Estimates of tuberculosis progression rate of children in China

In this paper, a discrete mathematical model is formulated to describe tuberculosis (TB) progression from latent infection to active disease. The data of national TB epidemiology surveys in China are taken to estimate the TB progression rate for children aged 0–14 years. The progression rate obtained in this paper gives a detailed and better estimate of TB progression rate among children.     

Sexual Dimorphism in Tuberculosis Incidence: Children Cases Compared to Adult Cases in Tuscany from 1997 to 2011

Background

In most countries, men seem to be more susceptible to tuberculosis (TB) than women, but only few studies have investigated the reasons of this gender incidence difference. The effect of sexual hormones on immunity is possible.

Methods

Data from children and adults, living in Tuscany, hospitalized for TB in all the thirty-one regional hospitals from January 1^st 1997 to December 31^st 2011, were analyzed using the International Classification of Disease, 9^th Revision, Clinical Modification.

Results

During the study period, 10,744 patients were hospitalized with TB diagnosis, precisely 279 (2.6%) children [0–14 years], 205 (1.9%) adolescents [15–18 years] and 10,260 (95.5%) adults [≥18 years]. The male population ranged from 249 patients (51.4%) in children and adolescents, to 6,253 (60.9%) in adults. Pulmonary TB was the most common form both in children and adults. Men were more likely than women to have pulmonary TB after puberty, while no significant differences were found between males and females in the hospitalized children. The male gender also resulted the most affected for the extra-pulmonary disease sites, excluding the lymphatic system, during the reproductive age.

Conclusions

Our findings suggest a possible role of sexual hormones in the development of TB. No significant male-female difference was found in TB incidence among children, while a sex ratio significantly different from 1∶1 emerged among reproductive age classes. An increased incidence difference also persisted in older men, suggesting that male-biased risk factors could influence TB progression. Some limitations of the study are the sample size, the method of discharge diagnosis which could be deficient in accuracy in some cases, the increasing number of immigrants and the lack of possible individual risk factors (smoke and alcohol). Further studies are needed to investigate the possible hormone-driven immune mechanisms determining the sexual dimorphism in TB.     

Modeling the joint epidemics of TB and HIV in a South African township

We present a simple mathematical model with six compartments for the interaction between HIV and TB epidemics. Using data from a township near Cape Town, South Africa, where the prevalence of HIV is above 20% and where the TB notification rate is close to 2,000 per 100,000 per year, we estimate some of the model parameters and study how various control measures might change the course of these epidemics. Condom promotion, increased TB detection and TB preventive therapy have a clear positive effect. The impact of antiretroviral therapy on the incidence of HIV is unclear and depends on the extent to which it reduces sexual transmission. However, our analysis suggests that it will greatly reduce the TB notification rate.     

Childhood Tuberculosis in Household Contacts of Newly Diagnosed TB Patients

Introduction

Childhood tuberculosis (TB), although estimated to account for a major proportion of the global TB disease burden, has a lower public health priority. Reliable research and surveillance data on childhood TB is limited in most regions of the world. This study was conducted to assess the burden of childhood TB among the household contacts of new TB patients in Karachi, Pakistan.

Methods

A retrospective analysis of children (<15 years) who were household contacts of new adult TB patients presenting to Marie Adelaide Leprosy Center (MALC) clinics in Karachi during the period of 2008 to 2010 was conducted.

Results

Of the household children contacts (n = 6613) screened, 317 were suspected and 121(1.8%) diagnosed with TB. These included 89 (73.6%) with pulmonary and 32 (26.4%) with extra-pulmonary disease. Smear positivity rate in pulmonary cases was 32.6%. Mean age of children diagnosed with TB was 11.7 (±2.8) years. Within the child-contacts screened, disease was found to be significantly higher among females (2.3%) in comparison to males (1.2%) (p-value <0.01). The commonest relationship of source cases to diagnosed children was the mother (n = 51, 42.1%). The source case was a female for 66.1% (n = 76) of the children.

Conclusion

A smear positivity rate of 32.6% amongst pulmonary cases suggests their potential to spread disease and emphasizes a need to review the contribution of children in transmission of TB within communities. Greater vulnerability of the female child and considerable role of mother in disease transmission highlights a need to increase focus on females in TB control programs in Pakistan.     

First direct estimate of the detection probability of bovine tuberculosis in possums by possum transmission

We conducted a field trial to determine whether percutaneous challenge of wild brushtail possums (Trichosurus vulpecula) with virulent Mycobacterium bovis, the causative agent of bovine tuberculosis (TB), resulted in subsequent transmission of M. bovis to other possums. We then used our results to make a preliminary first direct estimate of the ‘TB detection probability’ or transmission rate in wild possums. Seven free-living adult possums in the Rimutaka Forest Park, New Zealand, were captured, GPS-collared, experimentally challenged and then released. Possum populations surrounding the challenged individuals were examined for secondary cases 4–8 months post-challenge. Of 37 possums caught within the home ranges of the challenged individuals, one had confirmed TB. As no TB was detected in 355 other possums examined in this study, or 659 possums in a concurrent study in the immediate vicinity, we conclude that this represents the first documented case of onward transmission of M. bovis from an experimentally challenged possum in the wild. This pilot trial therefore gives some confidence that the new percutaneous challenge model for TB in possums can be used to obtain empirical estimates of TB detection probabilities. The calculated probability of onward transmission (‘detection’) here was just 0.027; however, with the possibility that further transmission events would have occurred from the one challenged possum removed from the trial before it had died, or if our trapping missed secondary cases, this value could be an underestimate. The implications of this low preliminary estimate are discussed.     

The epidemiology of tuberculosis in Phuentsholing General Hospital: a six-year retrospective study

ABSTRACT: BACKGROUND: This study was carried out to describe the epidemiology and treatment outcomes of TB infection in Bhutan at Phuentsholing General Hospital (PGH). Retrospective analysis of TB data was carried out using data from the TB registry of PGH from 2004-2009. Comparisons were made between TB, clinical presentation, diagnosis, and outcomes amongst male and female. RESULTS: A total of 735 patients were analyzed, 12.4% (91) of whom were children ([less than or equal to]14 years). The highest cases was reported in 2009 (148), lowest in 2004 (93). Males and females were equally infected with TB. The median age was 25 years, (range 11 months - 98 years; IQR=20-35). Extra-pulmonary Tuberculosis (EPT) 62.6% (57) was the commonest form of TB in children. Pleural effusion was more common in males 62.8% (27) (p=0.013). Smear positive pulmonary tuberculosis (SPPT) 54.3% (207) (p=0.02) and treatment defaulted 84.2% (16) (p=0.004) was higher in males. However, transfer-in cases 57.0% (90) (p=0.036) and treatment outcome-failure 92.3% (12) (p=0.002) were more in females than males. The cure rate for SPPT was 69.0% (293) and unknown treatment outcome for all forms of TB was 11.2% (82). CONCLUSION: TB infection has increase over the study period; SPPT increased more than other two forms of TB. The majority of the TB patients were in the age group of 15-34 years. Males and females were equally infected with TB and children made up 12.4% of TB patients. The cure rate amongst SPPT was 69%, which is much lower that the national target of 85% set by National Tuberculosis Control Programme (NTCP). Further studies need to be undertaken to identify the risk factor for TB in the economically productive age group. There is a need for improvement in the services, recording and reporting so as to meet the target of cure rate of 85% in SPPT patients.     

Diabetes Mellitus,Smoking Status,and Rate of Sputum Culture Conversion in Patients with Multidrug-Resistant Tuberculosis: A Cohort Study from the Country of Georgia

Introduction

Diabetes mellitus (DM) is a risk factor for active tuberculosis (TB) but little is known about the effect of DM on culture conversion among patients with multidrug-resistant (MDR)-TB. The primary aim was to estimate the association between DM and rate of TB sputum culture conversion. A secondary objective was to estimate the association between DM and the risk of poor treatment outcomes among patients with MDR-TB.

Materials and Methods

A cohort of all adult patients starting MDR-TB treatment in the country of Georgia between 2009–2011 was followed during second-line TB therapy. Cox proportional models were used to estimate the adjusted hazard rate of sputum culture conversion. Log-binomial regression models were used to estimate the cumulative risk of poor TB treatment outcome.

Results

Among 1,366 patients with sputum culture conversion information, 966 (70.7%) had culture conversion and the median time to conversion was 68 days (interquartile range 50–120). The rate of conversion was similar among patients with MDR-TB and DM (adjusted hazard ratio [aHR] 0.95, 95%CI 0.71–1.28) compared to patients with MDR-TB only. The rate of culture conversion was significantly less in patients that currently smoked (aHR 0.82, 95%CI 0.71–0.95), had low body mass index (aHR 0.71, 95%CI 0.59–0.84), second-line resistance (aHR 0.56, 95%CI 0.43–0.73), lung cavities (aHR 0.70, 95%CI 0.59–0.83) and with disseminated TB (aHR 0.75, 95%CI 0.62–0.90). The cumulative risk of poor treatment outcome was also similar among TB patients with and without DM (adjusted risk ratio [aRR] 1.03, 95%CI 0.93–1.14).

Conclusions

In adjusted analyses, DM did not impact culture conversion rates in a clinically meaningful way but smoking did.     

QuantiFERON?-TB Gold In-Tube Performance for Diagnosing Active Tuberculosis in Children and Adults in a High Burden Setting

Aim

To determine whether QuantiFERON®-TB Gold In-Tube (QFT) can contribute to the diagnosis of active tuberculosis (TB) in children in a high-burden setting and to assess the performance of QFT and tuberculin skin test (TST) in a prospective cohort of TB suspect children compared to adults with confirmed TB in Tanzania.

Methods

Sensitivity and specificity of QFT and TST for diagnosing active TB as well as indeterminate QFT rates and IFN-γ levels were assessed in 211 TB suspect children in a Tanzanian district hospital and contrasted in 90 adults with confirmed pulmonary TB.

Results

Sensitivity of QFT and TST in children with confirmed TB was 19% (5/27) and 6% (2/31) respectively. In adults sensitivity of QFT and TST was 84% (73/87) and 85% (63/74). The QFT indeterminate rate in children and adults was 27% and 3%. Median levels of IFN-γ were lower in children than adults, particularly children <2 years and HIV infected. An indeterminate result was associated with age <2 years but not malnutrition or HIV status. Overall childhood mortality was 19% and associated with an indeterminate QFT result at baseline.

Conclusion

QFT and TST showed poor performance and a surprisingly low sensitivity in children. In contrast the performance in Tanzanian adults was good and comparable to performance in high-income countries. Indeterminate results in children were associated with young age and increased mortality. Neither test can be recommended for diagnosing active TB in children with immature or impaired immunity in a high-burden setting.     

Incidence of tuberculosis and the predictive value of ELISPOT and Mantoux tests in Gambian case contacts

Background

Studies of Tuberculosis (TB) case contacts are increasingly being utilised for understanding the relationship between M. tuberculosis and the human host and for assessing new interventions and diagnostic tests. We aimed to identify the incidence rate of new TB cases among TB contacts and to relate this to their initial Mantoux and ELISPOT test results.

Methods and Findings

After initial Mantoux and ELISPOT tests and exclusion of co-prevalent TB cases, we followed 2348 household contacts of sputum smear positive TB cases. We visited them at 3 months, 6 months, 12 months, 18 months and 24 months, and investigated those with symptoms consistent with TB. Those who were diagnosed separately at a government clinic had a chest x-ray. Twenty six contacts were diagnosed with definite TB over 4312 person years of follow-up (Incidence rate 603/100,000 person years; 95% Confidence Interval, 370–830). Nine index and secondary case pairs had cultured isolates available for genotyping. Of these, 6 pairs were concordant and 3 were discordant. 2.5% of non-progressors were HIV positive compared to 12% of progressors (HR 6.2; 95% CI 1.7–22.5; p = 0.010). 25 secondary cases had initial Mantoux results, 14 (56%) were positive ; 21 had initial ELISPOT results, 11 (52%) were positive; 15 (71%) of 21 tested were positive by one or the other test. Of the 6 contacts who had concordant isolates with their respective index case, 4 (67%) were Mantoux positive at recruitment, 3 (50%) were ELISPOT positive; 5 (83%) were positive by one or other of the two tests. ELISPOT positive contacts, and those with discordant results, had a similar rate of progression to those who were Mantoux positive. Those negative on either or both tests had the lowest rate of progression.

Conclusions

The incidence rate of TB disease in Gambian TB case contacts, after screening for co-prevalent cases, was 603/100,000 person years. Since initial ELISPOT test and Mantoux tests were each positive in only just over half of cases, but 71% were positive by one or other test, positivity by either might be the best indication for preventive treatment. These data do not support the replacement of the Mantoux test by an ELISPOT test in The Gambia or similar settings.     

High Incidence of Tuberculosis in the Absence of Isoniazid and Cotrimoxazole Preventive Therapy in Children Living with HIV in Northern Ethiopia: A Retrospective Follow-Up Study

ObjectiveTo identify the incidence of and predictors for tuberculosis in children living with HIV in Northern Ethiopia.DesignObservational, retrospective follow-up study.MethodsA total of 645 HIV-infected children were observed between September 2009 and September 2014. Cox regression analysis was used to identify predictors for developing TB.ResultsThe incidence rate of tuberculosis was 4.2 per 100 child-years. Incidence of tuberculosis was higher for subjects who were not on cotrimoxazole preventive therapy, were not on isoniazid preventive therapy, had delayed motor development, had a CD4 cell count below the threshold, had hemoglobin level less than 10 mg/dl and were assessed as World Health Organization (WHO) clinical stage III or IV.ConclusionIncidence of TB in children living with HIV was high. This study reaffirmed that isoniazid preventive therapy is one of the best strategy to reduce incidence of TB in children living with HIV. All children living with HIV should be screened for TB but for children with delayed motor development, advanced WHO clinical stage, anemia or immune suppression, intensified screening is highly recommended.     

Classification and characterisation of extracellular vesicles-related tuberculosis subgroups and immune cell profiles

Around the world, tuberculosis (TB) remains one of the most common causes of morbidity and mortality. The molecular mechanism of Mycobacterium tuberculosis (Mtb) infection is still unclear. Extracellular vesicles (EVs) play a key role in the onset and progression of many disease states and can serve as effective biomarkers or therapeutic targets for the identification and treatment of TB patients. We analysed the expression profile to better clarify the EVs characteristics of TB and explored potential diagnostic markers to distinguish TB from healthy control (HC). Twenty EVs-related differentially expressed genes (DEGs) were identified, and 17 EVs-related DEGs were up-regulated and three DEGs were down-regulated in TB samples, which were related to immune cells. Using machine learning, a nine EVs-related gene signature was identified and two EVs-related subclusters were defined. The single-cell RNA sequence (scRNA-seq) analysis further confirmed that these hub genes might play important roles in TB pathogenesis. The nine EVs-related hub genes had excellent diagnostic values and accurately estimated TB progression. TB's high-risk group had significantly enriched immune-related pathways, and there were substantial variations in immunity across different groups. Furthermore, five potential drugs were predicted for TB using CMap database. Based on the EVs-related gene signature, the TB risk model was established through a comprehensive analysis of different EV patterns, which can accurately predict TB. These genes could be used as novel biomarkers to distinguish TB from HC. These findings lay the foundation for further research and design of new therapeutic interventions aimed at treating this deadly infectious disease.     

Intensified Tuberculosis Case Finding among Malnourished Children in Nutritional Rehabilitation Centres of Karnataka,India: Missed Opportunities

Background

Severe acute malnutrition (SAM) is the most serious form of malnutrition affecting children under-five and is associated with many infectious diseases including Tuberculosis (TB). In India, nutritional rehabilitation centres (NRCs) have been recently established for the management of SAM including TB. The National TB Programme (NTP) in India has introduced a revised algorithm for diagnosing paediatric TB. We aimed to examine whether NRCs adhered to these guidelines in diagnosing TB among SAM children.

Methods

A cross-sectional study involving review of records of all SAM children identified by health workers during 2012 in six tehsils (sub-districts) with NRCs (population: 1.8 million) of Karnataka, India.

Results

Of 1927 identified SAM children, 1632 (85%) reached NRCs. Of them, 1173 (72%) were evaluated for TB and 19(2%) were diagnosed as TB. Of 1173, diagnostic algorithm was followed in 460 (37%). Among remaining 763 not evaluated as per algorithm, tuberculin skin test alone was conducted in 307 (41%), chest radiography alone in 99 (13%) and no investigations in 337 (45%). The yield of TB was higher among children evaluated as per algorithm (4%) as compared to those who were not (0.3%) (OR: 15.3 [95%CI: 3.5-66.3]). Several operational challenges including non-availability of a full-time paediatrician, non-functioning X-ray machine due to frequent power cuts, use of tuberculin with suboptimal strength and difficulties in adhering to a complex diagnostic algorithm were observed.

Conclusion

This study showed that TB screening in NRCs was sub-optimal in Karnataka. Some children did not reach the NRC, while many of those who did were either not or sub-optimally evaluated for TB. This study pointed to a number of operational issues that need to be addressed if this collaborative strategy is to identify more TB cases amongst malnourished children in India.     

Exposure to Second-Hand Smoke and the Risk of Tuberculosis in Children and Adults: A Systematic Review and Meta-Analysis of 18 Observational Studies

Background

According to WHO Global Health Estimates, tuberculosis (TB) is among the top ten causes of global mortality and ranks second after cardiovascular disease in most high-burden regions. In this systematic review and meta-analysis, we investigated the role of second-hand smoke (SHS) exposure as a risk factor for TB among children and adults.

Methods and Findings

We performed a systematic literature search of PubMed, Embase, Scopus, Web of Science, and Google Scholar up to August 31, 2014. Our a priori inclusion criteria encompassed only original studies where latent TB infection (LTBI) and active TB disease were diagnosed microbiologically, clinically, histologically, or radiologically. Effect estimates were pooled using fixed- and random-effects models. We identified 18 eligible studies, with 30,757 children and 44,432 adult non-smokers, containing SHS exposure and TB outcome data for inclusion in the meta-analysis. Twelve studies assessed children and eight studies assessed adult non-smokers; two studies assessed both populations. Summary relative risk (RR) of LTBI associated with SHS exposure in children was similar to the overall effect size, with high heterogeneity (pooled RR 1.64, 95% CI 1.00–2.83). Children showed a more than 3-fold increased risk of SHS-associated active TB (pooled RR 3.41, 95% CI 1.81–6.45), which was higher than the risk in adults exposed to SHS (summary RR 1.32, 95% CI 1.04–1.68). Positive and significant exposure–response relationships were observed among children under 5 y (RR 5.88, 95% CI 2.09–16.54), children exposed to SHS through any parent (RR 4.20, 95% CI 1.92–9.20), and children living under the most crowded household conditions (RR 5.53, 95% CI 2.36–12.98). Associations for LTBI and active TB disease remained significant after adjustment for age, biomass fuel (BMF) use, and presence of a TB patient in the household, although the meta-analysis was limited to a subset of studies that adjusted for these variables. There was a loss of association with increased risk of LTBI (but not active TB) after adjustment for socioeconomic status (SES) and study quality. The major limitation of this analysis is the high heterogeneity in outcomes among studies of pediatric cases of LTBI and TB disease.

Conclusions

We found that SHS exposure is associated with an increase in the relative risk of LTBI and active TB after controlling for age, BMF use, and contact with a TB patient, and there was no significant association of SHS exposure with LTBI after adjustment for SES and study quality. Given the high heterogeneity among the primary studies, our analysis may not show sufficient evidence to confirm an association. In addition, considering that the TB burden is highest in countries with increasing SHS exposure, it is important to confirm these results with higher quality studies. Research in this area may have important implications for TB and tobacco control programs, especially for children in settings with high SHS exposure and TB burden.     

Incidence of TB and HIV in Prospectively Followed Household Contacts of TB Index Patients in South Africa

Objective

To report the incidence rates of TB and HIV in household contacts of index patients diagnosed with TB.

Design

A prospective cohort study in the Matlosana sub-district of North West Province, South Africa.

Methods

Contacts of index TB patients received TB and HIV testing after counseling at their first household visit and were then followed up a year later, in 2010. TB or HIV diagnoses that occurred during the period were determined.

Results

For 2,377 household contacts, the overall observed TB incidence rate was 1.3 per 100 person years (95% CI 0.9–1.9/100py) and TB incidence for individuals who were HIV-infected and HIV seronegative at baseline was 5.4/100py (95% CI 2.9–9.0/100py) and 0.7/100py (95% CI 0.3–1.4/100py), respectively. The overall HIV incidence rate was 2.2/100py (95% CI 1.3–8.4/100py).

Conclusions

In the year following a household case finding visit when household contacts were tested for TB and HIV, the incidence rate of both active TB and HIV infection was found to be extremely high. Clearly, implementing proven strategies to prevent HIV acquisition and preventing TB transmission and progression to disease remains a priority in settings such as South Africa.     

Association of BMI category change with TB treatment mortality in HIV-positive smear-negative and extrapulmonary TB patients in Myanmar and Zimbabwe

Objective

The HIV epidemic has increased the proportion of patients with smear-negative and extrapulmonary tuberculosis (TB) diagnoses, with related higher rates of poor TB treatment outcomes. Unlike in smear-positive pulmonary TB, no interim markers of TB treatment progress are systematically used to identify individuals most at risk of mortality. The objective of this study was to assess the association of body mass index (BMI) change at 1 month (±15 days) from TB treatment start with mortality among HIV-positive individuals with smear-negative and extrapulmonary TB.

Methods and Findings

A retrospective cohort study of adult HIV-positive new TB patients in Médecins Sans Frontières (MSF) treatment programmes in Myanmar and Zimbabwe was conducted using Cox proportional hazards regression to estimate the association between BMI category change and mortality. A cohort of 1090 TB patients (605 smear-negative and 485 extrapulmonary) was followed during TB treatment with mortality rate of 28.9 per 100 person-years. In multivariable analyses, remaining severely underweight or moving to a lower BMI category increased mortality (adjusted hazard ratio 4.05, 95% confidence interval 2.77–5.91, p<0.001) compared with remaining in the same or moving to a higher BMI category.

Conclusions

We found a strong association between BMI category change during the first month of TB treatment and mortality. BMI category change could be used to identify individuals most at risk of mortality during TB treatment among smear-negative and extrapulmonary patients.     

Accuracy of QuantiFERON-TB Gold Test for Tuberculosis Diagnosis in Children

ObjectivesTo evaluate the accuracy of the QuantiFERON-TB Gold assay (QFT-IT) in children with suspected active or latent TB infection (LTBI).MethodsA retrospective study was conducted on 621 children (0–14 years old) evaluated for TB infection or disease. Following clinical assessment, children were tested with the QFT-IT assay.ResultsAmong the 140 active TB suspects, we identified 19 cases of active disease. The overall sensitivity for active TB was 87.5%, ranging from 62.5% in children 25–36 months old to 100% in children older than 49 months. The overall specificity for active TB was 93.6%. Among the 481 children tested for LTBI screening, 38 scored positive and all but 2 had at least one risk factor for TB infection. Among the 26 children with indeterminate results, bacterial, viral or fungal pneumonia were later diagnosed in 11 (42.3%) cases and non-TB related extra-pulmonary infections in 12 (46.1%).ConclusionsOur results indicate that the children''s response to QFT-IT associates to active TB and risk factors for LTBI. Moreover, we show that mitogen response is also found in children of 1 year of age, providing support for QFT-IT use also in young children.     

Determining Mycobacterium tuberculosis Infection among BCG-Immunised Ugandan Children by T-SPOT.TB and Tuberculin Skin Testing

Background

Children with latent tuberculosis infection (LTBI) represent a huge reservoir for future disease. We wished to determine Mycobacterium tuberculosis (M.tb) infection prevalence among BCG-immunised five-year-old children in Entebbe, Uganda, but there are limited data on the performance of immunoassays for diagnosis of tuberculosis infection in children in endemic settings. We therefore evaluated agreement between a commercial interferon gamma release assay (T-SPOT.TB) and the tuberculin skin test (TST; 2 units RT-23 tuberculin; positive defined as diameter ≥10 mm), along with the reproducibility of T-SPOT.TB on short-term follow-up, in this population.

Methodology/Principal Findings

We recruited 907 children of which 56 were household contacts of TB patients. They were tested with T-SPOT.TB at age five years and then re-examined with T-SPOT.TB (n = 405) and TST (n = 319) approximately three weeks later. The principal outcome measures were T-SPOT.TB and TST positivity. At five years, 88 (9.7%) children tested positive by T-SPOT.TB. More than half of those that were T-SPOT.TB positive at five years were negative at follow-up, whereas 96% of baseline negatives were consistently negative. We observed somewhat better agreement between initial and follow-up T-SPOT.TB results among household TB contacts (κ = 0.77) than among non-contacts (κ = 0.39). Agreement between T-SPOT.TB and TST was weak (κ = 0.28 and κ = 0.40 for T-SPOT.TB at 5 years and follow-up, respectively). Of 28 children who were positive on both T-SPOT.TB tests, 14 (50%) had a negative TST. Analysis of spot counts showed high levels of instability in responses between baseline and follow-up, indicating variability in circulating numbers of T cells specific for certain M.tb antigens.

Conclusions/Significance

We found that T-SPOT.TB positives are unstable over a three-week follow-up interval, and that TST compares poorly with T-SPOT.TB, making the categorisation of children as TB-infected or TB-uninfected difficult. Existing tools for the diagnosis of TB infection are unsatisfactory in determining infection among children in this setting.     

The ongoing challenge of latent tuberculosis

The global health community has set itself the task of eliminating tuberculosis (TB) as a public health problem by 2050. Although progress has been made in global TB control, the current decline in incidence of 2% yr⁻¹ is far from the rate needed to achieve this. If we are to succeed in this endeavour, new strategies to reduce the reservoir of latently infected persons (from which new cases arise) would be advantageous. However, ascertainment of the extent and risk posed by this group is poor. The current diagnostics tests (tuberculin skin test and interferon-gamma release assays) poorly predict who will develop active disease and the therapeutic options available are not optimal for the scale of the intervention that may be required. In this article, we outline a basis for our current understanding of latent TB and highlight areas where innovation leading to development of novel diagnostic tests, drug regimens and vaccines may assist progress. We argue that the pool of individuals at high risk of progression may be significantly smaller than the 2.33 billion thought to be immune sensitized by Mycobacterium tuberculosis and that identifying and targeting this group will be an important strategy in the road to elimination.     

Radiological Findings in Young Children Investigated for Tuberculosis in Mozambique

IntroductionChest radiography remains a critical tool for diagnosing intrathoracic tuberculosis (TB) in young children who are unable to expectorate. We describe the radiological findings in children under 3 years of age investigated for TB in the district of Manhiça, southern Mozambique, an area with a high prevalence of TB and HIV.MethodsDigital antero-posterior and lateral projections were performed and reviewed by two independent readers, using a standardized template. Readers included a local pediatrician and a pediatric radiologist blinded to all clinical information. International consensus case definitions for intra-thoracic TB in children were applied.ResultsA total of 766 children were evaluated of whom 43 (5.6%) had TB. The most frequent lesion found in TB cases was air space consolidation (65.1%), followed by suggestive hilar lymphadenopathy (17.1%) and pleural effusion (7.0%). Air space consolidation was significantly more common in TB cases than in non-TB cases (odds ratio 8.9; 95% CI: 1.6-50.5), as were hilar lymphadenopathy (OR 17.2; 95% CI: 5.7-52.1). The only case with miliary infiltrates and 3 with pleural effusions occurred in HIV-infected children.ConclusionFrequent air space consolidation complicates radiological distinction between TB and bacterial pneumonia in young children, underscoring the need for epidemiological contextualization and consideration of all relevant signs and symptoms.