tachypnea 30 29.7 6 42.9 41 30.6 Fever > 38◦ C 39 38.6 9 64.3 56 41.8 Poor feeding 9 8.9 3 21.4 16 11.9 Poor weight gain 7 6.9 3 21.4 13 9.7 Intensive care admission required 0 0.0 6 42.9 6 4.5 Hepatomegaly 3 3.0 1 7.1 6 4.5 Splenomegaly 0 0.0 1 7.1 3 2.2 Irritability 6 5.9 7 41.2 13 9.7 Neurological signs 0 0.0 6 42.9 7 5.2 Lymph nodes palpable 2 2.0 1 7.1 9 6.7 Gastrointestinal symptoms (diarrhea, abdominal distention) 7 6.9 2 14.3 9 6.7 Vomiting 5 5.0 3 21.4 8 6.0 TB, tuberculosis. an extrapulmonary TB complication (18). We found a study TABLE 3 | Clinical forms of tuberculosis in 134 patients under 2 years old according to lung involvement. undertaken among 80 children diagnosed with TB at a medical center in southern Taiwan over a period of 24 years (1988– Clinical presentation Total 2012) with a similar approach to our study (19). However, this N∧ % study, published in 2013, was also principally focused on central nervous system (CNS) complications due to TB meningitis (19). Pulmonary 126 94.0 It would therefore be correct to say that factors related to TB Meningeal 14 10.4 complications in children under 2 years old in country with Lymphatic 13 9.7 low-incidence TB remain a surprisingly under-studied aspect. Pleural 4 3.0 The World Health Organization estimated that more than Miliary 4 3.0 80% of TB cases in children under 14 are concentrated in 22 Osseous 2 1.5 developing countries (1), mainly in Africa and South East Asia. Genitourinary 1 0.7 The difficulty of diagnosis, lack of resources for contact tracing Exclusively Pulmonary 101 75.4 in many areas and limited pediatric surveillance data in TB Combined (Pulmonary and extrapulmonary) 25 18.7 control programs (20) are some of the main reasons for lack of Exclusively extrapulmonary 8 6.0 knowledge on the real incidence of childhood TB worldwide and ∧ The same TB case may be in more than one category depending on the affected organs. subsequently to make an estimate of how many of these children Bold values include all TB cases categorized according to lung involvement. Values without will develop TB complications after treatment. bold type classify cases based on the affected organ. Regarding the epidemiological characteristics of our sample study, it is important to highlight that most of them were born in affecting nearly one in five of the cases studied. Risk factors for TB Spain (94.8%). They were therefore infected in a low-incidence complications at the time of TB diagnosis were extrapulmonary TB environment; only 7.5% of them were exposed in high- or combined forms and tachypnea. incidence TB countries overseas. The existence of a household Although especially younger children are found to have more TB case was associated with pulmonary TB forms in children illnesses, to develop TB easily and also suffer the most severe when compared to disseminated, meningeal, or combined forms forms of the disease, there is a lack of information regarding (p = 0.03). This could be explained by earlier TB diagnosis when the incidence of TB complications in this age range. In existing children are included in the contact tracing study with the index scientific databases such as MEDLINE through PubMed R free case in the same household. Consequently, delay in diagnosis search engine, most of the articles studying this issue are and development into more advanced forms of the disease tends limited to high-burden TB countries such as South Africa (14, to diminish. Contact tracing investigation was completed in 15), to specific clinical forms such as TB meningitis (16, 17), 75.4% of the cases, a higher percentage than that observed in or to reporting rare complications such as hypercalcemia as other studies in high-burden countries such as South Africa (14), Frontiers in Pediatrics | www.frontiersin.org 5 June 2019 | Volume 7 | Article 238 Soriano-Arandes et al. Tuberculosis Complications in Children TABLE 4 | Tuberculosis complications in 134 children under 2 years old during absent in most of the recruited children when taking into account the 2005–2013 period in Catalonia. total TB cases but was more prevalent in meningeal than in Variable Frequency/total TB Frequency/only Frequency/total TB pulmonary cases. Respiratory distress including tachypnea was cases (%) pulmonary TB meningitis also more frequent in TB meningitis cases than in pulmonary cases (%) cases (%) forms, presumably due to the CNS involvement in disseminated or meningeal TB. Development of complications In our study, 18.7% of the TB patients developed TB- Yes 25/134 (18.7) 7/101 (6.9) 11/14 (78.6) associated complications, and one of them died (0.7%). No 109/134 (81.3) 94/101 (93.1) 3/14 (21.4) Comparisons with other studies are difficult due to the lack Pulmonary 13/134 (9.7) 7/101 (6.9) 4/14 (28.6) of published data. The highest percentage of TB complications TB-related complications was observed among patients with TB meningitis, followed by Bronchiectasis 1/13 (7.7) 0/7 (0.0) 1/4 (25.0) the combined forms. A slightly higher rate of TB complications Lobar collapse 6/13 (46.1) 6/7 (85.7) 3/4 (75.0) was observed in a study among Spanish children diagnosed Bronchial stenosis 1/13 (7.7) 1/7 (14.3) 0/4 (0.0) with pulmonary TB (24). Lobar collapse was the most frequent (endobronchitis) complication in children under 2 with pulmonary TB. The Episodes of 5/13 (38.5) 0/7 (0.0) 0/4 (0.0) same was observed in another study where lung collapse might bronchospasm occur secondary to an endobronchial obstruction or an extrinsic Pleural TB-related 2/134 (1.5) compression caused by lymphadenopathy (24). In our study, complications bronchiectasis was found in only one case; this was likely to have Pleurisy* 2/2 (100.0) been caused by fibrosis of the bronchial wall occurring during Lymphatic 3/134 (2.2) disease or by traction resulting from areas of scar tissue (10). TB-related complications Regarding bronchospasm, it was possible to temporarily correlate Ulceration 1/3 (33.3) the episodes of wheezing after TB diagnosis. However, we were Cellulitis 1/3 (33.3) not able to demonstrate whether these episodes were caused Fistula 1/3 (33.3) by TB. Meningeal 3/134 (2.2) 3/14 (21.4) The incidence of the pleural involvement varies considerably, TB-related being much higher in high-incidence TB areas, affecting up to complications 40% of cases in South Africa (25). In Canada (26), a country Hydrocephalus/ 1/3 (33.3) 1/3 (33.3) with a lower TB incidence than Spain, Pineda et al. (27) detected Brain oedema pleural involvement in 4% of 202 patients with pulmonary TB, Mental disability/ 2/3 (66.7) 2/3 (66.7) whereas in our study, only 1.5% of children showed pleural TB Psychomotor retardation related complications. Spinal TB-related 2/134 (1.5) 1/14 (7.1) Peripheral lymphadenopathy is the most common clinical complications sign in infants diagnosed with TB, seen in 25–35% of Abscess/Vertebral 1/2 (50.0) 0/1 (0.0) extrathoracic TB cases, according to daita from the Spanish destruction Society of Pediatric Infectious Diseases (28). In our study, Paraplegia/ 1/2 (50.0) 1/1 (100.0) 10 children (7.5%) had extrapulmonary TB complications— Tetraplegia three of them were lymphatic TB-related (cellulitis, fistula, TB, tuberculosis. and ulceration)—accounting for 40% of all TB-complications. *Pleural TB complications were those requiring surgical intervention secondary to pleural The explanation for this could be due to the greater risk of TB as lesions of the thoracic walls with costal retractions or alterations produced by disseminated and combined forms in infants when compared to surgical procedures. older children or adults. TB meningitis is the most severe and life-threatening form and similar to that observed in Barcelona (21). Microbiological of the disease in infants (29). Prompt diagnosis and treatment confirmation was achieved in nearly one-third of the children is essential to the improvement in prognosis of the disease (32.8%), representing a higher percentage of confirmed TB cases by decreasing the case fatality rate (CFR) and the incidence when compared to other studies also from South Africa (15), of irreversible complications (30). The main risk factors for Mozambique (22), or Ethiopia (23). The percentage of cases an unfavorable prognosis, including death, are a low Glasgow with microbiological confirmation was limited, due to the lower Coma Scale value at diagnosis, and age under 2 (30). Ten performance of microbiological studies in children, especially in percent of our children had TB meningitis, much lower than younger ones (3), and partly due to the fact that good contact in the under 3-year-old age-group of the largest cohort of investigations are done which favor early diagnosis and avoid culture-confirmed childhood TB from South Africa (14). In a advanced and complicated forms. Finally, the rate of treatment study on TB meningitis in Romania, complications affected 36 completion was achieved in nearly 100% of our patients which is and 14% of children and adults, respectively (31); illustrating remarkable data compared to other studies (15, 22). the greater risk in children with this condition. Otherwise, Regarding clinical manifestations, our study shows great we found TB-complications in 78.6% of the cases of TB differences as compared to adult TB symptomatology. Fever was meningitis in our study, among which 21.4% (3/14) were Frontiers in Pediatrics | www.frontiersin.org 6 June 2019 | Volume 7 | Article 238 Soriano-Arandes et al. Tuberculosis Complications in Children TABLE 5 | Factors associated with tuberculosis complications in a cohort of 134 children under 2 years old. Variable N complications/total p-value cOR 95% CI p-value aOR 95% CI Gender Male 11/68 (16.2) 1 Female 14/66 (21.2) 0.45 1.4 0.58–3.34 Age 0–1 9/56 (16.1) 1 1–2 16/78 (20.5) 0.51 1.35 0.55–3.32 Low weight gain No 20/118 (16.9) 1 Yes 5/13 (38.5) 0.07 3.06 0.91–10.34 Active TB case at home No 15/46 (32.6) 1 1 Yes 8/75 (10.7) 0.004 0.25 0.09–0.64 0.18 0.44 0.13–1.45 Unknown 2/13 (15.4) 0.24 0.38 0.07–1.91 0.30 0.29 0.03–3.03 Country of exposition/VFR No 22/124 (17.7) 1 Yes 3/10 (30.0) 0.35 1.99 0.48–8.29 Duration of clinical manifestations 0 (No clinical manifestations) 2/50 (4.0) 1 0–2 weeks 16/58 (27.6) 0.005 9.14 1.98–42.10 >2 weeks 7/26 (26.9) 0.01 8.84 1.68–46.45 TB Localization Pulmonary only 7/101 (6.9) 1 1 Meningeal 11/14 (78.6) <0.001 49.24 11.10–218.42 <0.001 52.21 10.05–271.2 Extra or mixt 7/19 (36.8) 0.001 7.83 2.341–26.209 0.001 11.3 2.85–45.1 Microbiologic confirmation No 13/90 (14.4) 1 Yes 12/44 (27.3) 0.07 2.22 0.91–5.39 Chest XR or CT Done and normal 4/11 (36.4) 1 Changes compatible with TB 18/113 (15.9) 0.10 0.33 0.09–1.25 Abnormal but unlikely TB 3/10 (30.0) 0.76 0.75 0.12–4.66 Tachypnea No 12/92 (13.0) 1 1 Yes 13/41 (31.7) 0.01 3.09 1.26–7.57 0.03 4.24 1.17–15.35 Fever > 38◦ C No 9/76 (11.8) 1 Yes 16/56 (28.6) 0.02 2.98 1.20–7.37 Poor feeding No 19/114 (16.7) 1 Yes 5/16 (31.3) 0.17 2.27 0.71–7.29 Bivariate and multivariate analysis. cOR, crude Odds ratio; aOR, adjusted Odds ratio; CI, confidence interval; TB, tuberculosis; VFR, visiting friends and relatives; XR, X-ray; CT, computed tomography. related to CNS involvement, including psychomotor retardation Otherwise, as mentioned above, having a household TB contact and hydrocephalus. was a protective factor of these complications. At the multivariate Lastly, musculoskeletal involvement has been described in 10– level, tachypnea and extrapulmonary or combined forms were 20% of extrapulmonary TB cases, which would account for 1–2% associated factors with TB complications. Nevertheless, when the of all TB cases (32), data that is very similar to our results (25 and analysis was restricted to pulmonary TB cases, only tachypnea 1.5%, respectively). was an associated factor in TB complications. Among all TB cases, at bivariate analysis, we found that The fact that tachypnea at the time of TB diagnosis was an the presence of fever or tachypnea and the extrapulmonary independent variable associated to TB complications, could be or combined forms were associated with TB complications. explained by the fact that it is a compensatory response secondary Frontiers in Pediatrics | www.frontiersin.org 7 June 2019 | Volume 7 | Article 238 Soriano-Arandes et al. Tuberculosis Complications in Children TABLE 6 | Presence of TB complications in a cohort of children under 2 years old algorithm (35). However, as a prognosis factor, tachypnea with pulmonary TB. has only been associated to worst outcome in adults with Variable N complications p-value cOR 95% CI community-acquired pneumonia (36), but not yet in children. /total In contrast to the data from studies in areas with high incidence of TB and HIV coinfection such as South Africa (CFR Gender 21%) (37) or Myanmar (CFR 11.4%) (38), there was only one Male 3/53 (5.7) 1 death in our study representing a CFR of 0.7% over the total Female 4/48 (8.3) 0.6 1.51 0.32–7.14 TB cases. Other studies in Kenya (39) or among MDR TB Age cases in children (40) showed CFR percentages of 4 and 21%, 0–1 1/42 (2.4) 1 respectively. Since this is a cross-sectional retrospective study, 1–2 6/59 (10.2) 0.16 4.64 0.54–40.08 the data collection process was subject to limitations, and the Low weight gain possibility of missing information exists. It was difficult to obtain No 7/91 (7.7) 1 long-term data since most of the patients were discharged from Yes 0/7 (0.0) 0.99 0 the specialized medical unit at completion of treatment. Hence, Active TB case at home we cannot ensure that additional complications of the disease No 4/30 (13.3) 1 did not develop at a later stage. The relatively high percentage of Yes 3/62 (4.8) 0.17 0.33 0.07–1.58 TB meningitis (10.4%) in our sample might not be representative Unknown 0/9 (0.0) 0.99 0 of the childhood TB population, leading to selection bias due to Country of exposition/VFR the hospital-based design of our study. However, this difference No 7/97 (7.2) 1 was minimal if we take into consideration the data provided by Yes 0/4 (0.0) 0.99 0 the TB Control Program of Barcelona / Public Health Agency Duration of clinical manifestations of Barcelona for this age-group of children with TB meningitis 0 (No clinical manifestations) 1/45 (2.2) 1 during the 2000–2017 period (6.5%). Another limitation is that 0–2 weeks 5/39 (12.8) 0.09 6.47 0.72–58.00 we were able to determine if the children had complications >2 weeks 1/17 (5.9) 0.48 2.75 0.16–46.61 during and after TB treatment, but not when each of the events Microbiologic confirmation occurred or how long it lasted. It is not possible to distinguish No 7/74 (9.5) 1 between TB complications that lasted until the end of TB treatment and long-lasting sequelae (maintained during at least Yes 0/27 (0.0) 0.99 0 2 years after TB treatment completion). Chest XR or CT In conclusion, our findings show that TB incidence in children Changes compatible with TB 6/89 (6.7) 1 under 2-years of age is still relevant in developed countries, and Abnormal but unlikely TB 1/7 (14.3) 0.47 2.31 0.24–22.39 TB complications are frequent. Extrapulmonary TB forms in this Done and normal 0/5 (0.0) 0.99 0 pediatric age remain a challenge and require prompt diagnosis Tachypnea and treatment to prevent adverse outcomes. The presence of No 1/70 (1.4) 1 tachypnea at the time of TB diagnosis is an independent Yes 6/30 (20.0) 0.01 17.25 1.97–150.68 associated factor to the development of TB complications in Fever > 38◦ C infants. Hence, this clinical sign should be closely monitored No 2/61 (3.3) 1 in patients within this age group. It is necessary to perform Yes 5/39 (12.8) 0.09 4.34 0.80–23.59 further studies in this group of children in a prospective study Poor feeding designed to ascertain whether other factors associated with TB No 7/89 (7.9) 1 complications exist. Yes 0/9 (0.0) 0.99 0 cOR, crude Odds ratio; CI, confidence interval; TB, tuberculosis; VFR, visiting friends and AUTHOR CONTRIBUTIONS relatives; XR, X-ray; CT, computed tomography. AS-A: conceptualized and designed the study. AS-A, AR, AN-J, to hypoxemia for the small lung volume of restrictive lung disease AM-N, TV, MM, MC-S, LM, AC, VP, LG, NL, OC, NR, and or metabolic acid mechanism of sis caused by advanced TB PS-P: data collection. AS-A, SB, ÀO, JM, and JC: statistical disease. It is the earliest detectable clinical sign. Compensatory analysis. AS-A, AR, PS-P, TP-P, SB, ÀO, JM, and JC: drafted mechanisms, such as tachypnea, also operate to maximize initial manuscript. 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Kaung Nyunt KK, Han WW, Satyanarayana S, Isaakidis P, Hone S, Conflict of Interest Statement: The authors declare that the research was Khaing AA, et al. Factors associated with death and loss to follow-up in conducted in the absence of any commercial or financial relationships that could children on antiretroviral care in Mingalardon Specialist Hospital, Myanmar, be construed as a potential conflict of interest. 2006– 2016. PLoS ONE. (2018) 13:e0195435. doi: 10.1371/journal.pone.019 5435 Copyright © 2019 Soriano-Arandes, Brugueras, Rodríguez Chitiva, Noguera-Julian, 39. Onyango DO, Yuen CM, Masini E, Borgdorff MW. Epidemiology Orcau, Martín-Nalda, Millet, Vallmanya, Méndez, Coll-Sibina, Mayol, Clopés, of pediatric tuberculosis in Kenya and risk factors for Pineda, García, López, Calavia, Rius, Pérez-Porcuna, Soler-Palacín and Caylà. This mortality during treatment: a national retrospective cohort is an open-access article distributed under the terms of the Creative Commons study. J Pediatr. (2018) 201:115–21. doi: 10.1016/j.jpeds.2018. Attribution License (CC BY). The use, distribution or reproduction in other forums 05.017 is permitted, provided the original author(s) and the copyright owner(s) are credited 40. Jenkins HE, Yuen CM. The burden of multidrug-resistant tuberculosis and that the original publication in this journal is cited, in accordance with accepted in children. Int J Tuberc Lung Dis. (2018) 22:3–6. doi: 10.5588/ijtld. academic practice. No use, distribution or reproduction is permitted which does not 17.0357 comply with these terms. Frontiers in Pediatrics | www.frontiersin.org 10 June 2019 | Volume 7 | Article 238