Evaluation of the classifications of severity in acute respiratory distress syndrome in childhood by the Berlin Consensus and the Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVE: To compare two methods for defining and classifying the severity of pediatric acute respiratory distress syndrome: the Berlin classification, which uses the relationship between the partial pressure of oxygen and the fraction of inspired oxygen, and the classification of the Pediatric Acute Lung Injury Consensus Conference, which uses the oxygenation index. METHODS: This was a prospective study of patients aged 0 - 18 years with a diagnosis of acute respiratory distress syndrome who were invasively mechanically ventilated and provided one to three arterial blood gas samples, totaling 140 valid measurements. These measures were evaluated for correlation using the Spearman test and agreement using the kappa coefficient between the two classifications, initially using the general population of the study and then subdividing it into patients with and without bronchospasm and those with and without the use of neuromuscular blockers. The effect of these two factors (bronchospasm and neuromuscular blocking agent) separately and together on both classifications was also assessed using two-way analysis of variance. RESULTS: In the general population, who were 54 patients aged 0 - 18 years a strong negative correlation was found by Spearman's test (ρ -0.91; p < 0.001), and strong agreement was found by the kappa coefficient (0.62; p < 0.001) in the comparison between Berlin and Pediatric Acute Lung Injury Consensus Conference. In the populations with and without bronchospasm and who did and did not use neuromuscular blockers, the correlation coefficients were similar to those of the general population, though among patients not using neuromuscular blockers, there was greater agreement between the classifications than for patients using neuromuscular blockers (kappa 0.67 versus 0.56, p < 0.001 for both). Neuromuscular blockers had a significant effect on the relationship between the partial pressure of oxygen and the fraction of inspired oxygen (analysis of variance; F: 12.9; p < 0.001) and the oxygenation index (analysis of variance; F: 8.3; p = 0.004). CONCLUSION: There was a strong correlation and agreement between the two classifications in the general population and in the subgroups studied. Use of neuromuscular blockers had a significant effect on the severity of acute respiratory distress syndrome.

Tuberculosis among children and adolescents with rheumatic diseases - case series.

BACKGROUND: Rheumatic patients have a higher frequency of tuberculosis(TB) than the general population. This study aimed to describe children and adolescents with TB and rheumatic diseases(RD) who were being treated in a reference center. METHODS: A series of TB cases were investigated in a reference center for childhood TB in Rio de Janeiro, Brazil, from 1995 to 2022. RESULTS: Fifteen patients with underlying RD and TB were included with 8(53%) being female. The mean age at RD diagnosis was 7.10years (SD ± 0,57 years), and the mean age at TB diagnosis was 9.81 years(SD ± 0.88 years). A total of 9 cases of pulmonary TB(PTB) and 6 cases of extrapulmonary TB-pleural(2), joint/osteoarticular(1), cutaneous(1), ocular(1), and peritoneal(1)- were described. The RD observed in the 15 patients included juvenile idiopathic arthritis(9), juvenile systemic lupus erythematosus(3), juvenile dermatomyositis(1), polyarteritis nodosa(1), and pyoderma gangrenosum(1). Among the immunosuppressants/immunobiologics, methotrexate(8) was the most commonly used, followed by corticosteroids(6), etanercept(2), mycophenolate mofetil(1), cyclosporine A(1), adalimumab(1), and tocilizumab(1). The most common symptoms were fever and weight loss, and a predominance of PTB cases was noted. GeneXpert MTB/RIF® was performed in six patients and was detectable in two without rifampicin resistance; Xpert Ultra® was performed in five patients, and traces with indeterminate rifampicin resistance were detected in three. One female patient discontinued treatment, and another passed away. CONCLUSIONS: The case series demonstrated the importance of suspecting and investigating TB in RD affected patients who are using immunosuppressants/ immunobiologics, particularly in countries with high rates of TB such as Brazil.

Tuberculosis in children and adolescents with rheumatic diseases using biologic agents: an integrative review.

OBJECTIVE: To conduct a bibliographic review on tuberculosis (TB) disease in children and adolescents with rheumatic diseases, being managed with biologic therapy. DATA SOURCE: An integrative review with a search in the U.S. National Library of Medicine and the National Institutes of Health (PubMed) using the following descriptors and Boolean operators: (["tuberculosis"] AND (["children"] OR ["adolescent"]) AND ["rheumatic diseases"] AND (["tumor necrosis factor-alpha"] OR ["etanercept"] OR ["adalimumab"] OR ["infliximab"] OR ["biological drugs"] OR ["rituximab"] OR ["belimumab"] OR ["tocilizumab"] OR ["canakinumab"] OR ["golimumab"] OR ["secukinumab"] OR ["ustekinumab"] OR ["tofacitinib"] OR ["baricitinib"] OR ["anakinra"] OR ["rilonacept"] OR ["abatacept"]), between January 2010 and October 2021. DATA SYNTHESIS: Thirty-seven articles were included, with the total number of 36,198 patients. There were 81 cases of latent tuberculosis infection (LTBI), 80 cases of pulmonary tuberculosis (PTB), and four of extrapulmonary tuberculosis (EPTB). The main rheumatic disease was juvenile idiopathic arthritis. Among LTBI cases, most were diagnosed at screening and none progressed to TB disease during follow-up. Of the TB cases using biologics, most used tumor necrosis factor-alpha inhibitors (anti-TNFα) drugs. There was only one death. CONCLUSIONS: The study revealed a low rate of active TB in pediatric patients using biologic therapy. Screening for LTBI before initiating biologics should be done in all patients, and treatment, in cases of positive screening, plays a critical role in preventing progression to TB disease.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

Correlation of digital flow peak with spirometry in children with and without asthma.

INTRODUCTION: Spirometry and peak expiratory flow measurement (PEF) are combined during functional respiratory assessments. The new digital peak flow meter (DPM) evaluates the forced expiratory volume in the first second (FEV1) and PEF. OBJECTIVE: To compare lung function measurements using spirometry and DPM. METHODS: This cross-sectional analytical study assessed FEV1 and PEF in children with and without asthma. Statistical analysis was performed to assess the agreement between the measures using the intraclass correlation coefficient (ICC), Bland-Altman, and survival agreement plot. RESULTS: 125 (3-12 y) and 196 (6-18 y) children without and with asthma, respectively, were studied. In children without asthma, the ICC for FEV1 and PEF were 0.89 and 0.86, respectively, while the corresponding values were 0.87 and 0.79, respectively, in patients with asthma. The Bland-Altman method showed a difference of -0.4 to 0.5 for FEV1 in patients without asthma, with a tendency to increase as the FEV1 increased to a certain extent. In patients with asthma, the pattern was similar for FEV1, and the PEF had a greater dispersion than among those without asthma; however, a good agreement pattern was maintained. In the survival agreement plot, when accepting a tolerance of 0.150 mL for FEV1, there was an agreement of close to 55% in both groups. Likewise, when accepting a tolerance of 0.5 L/s for PEF, an agreement of close to 60% and 50% was observed in patients without and with asthma, respectively. CONCLUSION: DPM was effective as a measure of lung function in pediatric patients with and without asthma.

Clinical forms and diagnosis of tuberculosis in children and adolescents during the COVID-19 pandemic.

OBJECTIVE: The present study aimed to describe the clinical forms and the time taken to diagnose new tuberculosis cases and to statistically analyze the isolated and combined forms of the disease in children and adolescents treated at a university hospital in Rio de Janeiro during the first year of the COVID-19 pandemic in Brazil. METHODS: This was a cross-sectional study that used retrospective data on children (0-9 years old) and adolescents (10-18 years old) with pulmonary (PTB), extrapulmonary (EPTB), and combined tuberculosis (PTB + EPTB) followed up at the outpatient clinic from January 2019 to March 2021. Categorical data were analyzed by descriptive statistics and expressed as frequency and proportions. Categorical variables were compared using the Chi-square test, and numerical variables using Student's T-test. RESULTS: A total of 51 cases were included, 63% (32/51) of which comprised patients in the year of the pandemic (group A), while 37% (19/51) were patients attended in previous years (group B). In group A, 19% (6/32) of the patients presented PTB, 59% (16/32) had EPTB, and 31% (10/32) had PTB+EPTB. In group B, 42% (8/19) of the patients presented PTB, 42% (8/19) had EPTB, and 16% (3/19) had PTB+EPTB. CONCLUSION: Our study revealed more tuberculosis cases in the first year of the pandemic than in the same period of the previous year, with greater variation of sites affected by the disease, including rarer and more severe forms.

Vascular endothelial growth factor (VEGF) and interleukin-1 receptor antagonist (IL-1Ra) as promising biomarkers for distinguishing active from latent tuberculosis in children and adolescents.

Since distinguishing pulmonary (PTB) from latent tuberculosis (LTBI) in pediatric patients remains a challenge, we aimed to investigate the efficacy of immune mediators in diagnosing PTB and LTBI in this population. In this cross-sectional study performed with children and adolescents, serum levels of 20 biomarkers were assessed and data were analyzed according to age groups. We included 65 participants (PTB, n = 28 and LTBI, n = 37). Overall, levels of TNF-α, IL-1Ra, IL-6, IL-17A, VEGF, MMP-1, and procalcitonin were significantly higher (P < 0.05) in adolescents and children <10 years-old with PTB. Also, principal component analysis (PCA) showed that immune mediators were able to distinguish PTB from LTBI. VEGF and IL-1Ra presented the highest area under the curve (AUC) values, both separately (AUC 0.890 and 0.785) and combined (AUC 0.99). Taken together, we showed that VEGF and IL-1Ra are promising biomarkers to distinguish PTB from LTBI in pediatric patients, especially in children <5 years-old.

String test: a potentially useful tool in the diagnosis of pulmonary tuberculosis in Brazilian children and adolescents.

This study investigated the potential use of the String Test (ST) for the diagnosis of pulmonary tuberculosis (PTB) in children and adolescents. This is a case series of patients aged 4-15 years presenting with clinically presumed PTB and submitted to ST in three pediatric TB referral centers in Brazil, between November 2017 and July 2020. The ST was performed in the morning, after 4-12 h of fasting, followed by ingestion of the capsule by the patient, which was attached to the patient's malar region. The material was collected for simultaneous smear microscopy (acid-fast bacilli - AFB), culture and the molecular investigation by the GeneXpert MTB/RIF®. Thirty-three patients with presumed PTB were included and ST was performed in 26 (78.8%) of them and 7 (21.2%) patients could not swallow the cord. The diagnosis of PTB was established in 11 (42.3%) of the 26 patients who underwent the ST. The diagnosis of PTB was confirmed (by culture or GeneXpert MTB/RIF®) in 5 patients, 4 of whom were also positive by the ST. Two of them showed positivity by the GeneXpert MTB/RIF® only in the ST sample. Two other patients had a positive ST following the induced sputum test (AFB, GeneXpert MTB/RIF®, and positive culture in both specimens). Thus, ST was positive in 36.4% of the patients in whom PTB was diagnosed. ST could be a useful test for diagnosing PTB in children and adolescents.

Priority Activities in Child and Adolescent Tuberculosis to Close the Policy-Practice Gap in Low- and Middle-Income Countries.

Over the past 15 years, and despite many difficulties, significant progress has been made to advance child and adolescent tuberculosis (TB) care. Despite increasing availability of safe and effective treatment and prevention options, TB remains a global health priority as a major cause of child and adolescent morbidity and mortality-over one and a half million children and adolescents develop TB each year. A history of the global public health perspective on child and adolescent TB is followed by 12 narratives detailing challenges and progress in 19 TB endemic low and middle-income countries. Overarching challenges include: under-detection and under-reporting of child and adolescent TB; poor implementation and reporting of contact investigation and TB preventive treatment services; the need for health systems strengthening to deliver effective, decentralized services; and lack of integration between TB programs and child health services. The COVID-19 pandemic has had a significant negative impact on case detection and treatment outcomes. Child and adolescent TB working groups can address country-specific challenges to close the policy-practice gaps by developing and supporting decentral ized models of care, strengthening clinical and laboratory diagnosis, including of multidrug-resistant TB, providing recommended options for treatment of disease and infection, and forging strong collaborations across relevant health sectors.

Gene-Xpert Ultra for the diagnosis of extrapulmonary tuberculosis in children and adolescents.

This prospective study describes the use of Gene-Xpert Ultra for the diagnosis of extrapulmonary tuberculosis (EPTB) in children and adolescents, in Rio de Janeiro, Brazil. Eighteen patients were studied; the final diagnosis of EPTB was established in 13 (72%). Gene-Xpert Ultra results showed detection in 10/13 (77%) of EPTB cases (7 of these 10 with trace-positive results). Gene-Xpert Ultra proved to be a promising method for the diagnosis of childhood EPTB.

Diagnosis of tuberculosis: a consensus statement from the Brazilian Thoracic Association.

Early, accurate diagnosis of tuberculosis is one of the major pillars of the control of the disease. The purpose of this consensus statement is to provide health professionals with the most current, useful evidence for the diagnosis of tuberculosis in Brazil. To that end, the Tuberculosis Committee of the Brazilian Thoracic Association brought together 14 members of the Association with recognized expertise in tuberculosis in Brazil to compose the statement. A nonsystematic review of the following topics was carried out: clinical diagnosis, bacteriological diagnosis, radiological diagnosis, histopathological diagnosis, diagnosis of tuberculosis in children, and diagnosis of latent tuberculosis infection.

Tuberculosis among children and adolescents in Rio de Janeiro, Brazil - Focus on extrapulmonary disease.

OBJECTIVE: To compare the socio-demographic, clinical, and diagnostic characteristics and treatment outcomes between extrapulmonary tuberculosis (EPTB) and pulmonary tuberculosis (PTB) in children and adolescents in Rio de Janeiro, a high TB-burdened Brazilian city. METHODS: This retrospective study used data from patients with EPTB and PTB aged 0 - 18 years, notified on two national databases from 2014 to 2016. RESULTS: Among the 1008 patients, 144 (14.2%) had EPTB. Patients with EPTB showed higher odds of hospital-based diagnosis (odds ratio (OR): 6.76 [95% confidence interval (95% CI): 4.62-9.90]; p < 0.001), no laboratory confirmation (OR: 4.9 2.14 [95% CI: 3.07 - 7.85]; p < 0.001), and being <14 years old (OR: 3.13 [95% CI: 2.18-4.49]) than those with PTB. A diagnosis without laboratory investigation was observed among 301/864 (34.8%) patients with PTB, 48/144 (33.3%) with EPTB, and among those aged under five years with EPTB (15/27 [55.6%]). TB deaths were more frequent in patients with EPTB (5/144 [3.5%]) than in those with PTB (4/864[0.5%]) (p = 0.001); 4/5 (80%) TB deaths were due to TB meningitis; 50% died within 14 days of diagnosis. CONCLUSIONS: EPTB remains a clinical diagnostic challenge that needs to be addressed to fully benefit from the higher sensitivity laboratory investigations.

Diagnosis of pulmonary tuberculosis in children and adolescents: comparison of two versions of the Brazilian Ministry of Health scoring system.

The aim of this study was to evaluate the concordance between two versions of the scoring system (2011 and 2019), recommended by the Brazilian Ministry of Health, for the diagnosis of pulmonary tuberculosis (PTB) in children and adolescents. A retrospective descriptive study was performed to assess the medical records of children and adolescents with PTB, in TB units from Brazilian cities located in Rio de Janeiro, Minas Gerais, and Parana States, from January 1 st , 2004, to December 1 st , 2018. Patients aged 0 to 18 years old with a diagnosis of PTB were included. The comparison between the two scoring systems showed a moderate concordance according to the κ coefficient value = 0.625. Fourteen patients showed a reduction in the TB score, going from 30 points in the 2011, to 25 points or less in the 2019 one. Seventy one percent of these 14 patients had radiological changes suggestive of PTB and 86% had tuberculin skin tests greater than 10 mm. The study concluded that a moderate agreement was observed between the 2011 and 2019 scoring systems, with an increase in the number of patients scoring 25 points or less in 2019, which can eventually hinder the diagnosis of PTB.

Calvarial tuberculosis: two cases in children.

Tuberculosis of the skull or calvarial tuberculosis (CTB) is rare. The literature until 2019 reported less than 60 cases of CTB in childhood. The authors describe two patients with CTB associated with other manifestations of TB, such as: spine and rib injuries, peripheral adenopathy, hepatic and splenic involvement who improved with chemotherapy. The patients were a four-year-old and an eight-year-old child, whose diagnoses were confirmed by histopathological, bacteriological or molecular investigation. Both were not infected with the human immunodeficiency virus (HIV) and did not need orthopedic treatment.

The use of Gene-Xpert MTB RIF in the diagnosis of extrapulmonary tuberculosis in childhood and adolescence.

INTRODUCTION: Gene-Xpert MTB RIF (Xpert) is based on nucleic acid amplification by real-time polymerase chain reaction, which allows for the identification of Mycobacterium tuberculosis and rifampin resistance. We describe the use of Xpert for extrapulmonary tuberculosis (EPTB) in children and adolescents. METHODS: A case series of two reference centers in Rio de Janeiro from 2014-2019. RESULTS: The final diagnosis of EPTB was established in 11/36 (31%) patients, with five cases detectable by Xpert. For lymph node evaluation (9/11), diagnosis by Xpert occurred in 5/9 patients, all with caseous aspects. CONCLUSIONS: Xpert can facilitate the rapid diagnosis of lymph node tuberculosis.

Unfavorable Outcomes in Tuberculosis: Multidimensional Factors among Adolescents in Rio de Janeiro, Brazil.

Since 2018, adolescents have been included as a target group for tuberculosis (TB) surveillance by the WHO. However, they are considered a neglected population, as there are considerable gaps in information about them. We aimed to analyze the risk factors for unfavorable TB treatment outcomes among adolescents in Rio de Janeiro, a Brazilian city with a high burden of TB. This is a retrospective study of adolescents (10-18 years) with TB notified in Rio de Janeiro, from four national database systems, covering 2014-2016. "Extreme vulnerability" was defined as adolescents who presented one of the following characteristics: homelessness, incarceration, tobacco use, illicit drug use, or alcohol abuse. Logistic regression analysis was used to identify factors associated with favorable (cure/completed treatment) and unfavorable outcomes (lost to follow-up, death, and treatment failure). A total of 725 adolescents with TB were included: 610 (84.1%) were cured, 94 (13%) were lost to follow-up, six (0.8%) died because of TB, 13 (1.8%) died because of other causes, and two (0.3%) failed treatment. Unfavorable outcomes were associated with retreatment (adjusted odds ratio [aOR]: 4.51; 95% CI: 2.23-9.17), TB-HIV coinfection (aOR: 10.15; 95% CI: 4.15-25.34), extreme vulnerability (aOR: 3.01; 95% CI: 1.70-5.33), and living in the two districts (3.1 and 3.3) with worst conditions: large population and rates of homicides and shantytowns (aOR: 4.11; 95% CI: 1.79-9.46 and aOR: 5.35; 95% CI: 2.20-13.03, respectively). Our findings underscore the need for strengthening early identification and interventions for adolescents at high risk of unfavorable outcomes, especially those living in shantytowns.