Household Contacts Research Articles

Predictive metabolite signatures for risk of progression to active TB from QuantiFERON supernatants of Household Contacts of TB patients

The identification of individuals with the greatest risk of progression to active tuberculosis (TB) disease from the huge reservoir of Mycobacterium tuberculosis (Mtb) infected individuals continues to remain an arduous ascent in the global effort to control TB. In a two-year prospective study, we analysed metabolic profiles in the unstimulated and TB antigen stimulated QuantiFERON supernatants of 14 household contacts (HHCs) who progressed to TB (Progressors) and 14 HHCs who remained healthy (Non-Progressors). We identified 21 significantly dysregulated metabolites in the TB antigen-stimulated QuantiFERON supernatants of Progressors, of which the combination of Malic acid and N-Arachidonoylglycine had maximum AUC of 0.99. Eighteen significantly dysregulated metabolites were identified in the unstimulated QuantiFERON supernatants of Progressors, among which the combination of Orotic acid and the phosphatidylcholines PC (O-34:1), PC (O-18:1(9Z)/16:0), PC (O-18:1(11Z)/16:0) had the maximum AUC of 0.98. Most of the dysregulated metabolites belonged to the pathways of fatty acid metabolism, lipid metabolism and nitric oxide metabolism. Validation of these metabolic signatures in large, diverse cohorts would pave way for targetted intervention of TB disease.

Application of a TB care cascade to a novel household contact intervention in rural South Africa.

Four clinics implemented an intervention to increase TB household contact identification and evaluation in rural Eastern Cape, South Africa. We applied a care cascade framework to assess gaps in evaluation and treatment initiation from April 2021 to June 2023. We identified 1,698 contacts of 287 individuals with TB. The majority of contacts (71%) were screened; 9% of those with symptoms were fully evaluated, and of these, 14% were diagnosed with active TB. This intervention substantially increased TB contact identification and evaluation compared to prior efforts in the same area; however, additional barriers limited the ability to identify and treat secondary cases.

Comparative effectiveness of chest ultrasound, chest X-ray and computer-aided diagnostic (CAD) for tuberculosis diagnosis in low-resource setting: study protocol for a cross-sectional study from Ethiopia

IntroductionEarly and accurate diagnosis of pulmonary tuberculosis (TB) is crucial for timely treatment and prevention of transmission, but diagnostic challenges persist due to complex symptoms and limitations in diagnostic tools. Chest X-ray (CXR) is the standard imaging modality, but its sensitivity and specificity may vary. Recently, some promising alternatives emerged such as chest ultrasonography (CUS) – particularly valuable in resource-limited settings – and computer-aided diagnosis (CAD) systems – helping clinicians in the reading and interpretation of the CXR. However, direct comparisons of CUS, CXR, and CAD score in TB diagnosis are limited.Methods and analysisThis cross-sectional study will assess the diagnostic effectiveness of CUS in diagnosing TB compared to CXR and CAD score among index cases and household contacts. The study will be conducted at Wolisso St. Luke Hospital (Wolisso, Ethiopia). Index cases will be subjects with diagnosis of pulmonary tuberculosis within 7 days. Household contacts will be identified by administering a screening questionnaire to index cases. They will undergo CXR as for standard of care and consequent CAD analysis and CUS. The anticipated sample size is 136 subjects. The common accuracy metrics (sensitivity, specificity, positive and negative predictive values) will be calculated.Ethics and disseminationThe protocol was approved by the Oromia Health Bureau Research Ethics Committee (BFO/MBTFH/1-16/1908). All information obtained will be confidential. Selected investigators will have access to data, while international partners will sign a dedicated Data Protection Agreement. Eligible subjects will receive a brief information about the study before being asked to participate and they will provide a written informed consent. Results will be conveyed to stakeholders and disseminated through conferences and peer-reviewed journals.Clinical trial registrationNCT06409780, https://clinicaltrials.gov.

Household contact antigen-specific TNF and IL-2 T-cell responses and impact of index case Mycobacterium tuberculosis aerosolization and HIV Co-infection.

Exposure to pulmonary tuberculosis (PTB) culminates in heterogeneous outcomes, including variation in Mtb antigen-specific interferon-gamma (IFN-γ) T-cell responses. IFN-γ-independent cytokines, including tumor necrosis factor (TNF) and interleukin (IL-2), offer potential diagnostic improvements and insights into pathogenesis. We hypothesized that ESAT6/CFP10 TNF and IL-2 responses improve Mtb infection detection among exposed household contacts (HHCs) and are associated with index case Mtb aerosolization (i.e., cough aerosol culture positive for Mtb growth, CAC+]) and HIV co-infection. We enrolled individuals with PTB and their HHCs in a longitudinal study in Nairobi, Kenya. We measured TNF and IL-2 in HHCs from QuantiFERON-TB Plus TB1 tube supernatants. An additional 9.2% (25) HHCs beyond the 58.6% (129) with an IFN-γ response demonstrated an antigen-specific increase in IL-2 and TNF. HHCs of CAC + participants were more likely to have positive IL-2 (84.6% vs. 53.8%, p = 0.02) and IFN-γ (88.0% vs. 54.9%, p = 0.01), but not TNF responses, compared to CAC-negative individuals. While HIV co-infection in the index was negatively associated with IFN-γ responses in HHCs (35.7% vs. 62.3%, p = 0.03), IL-2 and TNF responses did not differ. Antigen-specific ESAT6/CFP10 IL-2 and TNF may increase rates of Mtb infection detection and provide insights into Mtb transmission and pathogenesis.

Genetic association of missense (rs2919643), intergenic (rs2057178) and a 3’UTR (rs1009170) variant with tuberculosis: A replication study from India

To investigate host genetic susceptibility to tuberculosis (TB), we conducted a replication study focussed on candidate SNPs, previously reported to be associated with TB. We examined nine candidate SNPs and genotyped them in an independent cohort of TB cases and household contacts from West Bengal, India. The association with TB was replicated for rs2919643 (Chr 18), rs2057178 (Chr 11) and rs1009170 (Chr 14). rs2919643-C (p=8.81E-5) was a risk allele and rs2057178-A (p=0.04188) was protective against TB in our population. Association of rs1009170; previously reported by us with TB was also replicated in the new set of samples (p=0.0359). rs2919643 is a missense variant present in linkage disequilibrium with a TB associated synonymous SNP rs61104666. The risk genotype rs2919643-CC was associated with higher levels of plasma RANTES and IL5 in household contacts. rs2919643 is an eQTL for an immunosuppressive gene SIGLEC15 and autophagy related gene EPG5. rs2057178 is an eQTL for a pseudogene and present within weak enhancer marks in the lungs. The genomic locus around this SNP rs1009170 encompasses an active transcription factor peak in CD14+ monocytes and also serves as an eQTL for NDUFB1, ATXN3 and SLC24A4. TB cases with rs1009170-TT genotype showed lower expression of plasma RANTES compared to the heterozygote. All three associated SNPs have putative regulatory role in lungs and immune associated cells and organs which may be relevant to TB pathogenesis.

Anti‑phenolic glycolipid‑I seropositivity among household contacts of leprosy patients in Egypt.

Leprosy is a chronic, debilitating disease lacking a definitive diagnostic biomarker. Serum anti-phenolic glycolipid-I (PGL-I) IgM antibody level is considered an important diagnostic and prognostic marker for leprosy patients. However, there is limited evidence on the role of anti-PGL-I IgM antibody level as early predictive biomarker of subclinical infection among Egyptian household contacts of leprosy patients. This study investigates the relationship between specific leprosy risk factors, diagnostic parameters of eighty-three leprosy cases, and serum anti-PGL-I IgM antibody levels in their corresponding household contacts. Our results demonstrate that anti-PGL-I IgM antibody level was significantly higher among contacts when more than four residents shared the same room with a leprosy case (p = 0.032). Additionally, anti-PGL-I IgM antibody level markedly increased in contacts of leprosy cases with disabilities (p = 0.001) or damaged nerves (p = 0.001). Our ROC curve analysis of anti-PGL-I antibody level as a predictor of exposure or infection among contacts revealed a cut-off value of 0.1, with a sensitivity of 75.0% and a specificity of 54.5%, indicating that most exposed household contacts are correctly identified. The overall accuracy of the ROC curve analysis was 72.3%, highlighting the practical utility of anti-PGL-I antibody level as a predictor for exposure or infection among household leprosy contacts. In conclusion, seropositivity of anti-PGL-I antibodies (> 0.1) among household leprosy contacts may be associated with a higher leprosy exposure risk. Continuous monitoring of anti-PGL-I antibody level in household leprosy contacts may potentially contribute to early detection and management of leprosy.

Estimated Effectiveness of Influenza Vaccines in Preventing Secondary Infections in Households

Influenza vaccine effectiveness (VE) is commonly assessed against prevention of illness that requires medical attention. Few studies have evaluated VE against secondary influenza infections. To determine the estimated effectiveness of influenza vaccines in preventing secondary infections after influenza was introduced into households. During 3 consecutive influenza seasons (2017-2020), primary cases (the first household members with laboratory-confirmed influenza) and their household contacts in Tennessee and Wisconsin were enrolled into a prospective case-ascertained household transmission cohort study. Participants collected daily symptom diaries and nasal swabs for up to 7 days. Data were analyzed from September 2022 to February 2024. Vaccination history, self-reported and verified through review of medical and registry records. Specimens were tested using reverse transcription-polymerase chain reaction to determine influenza infection. Longitudinal chain binomial models were used to estimate secondary infection risk and the effectiveness of influenza vaccines in preventing infection among household contacts overall and by virus type and subtype and/or lineage. The analysis included 699 primary cases and 1581 household contacts. The median (IQR) age of the primary cases was 13 (7-38) years, 381 (54.5%) were female, 60 (8.6%) were Hispanic, 46 (6.6%) were non-Hispanic Black, 553 (79.1%) were Non-Hispanic White, and 343 (49.1%) were vaccinated. Among household contacts, the median age was 31 (10-41) years, 833 (52.7%) were female, 116 (7.3%) were Hispanic, 78 (4.9%) were non-Hispanic Black, 1283 (81.2%) were non-Hispanic White, 792 (50.1%) were vaccinated, and 356 (22.5%) had laboratory-confirmed influenza during follow-up. The overall secondary infection risk of influenza among household contacts was 18.8% (95% CI, 15.9% to 22.0%). The risk was highest among children and was 20.3% (95% CI, 16.4% to 24.9%) for influenza A and 15.9% (95% CI, 11.8% to 21.0%) for influenza B. The overall estimated VE for preventing secondary infections among unvaccinated household contacts was 21.0% (95% CI, 1.4% to 36.7%) and varied by type; estimated VE against influenza A was 5.0% (95% CI, -22.3% to 26.3%) and 56.4% (95% CI, 30.1% to 72.8%) against influenza B. After influenza was introduced into households, the risk of secondary influenza among unvaccinated household contacts was approximately 15% to 20%, and highest among children. Estimated VE varied by influenza type, with demonstrated protection against influenza B virus infection.

CLINICAL FEATURES OF COVID-19 INFECTION IN NEWBORNS: A RETROSPECTIVE ANALYSIS

Background. The COVID-19 pandemic has significantly impacted all age groups, including newborns. During the fifth surge, the prevalence of the Omicron variant among infants increased dramatically. While SARS-CoV-2 is generally milder in children than adults, newborns are vulnerable due to their immature immune systems. Clinical manifestations in newborns can range from asymptomatic to severe cases with respiratory distress or multi-organ dysfunction. Purpose of study. Description of clinical manifestations, course and outcomes of coronavirus infection in newborns. Materials and methods of study. A retrospective analysis was conducted on 110 newborns with COVID-19 admitted to the Children’s Clinical Infectious Diseases Hospital of Almaty between 2021 and early 2022. The study used electronic medical records as the source of research data. Demographic data such as age and sex were collected, along with epidemiological data including international or domestic travel within two weeks prior to the onset of the disease, known exposure to a person with positive SARS-CoV-2 infection, and a history of pregnancy. Results. The infants’ mean age was 17 days, with 44 boys (40%) and 66 girls (60%). Four newborns were admitted to the hospital at less than seven days of life. When analyzing the severity of the cases, the following proportions of newborns were observed: (3/110, 2.7%) were asymptomatic, (44/110, 40%) had mild symptoms, (57/110, 51.8%) were moderately severe, (4/110, 3.6%) severe, and (2/110, 1.8%) had very severe illness. The majority (68.4%) were hospitalized within three days of symptom onset. Fever was common, and all infants underwent chest CTs. Despite some severe cases, 99% had favorable outcomes, with only one fatality. Conclusion. This study indicates that most COVID-19 infections in newborns were contracted from household contacts. Clinical symptoms in infants included fever, catarrhal symptoms, and signs of intoxication, with some showing normal temperatures. Laboratory findings varied, with common changes including monocytosis and neutrophilia. Respiratory complications, such as bronchitis and pneumonia, were prevalent. Comorbidities, particularly congenital disorders, increased the risk of severe outcomes and mortality. Most newborns recovered within 1-2 weeks, though viral carriage persisted in many.

USING SPUTUM AND TONGUE SWAB SPECIMENS FOR IN-HOME POINT-OF-CARE TARGETED UNIVERSAL TESTING FOR TB OF HOUSEHOLD CONTACTS: AN ACCEPTABILITY AND FEASIBILITY ANALYSIS.

Effective strategies are needed to facilitate early detection and diagnosis of tuberculosis (TB). The over-reliance on passive case detection, symptom screening, and collection of sputum, results in delayed or undiagnosed TB, which directly contributes to on-going TB transmission. We assessed the acceptability and feasibility of in-home, Targeted Universal TB Testing (TUTT) of household contacts using GeneXpert MTB/RIF Ultra at point-of-care (POC) during household contact investigations (HCIs) and compared the feasibility of using sputum vs. tongue swab specimens. Household contacts (HHCs) receiving in-home POC TUTT as part of the TB Home Study were asked to complete a post-test acceptability survey. The survey explored HHC's level of comfort, confidence in the test results, and the perceived appropriateness of in-home POC TUTT. We used the Metrics to Assess the Feasibility of Rapid Point-of-Care Technologies framework to assess the feasibility of using sputum and tongue swab specimens for in-home POC TUTT. Descriptive statistics were used to report participant responses and feasibility metrics. Of 313 eligible HHCs, 267/313 (85.3%) consented to in-home POC TUTT. Of those, 267/267 (100%) provided a tongue swab and 46/267 (17.2%) could expectorate sputum. All specimens were successfully prepared for immediate, in-home testing with Xpert Ultra on GeneXpert Edge. Of 164 tongue swab tests conducted, 160/164 (97.6%) generated a valid test result compared to 44/46 (95.7%) sputum-based tests. An immediate test result was available for 262/267 (98.1%) individuals based on in-home swab testing, and 44/46 (95.7%) based on in-home sputum testing. The mean in-home POC TUTT acceptability score (5=highly acceptable) was 4.5/5 (SD= 0.2). In-home, POC TUTT using either sputum or tongue swab specimens was highly acceptable and feasible. Tongue swab specimens greatly increase the proportion of HHCs tested compared to sputum. In-home POC TUTT using a combination of sputum and tongue swabs can mitigate shortcomings to case detection. TB transmission among household contacts of people with TB is a public health concern.The delivery of community-based diagnostic testing for TB is challenging and the reliance on sputum continue to hamper universal testing and result in diagnostic delay. This is the first study to assess the acceptability of universal in-home point-of-care TB testing of household contacts during household contact investigations.This study assesses the feasibility of different specimen types for immediate in-home point-of-care TB testing including tongue swabs and sputum. Household contacts perceived in-home targeted universal TB testing to be highly acceptable, prompting the need for further investigation into the cost-effectiveness of such strategies to improve early case detection.The use of tongue swabs as an additional or alternative sample type to sputum could increase testing and improve early case detection.

The impact of screening for tuberculosis exposure in the household in children with tuberculosis disease: A difficult riddle to solve.

Tuberculosis (TB) infection is transmitted by sharing the same airway with people with active TB. Children are often not considered the source of TB bacilli, and index case investigation is carried out after diagnosis. Here, we describe the impact of the presence of a household index case on childhood TB disease. The data of patients aged between 1 month and 18 years who were diagnosed with TB were collected. We compared patients according to whether they had an index case in the household or not. A total of 202 TB patients were enrolled, of whom 62 (30.7%) had a household index case. There was no significant difference in having a household index case between TB patients under the age of five (23.3%) and older children (33.8%) (p = .140). Pulmonary TB was present in 61.4% of the cases, and extrapulmonary TB was present in 38.6% of the cases. The rate of patients who had a household index case was significantly higher in pulmonary TB (46.8%) compared to extrapulmonary TB (5.1%) (p < .001). Pulmonary TB patients with a history of household contact were more likely to have diagnostic radiological findings (93.1%) compared to those without (75.8%) (p = .009). However, pulmonary TB patients without household contact history had a higher rate of diagnostic microbiological findings (59.1%) and constitutional symptoms (63.6%) (p = .019 and p = .013, respectively). Household contact research is an important epidemiological tool. However, considering the contact rates in the household, new and more comprehensive public health programs are required to prevent the spread of childhood tuberculosis.

Analysis of the Behavior of Household Contacts TB Patients in Providing Tuberculosis Prevention Therapy (TPT) at The Work Area Sri Padang Public Health Center Tebing City in 2024

Tuberculosis is an infectious disease caused by the bacteria Mycobacterium tuberculosis. Around 3.5-10% of people who come into contact with TB patients will be infected but will not get TB, of which 5-10% are likely to get TB in their lifetime. Research is needed on the provision of Tuberculosis Prevention Therapy (TPT) to household contacts of TB patients considering that all TB patients found have received treatment. This study is a qualitative study using a descriptive research design where researchers investigate carefully to obtain more in-depth information about the description of the behavior of household contacts of TB patients in providing tuberculosis prevention therapy (TPT) in the work area of ??the Sri Padang Health Center, Tebing Tinggi City. The research variables are knowledge, attitudes, beliefs, and family support. The results of the study are good knowledge will help them undergo preventive therapy with more discipline; An attitude of alertness and caution towards the risk of TB transmission in household contacts shows a good understanding of the dangers of TB disease; Strong belief in various aspects related to TPT, including its effectiveness, support from health workers, and safety of therapy, is very important to ensure that household contacts of TB patients can undergo TPT successfully and effectively; and family play an important role in the decision to undergo or not undergo TPT. The suggestion is that the level of knowledge of household contacts about TPT still needs to be improved, trust, provision of clear information about the side effects of the drug.

Discovery of a blood-based miRNA signature that can predict onset of active tuberculosis among household contacts of TB patients

BackgroundNon-sputum based predictive biomarkers capable of identifying individuals with high risk of progression to active tuberculosis (TB) are critical for global TB control. MicroRNAs (miRNAs) are significant regulators involved in TB pathogenesis and hence we aimed to identify a miRNA signature capable of predicting progression to TB disease.MethodsWe compared the differential miRNA expression profile of QuantiFERON supernatants of TB Progressors, defined as healthy household contacts (HHCs) of TB patients, who developed active TB disease during a 2-year follow-up period, and Non-progressors defined as HHCs from the same longitudinal cohort who did not develop TB disease during the entire follow-up period, using the nanostring nCounter platform. Receiver Operator Characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of the identified miRNA biomarkers, followed by random forest analysis to determine the best predictive model.ResultsWe identified 30 differentially regulated miRNAs between the two groups. Of these, hsa-miR-585-3p and hsa-miR-92a-3p were up-regulated with a maximum fold change of 1.74 and 1.71 respectively, while hsa-miR-223-3p and hsa-miR-451a were down-regulated by −2.05 and −2.04 fold respectively. Random forest analysis revealed that hsa-miR-181a-5p, hsa-miR-204-5p, hsa-miR-197-3p, hsa-miR-92a-3p, hsa-miR-451a, hsa-miR-24-3p, and hsa-miR-487a-3p exhibited 100% accuracy in identifying Progressors. This panel of 7 miRNAs demonstrated excellent diagnostic performance characteristics with 100% sensitivity and specificity.ConclusionWe propose that the identified miRNA signature has the potential to serve as a very useful tool for early identification of individuals who bear the highest risk of progression to TB, so that they can be targeted for timely intervention.

Autochthonous dengue outbreak in Lombardy, Italy: enhanced surveillance and vector control measures

Abstract Description of the problem On 18 August 2023, the first autochthonous case of dengue was registered in Lombardy, in a person living in a village in Lodi province. The case, a man with no history of travels prior to symptoms onset, developed flu-like symptoms on 3 August. After initial suspicion of WNV infection, he was confirmed to have a DENV-1 infection. Following the notification, measures to control the spread of the disease were activated, including alert of healthcare professionals, vector control activities, entomological monitoring and active case finding among household contacts and people living close to the case. Moreover, a serological screening was proposed to population of the entire municipality, along with a survey collecting data about travels abroad and symptoms. Results Forty-one confirmed and six probable autochthonous cases were identified. The last case developed symptoms on 20 October. Among confirmed cases, 24 were identified after admission to Emergency Department, 16 through community screening and one at the time of blood donation. 38/41 confirmed cases were symptomatic, with fever, rash and retro-orbital pain being the most common symptoms. Mean age was 55,5 years (3-88), while male: female ratio was 2:1. Hospitalisation was required for 7/41 cases. Community screening was offered from 25 August to 8 October and 416 individuals participated. Among them 10 tested positive for DENV IgG and 27 for DENV IgM (16 were subsequently confirmed as DENV cases, 6 remained probable and 5 were ruled out as non-cases). The primary case of the outbreak was not identified. Vector control activities and entomological monitoring were conducted on 21 August within 200-m radius area around the residence and places visited by index case. Subsequent interventions were conducted in all public areas and sensitive sites of the municipality. Lessons Enhancement of surveillance through community screening allowed identification of several additional autochthonous cases. Key messages • Strengthening of surveillance, vector control activities and entomological monitoring is crucial to prevent and control future outbreaks in non-endemic areas with stable presence of Aedes mosquitoes. • To minimize the risk of introduction and spread of dengue virus in non-endemic areas, it is essential to raise awareness among travellers and general population about preventive and control measures.

A prolonged outbreak of tuberculosis associated with an intellectual disability daycentre in Ireland

Abstract One of the factors impeding tuberculosis elimination in low burden countries is its persistence and concentration in vulnerable populations. This is a complex, prolonged Tuberculosis (TB) outbreak in a daycentre for adults with intellectual disability in Ireland. This is a particularly vulnerable population with special considerations for Public Health (PH) management. There are eight cases of active TB, 46 cases of Latent TB Infection (LTBI) and a cumulative total of 116 contacts associated with this outbreak, with diagnosis spanning 15 years. The last three cases were identical on Whole Genome Sequencing. The index case was an Irish-born, Caucasian, social care worker, with smear positive pulmonary TB, who was symptomatic in the facility for three months prior to diagnosis. Case 2 was a household contact of the index case and the other 6 cases were Service Users (SUs) at the facility. At least five of the subsequent seven cases are secondary cases of the index case. Significant to this outbreak was the change in Irish guidance, 2010, relating to the management of contacts of cases. Following the notification of the most recent case, July 2023, the Outbreak Control Team decided a retrospective review be conducted of all SU contacts of the seven cases associated with the facility. The contacts were stratified according to hierarchical risk. A total of six contacts met the criteria for review and offered screening, re-screening or treatment as appropriate. In this outbreak 21.8% of the total contacts and 16.1% of SU contacts completed treatment for LTBI. The significance of this outbreak lies in its duration, infectivity of the index case and particular vulnerabilities of the SUs. There were issues with overcrowding and difficulties in relation to symptom recognition, diagnosis and treatment. The PH team tailored their approach to meet the SU needs, demonstrating the importance of person-centred contact tracing in the disruption of transmission. Key messages • A factor impeding tuberculosis elimination in low burden countries is it’s persistence and concentration in vulnerable populations. • Adapting a patient-centred approach to contact tracing can lead to higher participation rate and the disruption of infection transmission.

Whole genome sequencing of M. tuberculosis for disease control in high-burden settings: study protocol for a cluster randomized controlled trial evaluating different community-wide intervention strategies in rural Madagascar

BackgroundRetrospective and descriptive molecular epidemiology studies have shown that Mycobacterium tuberculosis whole genome sequencing can identify outbreaks and disease transmission events with higher resolution than conventional epidemiological investigations. Those studies have strengthened our understanding of genomic polymorphisms correlating with person-to-person transmission and helped resolve putative transmission clusters. To date, systematic genomic surveillance programs implemented for M. tuberculosis were only implemented in low-incidence settings. The purpose of this study is to determine whether there is an impact of routine M. tuberculosis whole genome sequencing on tuberculosis case detection in a high-incidence setting.MethodsA cluster randomized controlled trial will be performed. Forty-eight rural village groups (or Fokontany) in the Vohibato district of Madagascar will be randomized to one of three interventions arms. Arm 1 (standard of care) involves healthcare facility-based passive case detection with smear microscopy testing. Arm 2 (best practice) consists of active case finding and Xpert MTB/RIF Ultra PCR testing followed by household contact investigations. Arm 3 (novel intervention) includes the same interventions as arm 2, with addition of sputum culture and M. tuberculosis whole genome sequencing for all newly diagnosed cases. In arm 3, molecular suggested putative outbreaks are investigated, and additional TB suspects are appropriately tested. The intervention observational period will be 2 years. The primary outcome will be the number of detected cases/100,000/year in each arm after 1 year of intervention.DiscussionThis study is designed to determine whether there is an impact of prospective whole genome sequencing-based molecular typing on tuberculosis case detection in high-incidence settings. Investigating potential outbreaks and focusing active case finding in spatiotemporal settings where disease transmission is suggested by genomic typing is hypothesized to improve case detection in rural communities.Trial registrationClinicalTrials.gov NCT05406453. Retrospectively registered on June 6, 2022.

Africa Health Research Institute (AHRI) Household Contact study: a study protocol, statistical analysis and modelling plan

Household case-contact studies are an established method to estimate the relative infectiousness of people with pulmonary tuberculosis. Testing of child household contacts with a QuantiFERON TB Gold plus (QFT) assay provides a proxy measure of M. tuberculosis infection in exposed household members. This study aims to generate data about the effect of antiretroviral treatment (ART) and of tuberculosis symptoms on risk of intra-household M. tuberculosis transmission to children and investigate the conditions under which symptom-agnostic screening should be considered, which could provide evidence to support a paradigm shift in tuberculosis screening strategy. Index people diagnosed with bacteriologically-confirmed pulmonary tuberculosis who have been identified by routine health services and starting tuberculosis treatment at one of the 12 health facilities serving the population of the Africa Health Research Institute health and demographic surveillance area will be eligible for recruitment. For each consenting index participant, we will enroll all household members aged 2-14 years who will undergo a symptom screen and provide a blood sample for a QFT and HIV test. We will compare the proportion of child contacts who are QFT-positive in households of (i) index adults who are living with HIV and taking ART vs not taking ART and (ii) index adults engaged in ART care who report no symptoms vs those who report symptoms. We will use a novel mathematical model, incorporating new insights into TB natural history and transmission, to determine the circumstances under which screening for TB, regardless of reported symptoms, would have most impact on tuberculosis incidence and mortality, and explore comparative cost-effectiveness of interventions along the diagnostic pathway at different levels of the health system. Estimates of relative risk of intra-household M. tuberculosis transmission, combined with healthcare utilisation and cost data, will allow us to generate mathematical model estimates of the potential epidemiological impact and relative cost-effectiveness of different approaches to tuberculosis case-finding including symptom-agnostic tuberculosis screening at different levels of the health system.

Mapping the distribution of tuberculosis cases and associated factors identified through routine program implementation and community-based active screening in Central Ethiopia.

Smear-positive TB patients greatly contribute to community-level transmission of this disease. Locating hotspots would make it easier to prioritize and target control interventions. This study aimed to assess the spatial distribution of smear-positive index TB cases and their secondary cases and the predictors of clustering of smear-positive TB cases. This study was conducted in the Silti Zone of Central Ethiopia from 2020 to 2022. The data of smear-positive index TB patients were collected from the unit TB registries of healthcare facilities. Contacts of all index TB patients were screened in the community and tested to identify secondary TB patients. We performed spatial analysis, including Moran's I statistic, the Getis-Ord Gi* statistic and geographically weighted regression (GWR), to assess the global distribution, local clustering and predictors of clustering of smear-positive TB patients, respectively. Additionally, we used inverse distance weighting (IDW) interpolation to predict the distribution of smear-positive TB cases and develop a continuous raster map for places with no data. Spatial autocorrelation analysis revealed that the distribution of smear-positive TB patients exhibited significant clustering (Moran's I = 0.70029; p value < 0.000). The Getis-Ord Gi* output indicated the presence of statistically significant hotspots as well as cold spots in the study area. Significant hotspots were found in 11 Kebeles of the Silti, Dalocha and Misrak Silti districts. Significant coldspots were also found in five kebeles of the Silti and Misrak districts. GWR analysis revealed that no education, primary education, family size and thatched roof houses were significant predictors of the spatial clustering of smear-positive TB cases. We also found that the majority of the secondary TB cases were found in hotspots identified through spatial analysis. The study revealed a heterogenous distribution of smear positive TB in the study area and it could act as a model that can be replicated in other regions. The identified hotspots of TB could be targeted through location-based interventions such as systematic active screening in the form of outreach programs to improve the performance of TB prevention and control, including reducing the transmission of TB. Educational status, family size and housing type were some of the factors that significantly influenced the spatial distribution of smear-positive TB in the study area. The distribution of secondary TB cases found through household contact screening coincided with the identified hotspots, indicating greater transmission of the disease in these places.

Sputum and tongue swab molecular testing for the in-home diagnosis of tuberculosis in unselected household contacts: a cost and cost-effectiveness analysis.

Delayed and missed diagnosis are a persistent barrier to tuberculosis control, partly driven by limitations associated with sputum collection and an unmet need for decentralized testing. Household contact investigation with point-of-care testing of non-invasive specimens like tongue swabs are hitherto undescribed and may be a cost-effective solution to enable community-based active case finding. In-home, molecular point-of-care testing was conducted using sputum and tongue specimens collected from all household contacts of confirmed tuberculosis cases. A health economic assessment was executed to estimate and compare the cost and cost-effectiveness of different in-home, point-of-care testing strategies. Incremental cost effectiveness ratios of strategies utilizing different combination testing algorithms using sputum and/or tongue swab specimens were compared. The total implementation cost of delivering the standard of care for a 2-year period was $84 962. Strategies integrating in-home point-of-care testing ranged between $87 844 - $93 969. The cost-per-test for in-home, POC testing of sputum was the highest at $20·08 per test. Two strategies, Point-of-Care Sputum Testing and Point-of-Care Combined Sputum and Individual Tongue Swab Testing were the most cost-effective with ICERs of $543·74 and $547·29 respectively, both below a $2,760 willingness-to-pay threshold. An in-home, point-of-care molecular testing strategy utilizing combination testing of tongue swabs and sputum specimens would incur an additional 10.6% program cost, compared to SOC, over a 2-year period. The increased sample yield from tongue swabs combined with immediate result notification following, in-home POC testing would increase the number of new TB cases detected and linked to care by more than 800%.

Management implications of latent TB among under-five children at risk: Insights from a community study in Mumbai, India.

Latent tuberculosis infection (LTBI) management is crucial to WHO's End TB Strategy. Indian guidelines recommend treating under-five children with household TB contacts after ruling out active TB, regardless of TBI testing. However, the precise LTBI burden among children in high TB burden settings like India is unknown. A community-based study in Mumbai's urban slums screened and managed under-five children at LTBI risk to understand its epidemiology and inform TB control interventions. Total 369 eligible under-five children were enrolled for the study. LTBI screening was done using Tuberculin skin test and Interferon gamma release assay. Active TB was ruled out before initiation of TB preventive therapy among LTBI positives. Statistical tests like chi-square, logistic regression analysis and Hosmer-Lemeshow test were used. Overall, LTBI prevalence among under-five children was 12.4% by IGRA and 21.4% by TST. Undernourished children had significantly lower LTBI positivity by IGRA (p = 0.027), while those with household contacts, longer contact duration and drug-resistant tuberculosis (DR-TB) exhibited proportionally greater IGRA positivity (p = <0.001). The study found a lower LTBI prevalence among under-five children compared to adults, with key risk factors being HHC, DR-TB contact, and prolonged exposure. These findings suggest the need to revise or revisit the TPT framework for this age group in India, particularly by implementing a test-and-treat approach.

Ebola Virus-Specific Neutralizing Antibody Persists at High Levels in Survivors 2 Years After Resolution of Disease in a Sierra Leonean Cohort.

Ebola virus (EBOV) infection results in Ebola virus disease (EVD), an often severe disease with a nonspecific presentation. Since its recognition, periodic outbreaks of EVD continue to occur in sub-Saharan Africa. The 2013-2016 West African EVD outbreak was the largest recorded, resulting in a substantial cohort of EVD survivors with persistent health complaints and variable immune responses. In this study, we characterize humoral immune responses in EVD survivors and their contacts in Eastern Sierra Leone. We found high levels of EBOV IgG in EVD survivors and lower yet substantial antibody levels in household contacts, suggesting subclinical transmission. Neutralizing antibody function was prevalent but variable in EVD survivors, raising questions about the durability of immune responses from natural infection with EBOV. Additionally, we found that certain discrete symptoms-ophthalmologic and auditory-are associated with EBOV IgG seropositivity, while an array of symptoms are associated with the presence of neutralizing antibody.