Strengthening Tuberculosis Services for Children and Adolescents in Low Endemic Settings.

In low tuberculosis-burden countries, children and adolescents with the highest incidence of tuberculosis (TB) infection or disease are usually those who have immigrated from high-burden countries. It is, therefore, essential that low-burden countries provide healthcare services to immigrant and refugee families, to assure that their children can receive proper testing, evaluation, and treatment for TB. Active case-finding through contact tracing is a critical element of TB prevention in children and in finding TB disease at an early, easily treated stage. Passive case-finding by evaluating an ill child is often delayed, as other, more common infections and conditions are suspected initially. While high-quality laboratory services to detect Mycobacterium tuberculosis are generally available, they are often underutilized in the diagnosis of childhood TB, further delaying diagnosis in some cases. Performing research on TB disease is difficult because of the low number of cases that are spread over many locales, but critical research on the evaluation and treatment of TB infection has been an important legacy of low-burden countries. The continued education of medical providers and the involvement of educational, professional, and non-governmental organizations is a key element of maintaining awareness of the presence of TB. This article provides the perspective from North America and Western Europe but is relevant to many low-endemic settings. TB in children and adolescents will persist in low-burden countries as long as it persists throughout the rest of the world, and these wealthy countries must increase their financial commitment to end TB everywhere.

Distinguishing Features of Adolescents With Undiagnosed Infectious Tuberculosis Attending a Pediatric Emergency Department.

More than 10 days of fever or 13 days of cough differentiated adolescent patients presenting to a pediatric emergency department with infectious tuberculosis (TB) from most patients with pneumonia. Upper lobe involvement was significantly more common in patients with TB. Symptom- and radiograph-based algorithms could minimize TB exposure and aid diagnosis.

Epidemiology, clinical features and outcomes of incident tuberculosis in children in Canada in 2013-2016: results of a national surveillance study.

PURPOSE: Childhood tuberculosis disease is difficult to diagnose and manage and is an under-recognised cause of morbidity and mortality. Reported data from Canada do not focus on childhood tuberculosis or capture key epidemiologic, clinical and microbiologic details. The purpose of this study was to assess demographics, presentation and clinical features of childhood tuberculosis in Canada. METHODS: We conducted prospective surveillance from 2013 to 2016 of over 2700 paediatricians plus vertical tuberculosis programmes for incident tuberculosis disease in children younger than 15 years in Canada using the Canadian Paediatric Surveillance Program (CPSP). RESULTS: In total, 200 cases are included in this study. Tuberculosis was intrathoracic in 183 patients of whom 86% had exclusively intrathoracic involvement. Central nervous system tuberculosis occurred in 16 cases (8%). Fifty-one per cent of cases were hospitalised and 11 (5.5%) admitted to an intensive care unit. Adverse drug reactions were reported in 9% of cases. The source case, most often a first-degree relative, was known in 73% of cases. Fifty-eight per cent of reported cases were Canadian-born Indigenous children. Estimated study rates of reported cases (per 100 000 children per year) were 1.2 overall, 8.6 for all Indigenous children and 54.3 for Inuit children. CONCLUSION: Childhood tuberculosis may cause significant morbidity and resource utilisation. Key geographies and groups have very high incidence rates. Elimination of childhood tuberculosis in Canada will require well-resourced community-based efforts that focus on these highest risk groups.

Impact of the COVID-19 pandemic on the provision of routine childhood immunizations in Ontario, Canada.

BACKGROUND: The COVID-19 pandemic has a worldwide impact on all health services, including childhood immunizations. In Canada, there is limited data to quantify and characterize this issue. METHODS: We conducted a descriptive, cross-sectional study by distributing online surveys to physicians across Ontario. The survey included three sections: provider characteristics, impact of COVID-19 on professional practice, and impact of COVID-19 on routine childhood immunization services. Multivariable logistic regression identified factors associated with modification of immunization services. RESULTS: A total of 475 respondents answered the survey from May 27th to July 3rd 2020, including 189 family physicians and 286 pediatricians. The median proportion of in-person visits reported by physicians before the pandemic was 99% and dropped to 18% during the first wave of the pandemic in Ontario. In total, 175 (44.6%) of the 392 respondents who usually provide vaccination to children acknowledged a negative impact caused by the pandemic on their immunization services, ranging from temporary closure of their practice (n = 18; 4.6%) to postponement of vaccines in certain age groups (n = 103; 26.3%). Pediatricians were more likely to experience a negative impact on their immunization services compared to family physicians (adjusted odds ratio [aOR] = 2.64, 95% CI: 1.48-4.68), as well as early career physicians compared to their more senior colleagues (aOR = 2.69, 95% CI: 1.30-5.56), whereas physicians from suburban settings were less impacted than physicians from urban settings (aOR = 0.62, 95% CI: 0.39-0.99). Some of the proposed solutions to decreased immunization services included assistance in accessing personal protective equipment, dedicated centers or practices for vaccination, universal centralized electronic immunization records and education campaigns for parents. CONCLUSIONS: COVID-19 has caused substantial modifications to pediatric immunization services across Ontario. Strategies to mitigate barriers to immunizations during the pandemic need to be implemented in order to avoid immunity gaps that could lead to an eventual increase in vaccine preventable diseases.

Choosing Wisely: Computed Tomography in the Diagnosis of Adolescents With Intrathoracic Tuberculosis.

In a retrospective study of adolescents with intrathoracic tuberculosis (TB), 26 out of the 81 (32%) patients had undergone chest computed tomography (CT). Chest CT was considered unnecessary in 7 (27%), necessary in 7 (27%), and possibly/probably helpful in 12 (46%). Promptly obtaining specimens for sputum smear microscopy, molecular testing, as well as culture for Mycobacterium tuberculosis could avoid several unnecessary CTs.

Prevalence of tuberculosis infection and disease in children referred for tuberculosis medical surveillance in Ontario: a single-cohort study.

BACKGROUND: There are few data about the utility of the Canadian tuberculosis medical surveillance system for detecting tuberculosis in children and adolescents. We sought to assess the prevalence of tuberculosis infection and disease in children and adolescents referred by the tuberculosis medical surveillance program who were evaluated at The Hospital for Sick Children (SickKids) tuberculosis program. METHODS: We retrospectively studied clinical records, radiographic findings and results of interferon-γ release assays (IGRAs) of all children less than 18 years of age referred by the tuberculosis medical surveillance program and evaluated at SickKids between November 2012 and June 2016. RESULTS: The median age of the 216 children was 10.0 years. Most were born in the Philippines (157 [72.7%]) or India (39 [18.0%]). Of the 216, 166 (76.8%) had a history of prior treatment for tuberculosis, and 34 (15.7%) were federal-sponsored refugees from settings with a high tuberculosis burden. Negative IGRA results were found in 110/130 (84.6%) of those with prior tuberculosis treatment. Thirty-one children (14.4%) had any chest radiographic abnormality, of whom 4 had changes thought to be due to tuberculosis. No child received a diagnosis of active tuberculosis at assessment or during follow-up; 3 (1.4%) were treated for latent tuberculosis infection following IGRA testing at SickKids. A positive IGRA result was associated with contact with infectious tuberculosis (odds ratio [OR] 5.97, 95% confidence interval [CI] 2.06-17.52) and older age at first clinic visit (OR 2.98, 95% CI 1.24-8.30) but not with radiographic abnormalities or history of prior tuberculosis treatment. INTERPRETATION: Most children were referred because of a history of prior treatment for tuberculosis; few had clinical or laboratory evidence of infection or prior disease. The tuberculosis medical surveillance process did not identify any children who required treatment for active disease and requires improvement.

Optimizing Blood Collection and Processing for Quantiferon-TB Gold in-Tube Testing Gives Low Rates of Indeterminate Results: Clinical Implications.

The rate of low-mitogen indeterminate interferon-gamma release assay results at a hospital with expert pediatric phlebotomy and rapid incubation of specimens was 0.96%. All low-mitogen indeterminate results were found to be associated with an immunocompromised or anergic state. We describe a child where an unexpected indeterminate interferon-gamma release assay test pointed to an underlying anergic condition and was of diagnostic significance.

Tuberculous lymphadenitis of the head and neck in Canadian children: Experience from a low-burden region.

BACKGROUND: Children are more likely than adults to develop extra-pulmonary tuberculosis (EPTB), which often presents as cervical lymphadenopathy. The role of surgery in management is uncertain. We reviewed all head and neck EPTB cases presenting to our tertiary care pediatric institution over a twelve-year period. METHODS: All children 18 years of age and younger with EPTB involving the head and neck were included. We recorded clinical data and age at diagnosis, birth country, BCG vaccination status, as well as radiographic, surgical, histological, and microbiological results. RESULTS: All 16 patients presented with cervical lymphadenopathy. Fourteen were born outside of Canada in TB endemic areas and all had foreign-born parents. Diagnosis was confirmed microbiologically from lymph node biopsies in 14 cases. Multi-drug resistant TB was identified in two cases: both had previous excisional node biopsies that had not been cultured. Two patients had culture negative suppuration despite adequate anti-tuberculous treatment that required surgery for cure. CONCLUSION: Ongoing suppuration despite appropriate drug therapy is seen in a minority of patients. We found that excisional lymph node biopsy of diseased cervical lymph nodes is diagnostic, and also therapeutic in some cases with ongoing suppuration despite appropriate drug therapy. Mycobacterial culture of lymph nodes is important for diagnosis and determination of drug resistance patterns.

Culture-positive Pediatric Tuberculosis in Toronto, Ontario: Sources of Infection and Relationship of Birthplace and Mycobacterial Lineage to Phenotype.

BACKGROUND: Few data relate Mycobacterium tuberculosis (Mtb) lineage and disease phenotype in the pediatric population or examine the contribution of travel to the tuberculosis (TB)-endemic country in North America. We examined clinical, demographic and Mtb genotype data from patients with TB who were treated in Toronto between 2002 and 2012. METHODS: Consecutive Mtb culture-positive, pediatric patients were included. Clinical data were collected from a prospectively populated clinical database. Mtb case isolate genotypes were identified using Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat (MIRU-VNTR) and spoligotyping and were categorized into phylogeographic lineages for analysis. RESULTS: The 77 patients included 30.4% of all culture-positive pediatric TB cases in Ontario from 2002 to 2012. Seventy-six (99%) patients were first or second generation Canadians. Foreign-born patients were more likely to have extrathoracic disease [odds ratios (OR) = 3.0; 95% confidence interval (CI): 1.04-8.71; P < 0.05] and less likely to have a genotype match in the Public Health Ontario Laboratories database [OR = 0.32 (95% CI: 0.11-0.90); P < 0.05] than Canadian-born patients. For those without a known TB contact, Canadian-born patients were more likely to have travelled to a TB-endemic country [OR = 13.0 (95% CI: 2.5-78.5); P < 0.001]. Extrathoracic disease was less likely in patients infected with the East Asian Mtb lineage [OR = 0.1 (95% CI: 0.01-0.9); P < 0.05] and more likely in those infected with the Indo-Oceanic Mtb lineage [OR = 5.4 (95% CI: 1.5-19.2); P < 0.05]. CONCLUSIONS: Travel to TB-endemic countries likely plays an important part in the etiology of pediatric TB infection and disease, especially in Canadian-born children. Mtb lineage seems to contribute to disease phenotype in children as it has been described in adults.

Invasive Pneumococcal Disease Among Immunocompromised Persons: Implications for Vaccination Programs.

BACKGROUND: In 2012/2013, a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) was recommended for immunocompromised adults in the United States and Canada. To assess the potential benefits of this recommendation, we assessed the serotype-specific burden of invasive pneumococcal disease (IPD) among immunocompromised individuals. METHODS: From 1995 to 2012, population-based surveillance for IPD was conducted in Metropolitan Toronto and Peel Region, Canada. Disease incidence and case fatality were measured in immunocompromised populations over time, and the contribution of different serotypes determined. RESULTS: Overall, 2115/7604 (28%) episodes of IPD occurred in immunocompromised persons. IPD incidence was 12-fold higher (95% confidence interval [CI], 8.7-15) in immunocompromised compared to immunocompetent persons; the case fatality rate was elevated in both younger (odds ratio [OR] 1.8) and older (OR 1.3) adults. Use of immunosuppressive medications was associated with a 2.1-2.7 fold increase in the risk of IPD. Five years after PPV23 program implementation, IPD incidence had declined significantly in immunocompromised adults (IRR 0.57, 95% CI, .40-.82). Ten years after pediatric PCV7 authorization, IPD due to PCV7 serotypes had decreased by 90% (95% CI, 77%-96%) in immunocompromised persons of all ages. In 2011/2012, 37% of isolates causing IPD in immunocompromised persons were PCV13 serotypes and 27% were PPV23/not PCV13 serotypes. CONCLUSIONS: Immunocompromised individuals comprised 28% of IPD. Both PPV23 and herd immunity from pediatric PCV7 were associated with reductions in IPD in immunocompromised populations. PCV13 vaccination of immunocompromised adults may substantially reduce the residual burden until herd immunity from pediatric PCV13 is fully established.

Relating Tuberculosis (TB) Contact Characteristics to QuantiFERON-TB-Gold and Tuberculin Skin Test Results in the Toronto Pediatric TB Clinic.

BACKGROUND: Few data relate interferon-γ-release-assay results in children to source case sputum status, the best predictor of infectiousness of tuberculosis (TB) patients. We evaluated the QuantiFERON-Gold-in-tube assay (QFT) and tuberculin skin test (TST) in children with different types of TB exposure. METHODS: The TST and QFT were performed in referred TB-exposed children and adolescents who had not undergone prior TST screening (tested in parallel), and the QFT was performed in referred TST-positive individuals. Source case characteristics were obtained from referring public health units. We excluded children with known immunocompromising conditions and those known to have TB disease at the time of evaluation. RESULTS: For 103 patients tested in parallel, overall test agreement was very good in the Bacillus Calmette-Guerein (BCG) unimmunized contacts (κ = 0.83) and contacts of household smear-positive (HS+) cases (κ = 0.67), but test agreement was poor in those with lower-risk contact (κ = 0.34). Only 3 of 59 HS+ patients were QFT-positive and TST-negative. On multivariate analysis, a positive QFT was strongly associated with HS+ exposure (odds ratio [OR], 6.6; 95% confidence interval [CI], 2.2-20]) but not BCG; and a positive TST was associated with BCG alone. For 92 referred TST-positive individuals, the QFT was negative in 21% of HS+ contacts, 65% of lower-risk contacts (OR, 6.8; 95% CI, 1.9-25), and 82% of the patients with unknown contact history (OR, 15.5; 95% CI, 5-54). Application of the Canadian 2010 guidelines would exclude from treatment 43 (72%) of the 73 TST+, QFT- patients. CONCLUSIONS: For close contacts of HS+ individuals, the QFT added little sensitivity to the TST for detection of TB infection. The QFT correlated much better with exposure than the TST, especially in BCG-immunized children, and it has the greatest potential benefit for evaluation of those at lower risk of latent TB infection.