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1.  Optimizing the Detection of Recent Tuberculosis Infection in Children in a High Tuberculosis–HIV Burden Setting 
Rationale: Children who are young, malnourished, and infected with HIV have significant risk of tuberculosis (TB) morbidity and mortality following TB infection. Treatment of TB infection is hindered by poor detection and limited pediatric data.
Objectives: Identify improved testing to detect pediatric TB infection.
Methods: This was a prospective community-based study assessing use of the tuberculin skin test and IFN-γ release assays among children (n = 1,343; 6 mo to <15 yr) in TB-HIV high-burden settings; associations with child characteristics were measured.
Measurements and Main Results: Contact tracing detects TB in 8% of child contacts within 3 months of exposure. Among children with no documented contact, tuberculin skin test and QuantiFERON-TB Gold In-Tube positivity was greater than T-SPOT.TB. Nearly 8% of children had IFN-γ release assay positive and skin test negative discordance. In a model accounting for confounders, all tests correlate with TB contact, but IFN-γ release assays correlate better than the tuberculin skin test (P = 0.0011). Indeterminate IFN-γ release assay results were not associated with age. Indeterminate QuantiFERON-TB Gold In-Tube results were more frequent in children infected with HIV (4.7%) than uninfected with HIV (1.9%), whereas T-SPOT.TB indeterminates were rare (0.2%) and not affected by HIV status. Conversion and reversion were not associated with HIV status. Among children infected with HIV, tests correlated less with contact as malnutrition worsened.
Conclusions: Where resources allow, use of IFN-γ release assays should be considered in children who are young, recently exposed, and infected with HIV because they may offer advantages compared with the tuberculin skin test for identifying TB infection, and improve targeted, cost-effective delivery of preventive therapy. Affordable tests of infection could dramatically impact global TB control.
doi:10.1164/rccm.201406-1165OC
PMCID: PMC4407483  PMID: 25622087
HIV; latent tuberculosis infection; pediatrics; IFN-γ release tests; tuberculin test
2.  Use of string test and stool specimens to diagnose pulmonary tuberculosis☆ 
SUMMARY
Background
The Xpert MTB/RIF (MTB/RIF) test has advanced the field of tuberculosis (TB) diagnostics; however, depending on age and HIV status, 10–85% of individuals with presumed pulmonary TB (PTB) are unable to produce sputum.
Methods
The feasibility of using MTB/RIF and culture on stool and string test specimens from 13 adult patients with presumed PTB was studied.
Results
The string test was well tolerated with a median Wong Baker Faces score of 2. The string test had 100% sensitivity and specificity by MTB/RIF and 87.5% sensitivity and 100% specificity by culture. In stool, Mycobacterium tuberculosis DNA was detected in all cases of culture-confirmed PTB.
Conclusion
The string test and stool provide diagnostic specimens that warrant further investigation.
doi:10.1016/j.ijid.2015.10.022
PMCID: PMC4780405  PMID: 26523638
Tuberculosis; String test; Stool; Xpert MTB/RIF
3.  HIV Progression Perturbs the Balance of the Cell-Mediated and Anti-Inflammatory Adaptive and Innate Mycobacterial Immune Response 
Mediators of Inflammation  2016;2016:1478340.
Introduction. Our objective is to understand how HIV infection increases the risk of progression from latent tuberculosis (TB) to active disease. We understand now that immunity is a balance of competing immune responses by multiple cell types. Since T-lymphocyte production of interferon-gamma (IFN-γ) in response to Mycobacterium tuberculosis (Mtb) antigens fails to differentiate disease from latent infection, we applied a comprehensive profiling methodology to define immune biomarkers that reliably predict a patient's TB risk. Methods. We established a cohort of HIV-infected adults with TB disease from Swaziland. Multiparametric flow cytometry was used to quantify the mycobacterial-specific anti-inflammatory (IL-4 and IL-10) and proinflammatory (IFN-γ) immune response. Results. From 12 HIV-infected Swaziland patients with TB disease, the CD4+, CD8+, Double Negative, and CD56+CD3− lymphocytes increase their IL-4 : IFN-γ ratio as HIV disease worsens (Spearman r of −0.59; −0.59; −0.60; and −0.59, resp.; p < 0.05). Similarly, HIV severity is associated with an increased IL-10 : IFN-γ ratio (Spearman r of −0.76; p = 0.01). Conclusion. As HIV disease progresses, both the adaptive and innate branches skew away from an inflammatory and towards anti-inflammatory phenotype.
doi:10.1155/2016/1478340
PMCID: PMC4781991  PMID: 27006526
4.  Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis 
The Lancet. Respiratory medicine  2015;3(6):451-461.
Summary
Background
Microbiological confirmation of childhood tuberculosis is rare because of the difficulty of collection of specimens, low sensitivity of smear microscopy, and poor access to culture. We aimed to establish summary estimates for sensitivity and specificity of of the Xpert MTB/RIF assay compared with microscopy in the diagnosis of pulmonary tuberculosis in children.
Methods
We searched for studies published up to Jan 6, 2015, that used Xpert in any setting in children with and without HIV infection. We systematically reviewed studies that compared the diagnostic accuracy of Xpert MTB/RIF (Xpert) with microscopy for detection of pulmonary tuberculosis and rifampicin resistance in children younger than 16 years against two reference standards—culture results and culture-negative children who were started on anti-tuberculosis therapy. We did meta-analyses using a bivariate random-effects model.
Findings
We identified 15 studies including 4768 respiratory specimens in 3640 children investigated for pulmonary tuberculosis. Culture tests were positive for tuberculosis in 12% (420 of 3640) of all children assessed and Xpert was positive in 11% (406 of 3640). Compared with culture, the pooled sensitivities and specificities of Xpert for tuberculosis detection were 62% (95% credible interval 51–73) and 98% (97–99), respectively, with use of expectorated or induced sputum samples and 66% (51–81) and 98% (96–99), respectively, with use of samples from gastric lavage. Xpert sensitivity was 36–44% higher than was sensitivity for microscopy. Xpert sensitivity in culture-negative children started on antituberculosis therapy was 2% (1–3) for expectorated or induced sputum. Xpert’s pooled sensitivity and specificity to detect rifampicin resistance was 86% (95% credible interval 53–98) and 98% (94–100), respectively.
Interpretation
Compared with microscopy, Xpert offers better sensitivity for the diagnosis of pulmonary tuberculosis in children and its scale-up will improve access to tuberculosis diagnostics for children. Although Xpert helps to provide rapid confirmation of disease, its sensitivity remains suboptimum compared with culture tests. A negative Xpert result does not rule out tuberculosis. Good clinical acumen is still needed to decide when to start antituberculosis therapy and continued research for better diagnostics is crucial.
Funding
WHO, Global TB Program of Texas Children’s Hospital.
doi:10.1016/S2213-2600(15)00095-8
PMCID: PMC4756280  PMID: 25812968
5.  Key actors’ perspectives on cost-effectiveness analysis in Uganda: a cross-sectional survey 
Background
Cost effectiveness analysis (CEA) is a useful tool for allocation of constrained resources, yet CEA methodologies are rarely taught or implemented in developing nations. We aimed to assess exposure to, and interest in CEA, and identify barriers to implementation in Uganda.
Methods
A cross-sectional survey was carried out in Uganda using a newly developed self-administered questionnaire (via online and paper based approaches), targeting the main health care actors as identified by a previous study.
Results
Overall, there was a 68% response rate, with a 92% (69/75) response rate among the paper-based respondents compared to a 40% (26/65) rate with the online respondents. Seventy eight percent (74/95) of the respondents had no exposure to CEA. None of those with a master of medicine degree had any CEA exposure, and 80% of technical officers, who are directly involved in policy formulation, had no CEA exposure. Barriers to CEA identified by more than 50% of the participants were: lack of information technology (IT) infrastructure (hardware and software); lack of local experts in the field of CEA; lack of or limited local data; limited CEA training in schools; equity or ethical issues; and lack of training grants incorporating CEA. 93% reported a lot of interest in learning to conduct CEA, and over 95% felt CEA was important for clinical decision making and policy formulation.
Conclusions
Among health care actors in Uganda, there is very limited exposure to, but substantial interest in conducting CEA and including it in clinical decision making and health care policy formation. Capacity to undertake CEA needs to be built through incorporation into medical training and use of regional approaches.
doi:10.1186/s12913-014-0539-8
PMCID: PMC4232642  PMID: 25363234
Cost-effectiveness analysis; Healthcare in Uganda; Constrained resources
6.  West Nile Virus Epidemic, Northeast Ohio, 2002 
Emerging Infectious Diseases  2005;11(11):1774-1777.
Serum samples and sociodemographic data were obtained from 1,209 Ohio residents. West Nile virus immunoglobulin M (IgM) and IgG antibodies were detected by enzyme-linked immunosorbent assay and confirmed. Children were 4.5 times more likely to become infected yet 110× less likely to have neuroinvasive disease develop.
doi:10.3201/eid1111.040933
PMCID: PMC3367333  PMID: 16318737
West Nile Virus; Seroepidemiologic Study; Seroprevalence; Risk Factors; Arboviruses; Flaviviridae; dispatch
7.  Does an Isoniazid Prophylaxis Register Improve Tuberculosis Contact Management in South African Children? 
PLoS ONE  2013;8(12):e80803.
Setting
We compared the change in child household contact management of pulmonary tuberculosis (TB) cases before and after the implementation of an isoniazid preventive therapy (IPT) register in an urban clinic setting in Cape Town, South Africa.
Objectives
We determined if the presence of an IPT register was associated with an increase in the number of child contacts identified per infectious case and the proportion of identified children who were started on IPT.
Design
We reviewed routine programme data on IPT delivery to children during two time periods (May 2008–October 2008 and May 2011–October 2011), before and after the implementation of an IPT register used by routine clinic personnel.
Results
Adult TB case demographic and clinical characteristics from the two observation periods were similar. During the post-register period, more child contacts per adult case were identified (0.7 (54 children) vs. 0.3 (24 children)), more of the identified children were started on IPT (54 vs. 4) and 37% of those who started, completed six months of treatment compared to the pre-register period where no adherence information was recorded.
Conclusions
After pilot implementation of an IPT register, documented identification of child contacts, IPT initiation and IPT adherence documentation in TB exposed children was improved. Our findings support further exploration of the potential impact of using standardised IPT recording and reporting in routine clinics in high-burden TB settings to improve TB prevention efforts targeted at young children. Future efforts to improve IPT delivery should be systematic and comprehensive in order to support a change in current operational IPT delivery practices in TB programs.
doi:10.1371/journal.pone.0080803
PMCID: PMC3858233  PMID: 24339884
8.  Evaluation of Tuberculosis Diagnostics in Children: 2. Methodological Issues for Conducting and Reporting Research Evaluations of Tuberculosis Diagnostics for Intrathoracic Tuberculosis in Children. Consensus From an Expert Panela 
The Journal of Infectious Diseases  2012;205(Suppl 2):S209-S215.
Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children.
In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.
doi:10.1093/infdis/jir879
PMCID: PMC3334504  PMID: 22476719
9.  Utility of Host Markers Detected in Quantiferon Supernatants for the Diagnosis of Tuberculosis in Children in a High-Burden Setting 
PLoS ONE  2013;8(5):e64226.
Background
The diagnosis of childhood tuberculosis (TB) disease remains a challenge especially in young and HIV-infected children. Recent studies have identified potential host markers which, when measured in Quantiferon (QFT-IT) supernatants, show promise in discriminating between Mycobacterium tuberculosis (M.tb) infection states. In this study, the utility of such markers was investigated in children screened for TB in a setting with high TB incidence.
Methodology and Principal Findings
76 children (29% HIV-infected) with or without active TB provided blood specimens collected directly into QFT-IT tubes. After overnight incubation, culture supernatants were harvested, aliquoted and frozen for future immunological research purposes. Subsequently, the levels of 12 host markers previously identified as potential TB diagnostic markers were evaluated in these supernatants for their ability to discriminate between M.tb infection and disease states using the Luminex platform. Of the 76 children included, 19 (25%) had culture confirmed TB disease; 26 (46%) of the 57 without TB had positive markers of M.tb infection defined by a positive QFT-IT test. The potentially most useful analytes for diagnosing TB disease included IFN-α2, IL-1Ra, sCD40L and VEGF and the most useful markers for discriminating between QFT-IT positive children as TB or latent infection included IL-1Ra, IP-10 and VEGF. When markers were used in combinations of four, 84% of all children were accurately classified into their respective groups (TB disease or no TB), after leave-one-out cross validation.
Conclusions
Measurement of the levels of IFN-α2, IL-1Ra, sCD40L, IP-10 and VEGF in QFT-IT supernatants may be a useful method for diagnosing TB disease and differentiating between active TB disease and M.tb infection in children. Our observations warrant further investigation in larger well-characterized clinical cohorts.
doi:10.1371/journal.pone.0064226
PMCID: PMC3655018  PMID: 23691173
10.  Effect of Ascaris Lumbricoides specific IgE on tuberculin skin test responses in children in a high-burden setting: a cross-sectional community-based study 
BMC Infectious Diseases  2012;12:211.
Background
M.tuberculosis (M.tb) is associated with enhanced T helper cell type 1 (Th1) immune responses while helminth infection is associated with T helper cell type 2 (Th2) immune responses. Our aim was to investigate whether helminth infection could influence the ability to generate an appropriate Th1 immune response that is characterized by a positive tuberculin skin test (TST), in M.tb exposed children.
Methods
We completed a community-based, cross sectional household contact tracing study, using matched enrolment of HIV negative children with and without documented household M.tb exposure. We documented demographics, clinical characteristics, HIV status, M.tb exposure (using a standard contact score) and M.tb infection status (TST > = 10 mm). Ascaris lumbricoides-specific IgE was used as proxy for Ascaris infection/exposure.
Results
Of 271 children (median age 4 years (range: 4 months to 15 years)) enrolled, 65 participants (24%) were serum positive for Ascaris IgE. There were 168 (62%) children with a documented household tuberculosis contact and 107 (40%) were (TST) positive overall.
A positive TST was associated with increasing age (Odds Ratio (OR) =1.17, p < 0.001), increasing M.tb contact score (OR = 1.17, p < 0.001), previous tuberculosis treatment (OR = 4.8, p = 0.06) and previous isoniazid preventive treatment (OR = 3.16, p = 0.01). A visible bacillus Calmette-Guérin (BCG) scar was associated with reduced odds of being TST positive (OR = 0.42, p = 0.01).
Ascaris IgE was not associated with TST status in univariate analysis (OR = 0.9, p = 0.6), but multivariable logistic regression analysis suggested an inverse association between Ascaris IgE status and a positive TST (OR = 0.6, p = 0.08), when adjusted for age, and M.tb contact score. The addition of an age interaction term to the model suggested that the age effect was stronger among Ascaris IgE positive children; the effect of being Ascaris IgE positive significantly reduced the odds of being TST positive amongst younger children while this effect weakened with increasing age.
Conclusions
Our preliminary findings highlight a high prevalence of both Ascaris exposure/infection and M.tb infection in children in an urban setting. Helminth exposure/infection may reduce the immune response following M.tb exposure when controlling for epidemiological and clinical covariates. These findings might be relevant to the interpretation of immunological tests of M.tb infection in children.
doi:10.1186/1471-2334-12-211
PMCID: PMC3482567  PMID: 22966931
Tuberculosis; Helminth infection; Ascaris, M.tb infection; Immune polarization; Paediatric tuberculosis
11.  Rapid GIS-based profiling of West Nile virus transmission: Defining environmental factors associated with an urban-suburban outbreak in Northeast Ohio, USA 
Geospatial health  2008;2(2):215-225.
Human West Nile virus (WNV) infection was first detected in Cuyahoga County, Ohio in 2002. During that year's extensive epidemic/epizootic among non-immune human and bird populations, the county experienced 155 cases of severe human WNV neuro-invasive disease (WNND, incidence: 11.1 cases/100,000), with 11 fatalities. Structured serosurveys indicated that 1.9%, or ~ 26,000 of county residents (pop. = 1,372,303) were infected that year. In early 2003, in order to better focus monitoring and control efforts, we used a Geographic Information System (GIS) approach and spatial statistical analysis to identify the association of environmental factors and human population structure with the observed local risk for WNV transmission. Within the varied range of urban/suburban/rural habitats across the 458 mi2 (1186 km2) county, exploratory analysis indicated significant clustering of WNND risk in inner-ring suburbs. Subsequent discriminant factor analysis based on inputs of census and land-use/ land cover data was found to effectively classify sub-areas of the county having low, medium, and high WNV risk. On a 4 mi2 (1036 ha.) quadrat scale of resolution, higher risk of human infection was significantly associated with higher-income areas, increased fractionation of habitat, and older housing, while it was negatively associated with areas of agricultural land, wetland, or forest. The areal classification of WNV transmission risk has been validated over time through detection of increased local Culex spp. mosquito density (2002–2006), and increased frequency of WNV positive mosquito pools within the medium- and high-risk quadrats. This timely working identification of the transmission scale effectively focused control interventions against newly invasive WNV in a complex North American habitat.
PMCID: PMC3140769  PMID: 18686270
Encephalitis/arbovirus; West Nile virus; epidemiologic factors; cluster analysis
12.  Operational challenges in managing Isoniazid Preventive Therapy in child contacts: A high-burden setting perspective 
BMC Public Health  2011;11:544.
Background
The study was conducted at a high TB-HIV burden primary health community clinic in Cape Town, South Africa. We describe the management of children under five years of age in household contact with a smear and/or culture-positive adult TB case.
Methods
This study was a record review of routinely-collected programme data.
Results
A total of 1094 adult TB case folders were reviewed. From all identified contacts, 149 children should have received IPT based on local guidelines; in only 2/149 IPT was initiated. Management of child contacts of sputum smear and/or culture-positive compared to sputum-negative TB patients were similar.
Conclusions
IPT delivery to children remains an operational challenge, especially in high TB-HIV burden communities. A tool to improve IPT management and targeting sputum smear and/or culture-positive TB child contacts may overcome some of these challenges and should be developed and piloted in such settings.
doi:10.1186/1471-2458-11-544
PMCID: PMC3150266  PMID: 21740580
13.  Exposure to West Nile Virus During the 2002 Epidemic in Cuyahoga County, Ohio: A Comparison of Pediatric and Adult Behaviors 
Public Health Reports  2007;122(3):356-361.
SYNOPSIS
Objectives.
Emerging evidence suggests that children are at higher risk for West Nile virus (WNV) exposure, but may have a lower risk for infection-related morbidity and mortality. Limited data exist regarding risk determinants of childhood WNV infection. We conducted a survey to analyze the differences between pediatric and adult behavior relevant to WNV exposure.
Methods.
Residents of participating sampled households responded to a questionnaire that measured knowledge, attitudes, personal protective behaviors, and clinical history to evaluate the association between personal behavior and exposure to WNV.
Results.
Children were more likely to have high levels of outdoor exposure compared to adults (83% vs. 70%). Children were less likely to avoid going outdoors (4% vs. 13%) and to wear long sleeves or pants compared to adults (8% vs. 19%). Both groups were highly educated about WNV. Television, not health-care provider education, was the most common source of WNV information. Participants were more concerned about WNV infection than pesticide usage.
Conclusions.
Our study demonstrates that children exhibit behaviors that could put them at greater risk for WNV infection and suggests that children could benefit from greater education about practices that can decrease WNV exposure to limit their risk for infection.
PMCID: PMC1847498  PMID: 17518307

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