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.

Application of whole genome sequence analysis to the study of Mycobacterium tuberculosis in Nunavut, Canada.

Canada has one of the lowest rates of tuberculosis (TB) in the world, however, among certain sub-populations, disease incidence rates approach those observed in sub-Saharan Africa, and other high incidence regions. In this study, we applied mycobacterial interspersed repetitive unit (MIRU) variable number of tandem repeat (VNTR) and whole genome sequencing (WGS) to the analysis of Mycobacterium tuberculosis isolates obtained from Northern communities in the territory of Nunavut. WGS was carried out using the Illumina MiSeq, with identified variants used to infer phylogenetic relationships and annotated to infer functional implications. Additionally, the sequencing data from these isolates were augmented with publically available WGS to evaluate data from the Nunavut outbreak in the broader Canadian context. In this study, isolates could be classified into four major clusters by MIRU-VNTR analysis. These could be further resolved into sub-clusters using WGS. No evidence for antimicrobial resistance, either genetic or phenotypic, was observed in this cohort. Among most subjects with multiple samples, reactivation/incomplete treatment likely contributed to recurrence. However, isolates from two subjects appeared more likely to have occurred via reinfection, based on the large number of genomic single nucleotide variants detected. Finally, although quite distinct from previously reported Canadian MTB strains, isolates obtained from Nunavut clustered most closely with a cohort of samples originating in the Nunavik region of Northern Quebec. This study demonstrates the benefit of using WGS for discriminatory analysis of MTB in Canada, especially in high incidence regions. It further emphasizes the importance of focusing epidemiological intervention efforts on interrupting transmission chains of endemic TB throughout Northern communities, rather than relying on strategies applied in regions where the majority of TB cases result from importation of foreign strains.

Serological and molecular epidemiological outcomes after two decades of universal infant hepatitis B virus (HBV) vaccination in Nunavut, Canada.

Chronic hepatitis B virus (HBV) infection within the Canadian Arctic is considered endemic (>2% prevalence). Within the Arctic region of Nunavut, a vaccination program targeted at newborn infants was initiated approximately 20years ago, along with interim grade school catch-up programs, with the result that individuals born after 1980 are presumed vaccinated. This study investigates the effectiveness of these programs and is the first seroepidemiological survey to determine HBV prevalence in Nunavut in the post-vaccination era. Anonymized serum specimens scheduled for destruction following medical testing were collected between April 2013 and April 2014 from individuals granting consent. Specimens were tested for HBV antibodies, surface antigen (HBsAg), and HBV DNA to perform molecular characterization. Four thousand eight hundred and two specimens (13% of the population) were collected, with a resulting median age of 29years (range 1week to 93years). The prevalence of antibody to the HBV core protein was 9.4%; however, a 10-fold decrease in the rate of HBV exposure was noted among those born after 1980 compared to those born before (1.8% vs. 19.8%, p<0.01). HBsAg positivity was primarily documented in individuals born before 1980 (2.5%), although cases still occurred among the vaccine age cohort (0.3%). HBV subgenotype B5 (previously B6) was the most prevalent genotype observed (81.8%) indicating persistence of locally acquired infection. Vaccine-based antibody as the sole serological marker was evident in the vaccine age cohort, although the rate of decay with increasing age was much greater than predicted (less than 10% in those aged 5-19years). Nearly two decades after the advent of HBV vaccination in Nunavut, HBV prevalence has decreased to 1.2%, indicating non-endemic prevalence. However, the persistence of infection and a lower than expected prevalence of vaccine-based immunity in the vaccine age cohort will require further investigation to understand the causes and consequences.

Laboratory characterization of invasive Haemophilus influenzae isolates from Nunavut, Canada, 2000-2012.

BACKGROUND: With invasive Haemophilus influenzae serotype b (Hib) disease controlled by vaccination with conjugate Hib vaccines, there is concern that invasive disease due to non-serotype b strains may emerge. OBJECTIVE: This study characterized invasive H. influenzae (Hi) isolates from Nunavut, Canada, in the post-Hib vaccine era. METHODS: Invasive H. influenzae isolates were identified by conventional methods at local hospitals; and further characterized at the provincial and federal public health laboratories, including detection of serotype antigens and genes, multi-locus sequence typing and antibiotic susceptibility. RESULTS: Of the 89 invasive H. influenzae cases identified from 2000 to 2012, 71 case isolates were available for study. There were 43 serotype a (Hia), 12 Hib, 2 Hic, 1 Hid, 1 Hie, 2 Hif and 10 were non-typeable (NT). All 43 Hia were biotype II, sequence type (ST)-23. Three related STs were found among the Hib isolates: ST-95 (n=9), ST-635 (n=2) and ST-44 (n=1). Both Hif belonged to ST-124 and the 2 Hic were typed as ST-9. The remaining Hid (ST-1288) and Hie (ST-18) belonged to 2 separate clones. Of the 10 NT strains, 3 were typed as ST-23 and the remaining 7 isolates each belonged to a unique ST. Eight Hib and 1 NT-Hi were found to be resistant to ampicillin due to ß-lactamase production. No resistance to other antibiotics was detected. CONCLUSION: During the period of 2000-2012, Hia was the predominant serotype causing invasive disease in Nunavut. This presents a public health concern due to an emerging clone of Hia as a cause of invasive H. influenzae disease and the lack of published guidelines for the prophylaxis of contacts. The clonal nature of Hia could be the result of spread within an isolated population, and/or unique characteristics of this strain to cause invasive disease. Further study of Hia in other populations may provide important information on this emerging pathogen. No antibiotic resistance was detected among Hia isolates; a small proportion of Hib and NT-Hi isolates demonstrated resistance to ampicillin due to ß-lactamase production.

Epidemiology of Lyme Disease, Nova Scotia, Canada, 2002-2013.

Ixodes scapularis ticks, which transmit Borrelia burgdorferi, the causative agent of Lyme disease (LD), are endemic to at least 6 regions of Nova Scotia, Canada. To assess the epidemiology and prevalence of LD in Nova Scotia, we analyzed data from 329 persons with LD reported in Nova Scotia during 2002-2013. Most patients reported symptoms of early localized infection with rash (89.7%), influenza-like illness (69.6%), or both; clinician-diagnosed erythema migrans was documented for 53.2%. In a separate serosurvey, of 1,855 serum samples screened for antibodies to B. burgdorferi, 2 were borderline positive (both with an indeterminate IgG on Western blot), resulting in an estimated seroprevalence of 0.14% (95% CI 0.02%-0.51%). Although LD incidence in Nova Scotia has risen sharply since 2002 and is the highest in Canada (16/100,000 population in 2013), the estimated number of residents with evidence of infection is low, and risk is localized to currently identified LD-endemic regions.

The Feasibility, Accuracy, and Impact of Xpert MTB/RIF Testing in a Remote Aboriginal Community in Canada.

BACKGROUND: Xpert MTB/RIF testing for Mycobacterium tuberculosis and rifampin resistance is being used extensively in countries with a high burden of TB. However, recent evidence suggests that it may not have the same accuracy or impact in high-income, low-burden TB countries. METHODS: A prospective, pragmatic study was done between March 2012 and March 2014 to determine the feasibility, accuracy, and impact on TB disease management provided by the Xpert test in a remote, medically underserved, predominantly Inuit population in Iqaluit, Nunavut, Canada. RESULTS: A total of 453 Xpert tests were run on sputum samples from 344 patients with suspected TB. Twenty-seven patients were identified as having active TB disease by culture. There were no cases of drug-resistant TB. Using culture as the gold standard, one Xpert test compared with one, two, or three sputum samples cultured per patient had a sensitivity of 85% (95% CI, 66%-95%) and a specificity of 99% (95% CI, 97%-100%) for detection of M tuberculosis. The indeterminate rate was 4.4% of all samples run. Treatment initiation was significantly shortened using Xpert vs the national standard of three smears (1.8 days vs 7.7 days, P < .007) and particularly shorter in smear-negative, culture-positive cases (1.8 days vs 37.1 days, P < .008). CONCLUSIONS: In a predominantly Inuit population in a remote region of Canada where the burden of TB is high and no TB testing facilities are available, onsite Xpert testing was feasible and accurate and shortened the time to TB treatment initiation.

The feasibility of the interferon gamma release assay and predictors of discordance with the tuberculin skin test for the diagnosis of latent tuberculosis infection in a remote Aboriginal community.

BACKGROUND: The tuberculin skin test (TST) is the standard test used to screen for latent TB infection (LTBI) in the northern Canadian territory of Nunavut. Interferon gamma release assays (IGRA) are T cell blood-based assays to diagnose LTBI. The Bacillus Calmette-Guerin (BCG) vaccine is part of the routine immunization schedule in Nunavut. The objective of this study was to test the feasibility, and predictors of discordance between the Tuberculin Skin Test (TST) and the IGRA assay in a medically under-serviced remote arctic Aboriginal population. METHODS: Both the TST and QuantiFERON-TB Gold (Qiagen group) IGRA tests were offered to people in their homes as part of a public health campaign aimed at high TB risk residential areas in Iqaluit, Nunavut, Canada. Feasibility was measured by the capacity of the staff to do the test successfully as measured by the proportion of results obtained. RESULTS: In this population of predominantly young Inuit who were mostly BCG vaccinated, the use of IGRA for the diagnosis of LTBI was feasible. IGRA testing resulted in more available test results reaching patients (95.6% vs 90.9% p = 0.02) but took longer (median 8 days (IGRA) vs 2 days (TST), p value < 0.0001). 44/256 participants (17.2%) had discordant results. Multivariable regression analysis suggested that discordant results were most likely to have received multiple BCG vaccinations (RR 20.03, 95% CI, 3.94-101.82)), followed by BCG given post infancy (RR 8.13, 95% CI, 2.54-26.03)) and then to a lesser degree when BCG was given in infancy (RR 6.43, 95% CI, 1.72-24.85). INTERPRETATION: IGRA is feasible in Iqaluit, Nunavut, a remote Arctic community. IGRA testing results in more test results available to patients compared to TST. This test could result in fewer patients requiring latent TB treatment among those previously vaccinated with BCG in a region with limited public health human resources.

Taima (stop) TB: the impact of a multifaceted TB awareness and door-to-door campaign in residential areas of high risk for TB in Iqaluit, Nunavut.

BACKGROUND: The incidence rate of active tuberculosis (TB) disease in the Canadian Territory of Nunavut has shown a rising trend over the past 10 years. In 2010 it was 60 times greater than the national incidence rate. The objective of the Taima (translates to "stop" in Inuktitut) TB study was to implement and evaluate a public health campaign to enhance existing TB prevention efforts in Nunavut. METHODS: A TB awareness campaign followed by a door-to-door screening campaign was carried out in Iqaluit, Nunavut. The aim of the campaign was to raise awareness about TB, and to provide in-home screening and treatment for people living in residential areas at high risk for TB. Screening was based on geographic location rather than on individual risk factors. RESULTS: During the general awareness campaign an increase in the number of people who requested TB testing at the local public health clinic was observed. However, this increase was not sustained following cessation of the awareness campaign. Targeted TB screening in high risk residential areas in Iqaluit resulted in 224 individuals having TSTs read, and detection of 42 previously unidentified cases of latent TB, (overall yield of 18.8% or number needed to screen = 5.3). These cases of latent TB infection (LTBI) were extra cases that had not been picked up by traditional screening practices (34% relative increase within the community). This resulted in a 33% relative increase in the completion of LTBI treatment within the community. The program directly and indirectly identified 5/17 new cases of active TB disease in Iqaluit during the study period (29.5% of all incident cases). CONCLUSIONS: While contact tracing investigations remain a cornerstone of TB prevention, additional awareness, screening, and treatment programs like Taima TB may contribute to the successful control of TB in Aboriginal communities.

Nanolitre real-time PCR detection of bacterial, parasitic, and viral agents from patients with diarrhoea in Nunavut, Canada.

BACKGROUND: Little is known about the microbiology of diarrhoeal disease in Canada's Arctic regions. There are a number of limitations of conventional microbiology testing techniques for diarrhoeal pathogens, and these may be further compromised in the Arctic, given the often long distances for specimen transport. OBJECTIVE: To develop a novel multiple-target nanolitre real-time reverse transcriptase (RT)-PCR platform to simultaneously test diarrhoeal specimens collected from residents of the Qikiqtani (Baffin Island) Region of Nunavut, Canada, for a wide range of bacterial, parasitic and viral agents. STUDY DESIGN/METHODS: Diarrhoeal stool samples submitted for bacterial culture to Qikiqtani General Hospital in Nunavut over an 18-month period were tested with a multiple-target nanolitre real-time PCR panel for major diarrhoeal pathogens including 8 bacterial, 6 viral and 2 parasitic targets. RESULTS: Among 86 stool specimens tested by PCR, a total of 50 pathogens were detected with 1 or more pathogens found in 40 (46.5%) stool specimens. The organisms detected comprised 17 Cryptosporidium spp., 5 Clostridium difficile with toxin B, 6 Campylobacter spp., 6 Salmonella spp., 4 astroviruses, 3 noroviruses, 1 rotavirus, 1 Shigella spp. and 1 Giardia spp. The frequency of detection by PCR and bacterial culture was similar for Salmonella spp., but discrepant for Campylobacter spp., as Campylobacter was detected by culture from only 1/86 specimens. Similarly, Cryptosporidium spp. was detected in multiple samples by PCR but was not detected by microscopy or enzyme immunoassay. CONCLUSIONS: Cryptosporidium spp., Campylobacter spp. and Clostridium difficile may be relatively common but possibly under-recognised pathogens in this region. Further study is needed to determine the regional epidemiology and clinical significance of these organisms. This method appears to be a useful tool for gastrointestinal pathogen research and may also be helpful for clinical diagnostics and outbreak investigation in remote regions where the yield of routine testing may be compromised.