The recent rapid expansion of multidrug resistant Ural lineage Mycobacterium tuberculosis in Moldova.

The projected trajectory of multidrug resistant tuberculosis (MDR-TB) epidemics depends on the reproductive fitness of circulating strains of MDR M. tuberculosis (Mtb). Previous efforts to characterize the fitness of MDR Mtb have found that Mtb strains of the Beijing sublineage (Lineage 2.2.1) may be more prone to develop resistance and retain fitness in the presence of resistance-conferring mutations than other lineages. Using Mtb genome sequences from all culture-positive cases collected over two years in Moldova, we estimate the fitness of Ural (Lineage 4.2) and Beijing strains, the two lineages in which MDR is concentrated in the country. We estimate that the fitness of MDR Ural strains substantially exceeds that of other susceptible and MDR strains, and we identify several mutations specific to these MDR Ural strains. Our findings suggest that MDR Ural Mtb has been transmitting efficiently in Moldova and poses a substantial risk of spreading further in the region.

Spatial Heterogeneity of Nontuberculous Mycobacterial Pulmonary Disease in Shanghai: Insights from a Ten-Year Population-Based Study.

OBJECTIVE: To investigate the spatial heterogeneity of nontuberculous mycobacterial pulmonary disease (NTM-PD) in Shanghai. METHODS: A population-based retrospective study was conducted using presumptive pulmonary tuberculosis surveillance data of Shanghai between 2010 and 2019. The study described the spatial distribution of NTM-PD notification rates, employing hierarchical Bayesian mapping for high-risk areas and the Getis-Ord Gi* statistic to identify hot spots and explore associated factors. RESULTS: Of 1652 NTM-PD cases, the most common species was Mycobacterium kansasii complex (MKC) (41.9%), followed by Mycobacterium avium complex (MAC) (27.1%) and Mycobacterium abscessus complex (MABC) (16.2%). MKC-PD patients were generally younger males with a higher incidence of pulmonary cavities, while MAC-PD patients were more often farmers or had a history of tuberculosis treatment. MKC-PD hot spots were primarily located in the areas alongside the Huangpu River, while MAC-PD hot spots were mainly in the western agricultural areas. Patients with MKC-PD and MAC-PD exhibited a higher risk of spatial clustering compared to those with MABC-PD. CONCLUSIONS: Different types of NTM-PD exhibit distinct patterns of spatial clustering and are associated with various factors. These findings underscore the importance of environmental and host factors in the epidemic of NTM-PD.

Corrigendum: Assessing heterogeneity of patient and health system delay among TB in a population with internal migrants in China.

[This corrects the article DOI: 10.3389/fpubh.2024.1354515.].

Spatial pattern of isoniazid-resistant tuberculosis and its associated factors among a population with migrants in China: a retrospective population-based study.

Background: Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) globally exhibits a high prevalence and serves as a potential precursor to multidrug-resistant tuberculosis (MDR-TB). Recognizing the spatial distribution of Hr-TB and identifying associated factors can provide strategic entry points for interventions aimed at early detection of Hr-TB and prevention of its progression to MDR-TB. This study aims to analyze spatial patterns and identify socioeconomic, demographic, and healthcare factors associated with Hr-TB in Shanghai at the county level. Method: We conducted a retrospective study utilizing data from TB patients with available Drug Susceptible Test (DST) results in Shanghai from 2010 to 2016. Spatial autocorrelation was explored using Global Moran's I and Getis-Ord Gi∗ statistics. A Bayesian hierarchical model with spatial effects was developed using the INLA package in R software to identify potential factors associated with Hr-TB at the county level. Results: A total of 8,865 TB patients with DST were included in this analysis. Among 758 Hr-TB patients, 622 (82.06%) were new cases without any previous treatment history. The drug-resistant rate of Hr-TB among new TB cases in Shanghai stood at 7.20% (622/8014), while for previously treated cases, the rate was 15.98% (136/851). Hotspot areas of Hr-TB were predominantly situated in southwestern Shanghai. Factors positively associated with Hr-TB included the percentage of older adult individuals (RR = 3.93, 95% Crl:1.93-8.03), the percentage of internal migrants (RR = 1.35, 95% Crl:1.15-1.35), and the number of healthcare institutions per 100 population (RR = 1.17, 95% Crl:1.02-1.34). Conclusion: We observed a spatial heterogeneity of Hr-TB in Shanghai, with hotspots in the Songjiang and Minhang districts. Based on the results of the models, the internal migrant population and older adult individuals in Shanghai may be contributing factors to the emergence of areas with high Hr-TB notification rates. Given these insights, we advocate for targeted interventions, especially in identified high-risk hotspots and high-risk areas.

Trends of Drug-Resistant Tuberculosis in an Urban and a Rural Area in China: A 10-Year Population-Based Molecular Epidemiological Study.

Objective: Drug resistance is the critical determinant for appropriate tuberculosis (TB) treatment regimens and an important indicator of the local TB burden. We aimed to investigate and compare trends in TB drug resistance in the urban Songjiang District of Shanghai from 2011 to 2020, and the rural Wusheng County of Sichuan Province from 2009 to 2020, to assess the effectiveness of local TB control and treatment programs. Methods: Whole-genome sequencing data of Mycobacterium tuberculosis were used to predict drug-resistance profiles and identify genomic clusters. Clustered, retreated cases of drug-resistant TB with identical resistance mutations, as well as all new resistant cases, were defined as transmitted resistance. The Cochran-Armitage trend test was used to identify trends in the proportions. Differences between groups were tested using the Wilcoxon rank sum or chi-square tests. Results: The annual proportions of rifampicin-resistant (RR), isoniazid-resistant (INH-R) and multidrug-resistant (MDR) TB cases did not change significantly in Songjiang. In Wusheng, however, the percentage of total TB cases that were RR decreased from 13.2% in 2009 to 3.7% in 2020, the INH-R cases decreased from 16.5% to 7.3%, and the MDR cases decreased from 10.7% to 3.7%. In retreated cases, the percentage of drug resistance decreased in both Songjiang and Wusheng, suggesting improved treatment programs. Transmitted resistance accounted for more than two thirds of drug-resistant cases over the entire study periods, and in recent years this proportion has increased significantly in Songjiang. Conclusion: In both urban Songjiang and rural Wusheng, drug-resistant TB is mostly the result of transmission of drug resistant strains and the percentage of transmitted resistance will likely increase with on-going improvements in the TB treatment programs. Reducing the prevalence of drug resistance depends principally upon decreasing transmission through the prompt diagnosis and effective treatment of drug-resistant TB cases.

Assessing heterogeneity of patient and health system delay among TB in a population with internal migrants in China.

Backgrounds: The diagnostic delay of tuberculosis (TB) contributes to further transmission and impedes the implementation of the End TB Strategy. Therefore, we aimed to describe the characteristics of patient delay, health system delay, and total delay among TB patients in Shanghai, identify areas at high risk for delay, and explore the potential factors of long delay at individual and spatial levels. Method: The study included TB patients among migrants and residents in Shanghai between January 2010 and December 2018. Patient and health system delays exceeding 14 days and total delays exceeding 28 days were defined as long delays. Time trends of long delays were evaluated by Joinpoint regression. Multivariable logistic regression analysis was employed to analyze influencing factors of long delays. Spatial analysis of delays was conducted using ArcGIS, and the hierarchical Bayesian spatial model was utilized to explore associated spatial factors. Results: Overall, 61,050 TB patients were notified during the study period. Median patient, health system, and total delays were 12 days (IQR: 3-26), 9 days (IQR: 4-18), and 27 days (IQR: 15-43), respectively. Migrants, females, older adults, symptomatic visits to TB-designated facilities, and pathogen-positive were associated with longer patient delays, while pathogen-negative, active case findings and symptomatic visits to non-TB-designated facilities were associated with long health system delays (LHD). Spatial analysis revealed Chongming Island was a hotspot for patient delay, while western areas of Shanghai, with a high proportion of internal migrants and industrial parks, were at high risk for LHD. The application of rapid molecular diagnostic methods was associated with reduced health system delays. Conclusion: Despite a relatively shorter diagnostic delay of TB than in the other regions in China, there was vital social-demographic and spatial heterogeneity in the occurrence of long delays in Shanghai. While the active case finding and rapid molecular diagnosis reduced the delay, novel targeted interventions are still required to address the challenges of TB diagnosis among both migrants and residents in this urban setting.

Transmission of fluoroquinolones resistance among multidrug-resistant tuberculosis in Shanghai, China: a retrospective population-based genomic epidemiology study.

Fluoroquinolones (FQ) are essential for the treatment of multidrug-resistant tuberculosis (MDR-TB). The FQ resistance (FQ-R) rate in MDR-TB in China and its risk factors remain poorly understood. We conducted a retrospective, population-based genomic epidemiology study of MDR-TB patients in Shanghai, China, from 2009 to 2018. A genomic cluster was defined as strains with genetic distances ≤ 12 single nucleotide polymorphisms. The transmitted FQ-R was defined as the same FQ resistance-conferring mutations shared by ≥ 2 strains in a genomic cluster. We used multivariable logistic regression analysis to identify the risk factors for drug resistance. Among the total 850 MDR-TB patients included in the study, 72.8% (619/850) were male, the median age was 39 (interquartile range 28, 55) years, 52.7% (448/850) were migrants, and 34.5% (293/850) were previously treated patients. Most of the MDR-TB strains belong to the Beijing lineage (91.7%, 779/850). Overall, the genotypic resistance rate of FQ was 34.7% (295/850), and 47.1% (139/295) FQ-R patients were in genomic clusters, of which 98 (33.2%, 98/295) were presumed as transmitted FQ-R. Patients with treatment-naïve (aOR = 1.84; 95% CI: 1.09, 3.16), diagnosed in a district-level hospital (aOR = 2.69; 95% CI: 1.56, 4.75), and streptomycin resistance (aOR = 3.69; 95% CI: 1.65, 9.42) were significantly associated with the transmission of FQ-R. In summary, the prevalence of FQ-R among MDR-TB patients was high in Shanghai, and at least one-third were transmitted. Enforced interventions including surveillance of FQ drug susceptibility testing and screening among MDR-TB before initiation of treatment were urgently needed.

Cost-Effectiveness of Community-Based Active Case Finding Strategy for Tuberculosis: Evidence from Shenzhen, China.

BACKGROUND: Active case finding (ACF) is a potentially promising approach for the early identification and treatment of tuberculosis (TB) patients. However, evidence on its cost-effectiveness, particularly in low- and middle-income countries, remains limited. This study evaluates the cost-effectiveness of a community-based ACF practice in Shenzhen, China. METHODS: We employed a Markov model-based decision analytic method to assess the costs and effectiveness of three TB detection strategies: PCF, basic ACF, and advanced ACF. The analysis was conducted from a societal perspective on a dynamic cohort over a 20-year horizon, focusing on active TB (ATB) prevalence and the incremental cost-effectiveness ratio (ICER). RESULTS: Compared to the PCF strategy, the basic and advanced ACF strategies effectively reduced ATB cases by 6.8 and 10.2 per 100,000 population, respectively, by the final year of this 20-year period. The ICER for the basic and advanced ACF strategies were ¥14,757 and ¥8,217 per QALY (short for quality-adjusted life-years), respectively. Both values fell below the cost-effectiveness threshold. CONCLUSION: Our findings indicate that the community-based ACF screening strategy, which targets individuals exhibiting TB symptoms, is cost-effective. This underscores the potential benefits of adopting similar community-based ACF strategies for symptomatic populations in TB-endemic areas.

Association between cytomegalovirus infection and cancer­related mortality in the US adults.

PURPOSE: In a nationwide cohort of US adults, an exploration of the association between cytomegalovirus (CMV) infection and cancer­related mortality was conducted. MATERIALS AND METHODS: We acquired data from the National Health and Nutrition Examination Survey III (1988-1994), including 11,138 individuals who were aged 18-90 years at enrollment and underwent CMV serology assessments. CMV infection was determined by CMV antibody testing. Cancer­related mortality status was ascertained until December 2019 utilizing the National Death Index linkage data and determined by neoplasms. The Cox proportional hazard model was applied to estimate the potential association between CMV infection and the risk of cancer-related mortality. RESULTS: During a median follow-up of 26.1 years, 1514 cancer­related deaths were identified in the study cohort. After adjusting for age, sex, and ethnicity, CMV infection was associated with a higher hazard of cancer­related mortality (hazard ratio [HR]: 1.39, 95 % CI: 1.13, 1.70). Further adjustments for body mass index, family income, and smoking status slightly attenuated the magnitude of the association (HR: 1.24, 95 % CI: 1.00, 1.53). However, no significant interaction was observed among gender by subgroup analysis. CONCLUSIONS: CMV infection might be an independent risk factor for cancer­related mortality among US adults. Future studies could focus on the mechanisms through which CMV infection influences mortality induced by neoplasms and develop targeted interventions to reduce the risk.

Genotypic and spatial analysis of transmission dynamics of tuberculosis in Shanghai, China: a 10-year prospective population-based surveillance study.

Background: With improved tuberculosis (TB) control programs, the incidence of TB in China declined dramatically over the past few decades, but recently the rate of decrease has slowed, especially in large cities such as Shanghai. To help formulate strategies to further reduce TB incidence, we performed a 10-year study in Songjiang, a district of Shanghai, to delineate the characteristics, transmission patterns, and dynamic changes of the local TB burden. Methods: We conducted a population-based study of culture-positive pulmonary TB patients diagnosed in Songjiang during 2011-2020. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms based on whole-genome sequencing, and risk factors for clustering were identified by logistic regression. Transmission inference was performed using phybreak. The distances between the residences of patients were compared to the genomic distances of their isolates. Spatial patient hotspots were defined with kernel density estimation. Findings: Of 2212 enrolled patients, 74.7% (1652/2212) were internal migrants. The clustering rate (25.2%, 558/2212) and spatial concentrations of clustered and unclustered patients were unchanged over the study period. Migrants had significantly higher TB rates but less clustering than residents. Clustering was highest in male migrants, younger patients and both residents and migrants employed in physical labor. Only 22.1% of transmission events occurred between residents and migrants, with residents more likely to transmit to migrants. The clustering risk decreased rapidly with increasing distances between patient residences, but more than half of clustered patient pairs lived ≥5 km apart. Epidemiologic links were identified for only 15.6% of clustered patients, mostly in close contacts. Interpretation: Although some of the TB in Songjiang's migrant population is caused by strains brought by infected migrants, local, recent transmission is an important driver of the TB burden. These results suggest that further reductions in TB incidence require novel strategies to detect TB early and interrupt urban transmission. Funding: Shanghai Municipal Science and Technology Major Project (ZD2021CY001), National Natural Science Foundation of China (82272376), National Research Council of Science and Technology Major Project of China (2017ZX10201302-006).

Assessing the spatial heterogeneity of tuberculosis in a population with internal migration in China: a retrospective population-based study.

Background: Internal migrants pose a critical threat to eliminating Tuberculosis (TB) in many high-burden countries. Understanding the influential pattern of the internal migrant population in the incidence of tuberculosis is crucial for controlling and preventing the disease. We used epidemiological and spatial data to analyze the spatial distribution of tuberculosis and identify potential risk factors for spatial heterogeneity. Methods: We conducted a population-based, retrospective study and identified all incident bacterially-positive TB cases between January 1st, 2009, and December 31st, 2016, in Shanghai, China. We used Getis-Ord Gi* statistics and spatial relative risk methods to explore spatial heterogeneity and identify regions with spatial clusters of TB cases, and then used logistic regression method to estimate individual-level risk factors for notified migrant TB and spatial clusters. A hierarchical Bayesian spatial model was used to identify the attributable location-specific factors. Results: Overall, 27,383 bacterially-positive tuberculosis patients were notified for analysis, with 42.54% (11,649) of them being migrants. The age-adjusted notification rate of TB among migrants was much higher than among residents. Migrants (aOR, 1.85; 95%CI, 1.65-2.08) and active screening (aOR, 3.13; 95%CI, 2.60-3.77) contributed significantly to the formation of TB high-spatial clusters. With the hierarchical Bayesian modeling, the presence of industrial parks (RR, 1.420; 95%CI, 1.023-1.974) and migrants (RR, 1.121; 95%CI, 1.007-1.247) were the risk factors for increased TB disease at the county level. Conclusion: We identified a significant spatial heterogeneity of tuberculosis in Shanghai, one of the typical megacities with massive migration. Internal migrants play an essential role in the disease burden and the spatial heterogeneity of TB in urban settings. Optimized disease control and prevention strategies, including targeted interventions based on the current epidemiological heterogeneity, warrant further evaluation to fuel the TB eradication process in urban China.

Discrepancy in the transmissibility of multidrug-resistant mycobacterium tuberculosis in urban and rural areas in China.

The fitness of multidrug-resistant tuberculosis (MDR-TB) is thought to be an important determinant of a strain's ability to be transmitted. Studies in the laboratory have demonstrated that MDR-TB strains have reduced fitness but the relative transmissibility of MDR-TB versus drug-susceptible (DS) TB strains in human populations remains unresolved. We used data on genomic clustering from our previous molecular epidemiological study in Songjiang (2011-2020) and Wusheng (2009-2020), China, to compare the relative transmissibility of MDR-TB versus DS-TB. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms and the risk for MDR-TB clustering was analyzed by logistic regression. In total, 2212 culture-positive pulmonary TB patients were enrolled in Songjiang and 1289 in Wusheng. The clustering rates of MDR-TB and DS-TB strains were 19.4% (20/103) and 26.3% (509/1936), respectively in Songjiang, and 43.9% (29/66) and 26.0% (293/1128) in Wusheng. The risk of MDR-TB clustering was 2.34 (95% CI 1.38-3.94) times higher than DS-TB clustering in Wusheng and 0.64 (95% CI 0.38-1.06) times lower in Songjiang. Neither lineage 2, compensatory mutations nor rpoB S450L were significantly associated with MDR-TB transmission, and katG S315 T increased MDR-TB transmission only in Wusheng (OR 5.28, 95% CI 1.42-19.21). MDR-TB was not more transmissible than DS-TB in either Songjiang or Wusheng. It appears that the different transmissibility of MDR-TB in Songjiang and Wusheng is likely due to differences in the quality of the local TB control programmes. Suggesting that the most effective way to control MDR-TB is by improving local TB control programmes.

Time-trend analysis of tuberculosis diagnosis in Shenzhen, China between 2011 and 2020.

Objective: To describe the trend of tuberculosis (TB) diagnosis in the migrant city Shenzhen, China, and analyze the risk factors of diagnosis delays. Methods: Demographic and clinical information of TB patients from 2011 to 2020 in Shenzhen were extracted. A bundle of measures to enhance TB diagnosis had been implemented since late 2017. We calculated the proportions of patients who underwent a patient delay (>30 days from syndrome onset to first care-seeking) or a hospital delay (>4 days from first care-seeking to TB diagnosis). Multivariable logistic regression was used to analyze the risk factors of diagnosis delays. Results: During the study period, 43,846 patients with active pulmonary TB were diagnosed and registered in Shenzhen. On average, the bacteriological positivity rate of the patients was 54.9%, and this increased from 38.6% in 2017 to 74.2% in 2020. Overall, 30.3 and 31.1% of patients had a patient delay or a hospital delay, respectively. Molecular testing significantly increased bacteriological positivity and decreased the risk of hospital delay. People >35 years old, the unemployed, and residents had a higher risk of delays in both patient care-seeking and hospital diagnosis than younger people, workers, or migrants. Compared with passive case-finding, active case-finding significantly decreased the risk of patient delay by 5.47 (4.85-6.19) times. Conclusion: The bacteriological positivity rate of TB patients in Shenzhen increased significantly but the diagnosis delays were still serious, which may need more attention when active case-finding in risk populations and optimization of molecular testing.

The Impact of COVID-19 Lockdown on Cases of and Deaths From AIDS, Gonorrhea, Syphilis, Hepatitis B, and Hepatitis C: Interrupted Time Series Analysis.

BACKGROUND: China implemented a nationwide lockdown to contain COVID-19 from an early stage. Previous studies of the impact of COVID-19 on sexually transmitted diseases (STDs) and diseases caused by blood-borne viruses (BBVs) in China have yielded widely disparate results, and studies on deaths attributable to STDs and BBVs are scarce. OBJECTIVE: We aimed to elucidate the impact of COVID-19 lockdown on cases, deaths, and case-fatality ratios of STDs and BBVs. METHODS: We extracted monthly data on cases and deaths for AIDS, gonorrhea, syphilis, hepatitis B, and hepatitis C between January 2015 and December 2021 from the notifiable disease reporting database on the official website of the National Health Commission of China. We used descriptive statistics to summarize the number of cases and deaths and calculated incidence and case-fatality ratios before and after the implementation of a nationwide lockdown (in January 2020). We used negative binominal segmented regression models to estimate the immediate and long-term impacts of lockdown on cases, deaths, and case-fatality ratios in January 2020 and December 2021, respectively. RESULTS: A total of 14,800,330 cases of and 127,030 deaths from AIDS, gonorrhea, syphilis, hepatitis B, and hepatitis C were reported from January 2015 to December 2021, with an incidence of 149.11/100,000 before lockdown and 151.41/100,000 after lockdown and a case-fatality ratio of 8.21/1000 before lockdown and 9.50/1000 after lockdown. The negative binominal model showed significant decreases in January 2020 in AIDS cases (-23.4%; incidence rate ratio [IRR] 0.766, 95% CI 0.626-0.939) and deaths (-23.9%; IRR 0.761, 95% CI 0.647-0.896), gonorrhea cases (-34.3%; IRR 0.657, 95% CI 0.524-0.823), syphilis cases (-15.4%; IRR 0.846, 95% CI 0.763-0.937), hepatitis B cases (-17.5%; IRR 0.825, 95% CI 0.726-0.937), and hepatitis C cases (-19.6%; IRR 0.804, 95% CI 0.693-0.933). Gonorrhea, syphilis, and hepatitis C showed small increases in the number of deaths and case-fatality ratios in January 2020. By December 2021, the cases, deaths, and case-fatality ratios for each disease had either reached or remained below expected levels. CONCLUSIONS: COVID-19 lockdown may have contributed to fewer reported cases of AIDS, gonorrhea, syphilis, hepatitis B, and hepatitis C and more reported deaths and case-fatality ratios of gonorrhea, syphilis, and hepatitis C in China.

Impact of combination preventative interventions on hospitalization and death under the pandemic of SARS-CoV-2 Omicron variant in China.

With a large population most susceptible to Omicron and emerging SARS-CoV-2 variants, China faces uncertain scenarios if reopening its border. Thus, we aimed to predict the impact of combination preventative interventions on hospitalization and death. An age-stratified susceptible-infectious-quarantined-hospitalized-removed-susceptible (SIQHRS) model based on the new guidelines of COVID-19 diagnosis and treatment (the ninth edition) was constructed to simulate the transmission dynamics of Omicron within 365 days. At baseline, we assumed no interventions other than 60% booster vaccination in individuals aged ≤60 years and 80% in individuals aged >60 years, quarantine and hospitalization. Oral antiviral medications for COVID-19 and nonpharmaceutical interventions (NPIs) such as social distancing and antigen self-testing were considered in subsequent scenarios. Sensitivity analyses were conducted to reflect different levels of interventions. A total of 0.73 billion cumulative quarantines (95% CI 0.53-0.83), 33.59 million hospitalizations (22.41-39.31), and 0.62 million deaths (0.40-0.75) are expected in 365 days. The case fatality rate with pneumonia symptoms (moderate, severe and critical illness) is expected to be 1.83% (1.68-1.99%) and the infected fatality rate is 0.38‰ (0.33-0.4‰). The highest existing hospitalization and ICU occupations are 3.11 (0.30-3.85) and 20.33 (2.01-25.20) times of capacity, respectively. Sensitivity analysis showed that interventions can be adjusted to meet certain conditions to reduce the total number of infections and deaths. In conclusion, after sufficient respiratory and ICU beds are prepared and the relaxed NPIs are in place, the SARS-CoV-2 Omicron variant would not seriously impact the health system.

Whole-Genome Sequencing and Epidemiological Investigation of Tuberculosis Outbreaks in High Schools in Hunan, China.

Background: Tuberculosis (TB) seriously threatens individual and public health. Recently, TB outbreaks in schools have been reported more frequently in China and have attracted widespread attention. We reported three TB outbreaks in high schools in Hunan Province, China. Methods: When a tuberculosis patient was reported in a school, we carried out field epidemiological investigations, including tuberculin skin testing (TST), chest X-ray (CXR) and laboratory test for all close contacts, and whole-genome sequencing (WGS) analyses to understand the transmission patterns, the causes and the risk factors for the outbreaks, thereby providing a foundation for the control of TB epidemics in schools. Results: A total of 49 students with TB patients were identified in the three schools where TB outbreaks occurred, including nine patients in School A, 14 patients in School B, and 26 patients in School C. In Schools A, B and C, the putative attack rates in the classes of the index case were 13.8% (8/58), 7.6% (5/66), and 40.4% (21/52), while the putative attack rates of expanding screening in the school were 0.3% (1/361), 0.2% (9/3955), and 0.2% (5/2080), respectively. Thirteen patients had patient delay, with a median delay interval of 69 days (IQR 30.5-113 days). Twelve patients had a healthcare diagnostic delay with a median delay interval of 32 days (IQR 24-82 days). Phylogenetic analysis of culture-positive patients revealed that most of them shared a small genetic distance (≤12 SNPs), with three separate genetic clusters (including one MDR-TB genomic cluster), indicating the recent transmission of Mycobacterium tuberculosis strains. Conclusion: This combination of field investigation and WGS analysis revealed the transmission of three TB outbreaks in schools. Reinforced implementation is needed to improve timely case finding and reduce diagnosis delay in routine TB control in the school population.

High proportion of tuberculosis transmission among social contacts in rural China: a 12-year prospective population-based genomic epidemiological study.

ABSTRACTTuberculosis (TB) is more prevalent in rural than urban areas in China, and delineating TB transmission patterns in rural populations could improve TB control. We conducted a prospective population-based study of culture-positive pulmonary TB patients diagnosed between July 1, 2009 and December 31, 2020 in two rural counties in China. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms, based on whole-genome sequencing. Risk factors for clustering were identified by logistic regression. Transmission links were sought through epidemiological investigation of genomic-clustered patients. Of 1517 and 751 culture-positive pulmonary TB patients in Wusheng and Wuchang counties, respectively, 1289 and 699 strains were sequenced. Overall, 624 (31.4%, 624/1988) patients were grouped into 225 genomic clusters. Epidemiological links were confirmed in 41.8% (196/469) of clustered isolates, including family (32.7%, 64/196) and social contacts (67.3%, 132/196). Social contacts were generally with relatives, within the community or in shared aggregated settings outside the community, but the proportion of clustered contacts in each category differed between the two sites. The time interval between diagnosis of student cases and contacts was significantly shorter than family and social contacts, probably due to enhanced student contact screening. Transmission of multidrug-resistant (MDR) strains was likely responsible for 81.4% (83/102) of MDR-TB cases, with minimal acquisition of additional resistance mutations. A large proportion of TB transmission in rural China occurred among social contacts, suggesting that active screening and aggressive contact tracing could benefit TB control, but contact screening should be tailored to local patterns of social interactions.

Spatial analysis of tuberculosis treatment outcomes in Shanghai: implications for tuberculosis control.

OBJECTIVES: Tuberculosis (TB) treatment outcomes are a key indicator in the assessment of TB control programs. We aimed to identify spatial factors associated with TB treatment outcomes, and to provide additional insights into TB control from a geographical perspective. METHODS: We collected data from the electronic TB surveillance system in Shanghai, China and included pulmonary TB patients registered from January 1, 2009 to December 31, 2016. We examined the associations of physical accessibility to hospitals, an autoregression term, and random hospital effects with treatment outcomes in logistic regression models after adjusting for demographic, clinical, and treatment factors. RESULTS: Of the 53,475 pulmonary TB patients, 49,002 (91.6%) had successful treatment outcomes. The success rate increased from 89.3% in 2009 to 94.4% in 2016. The successful treatment outcome rate varied among hospitals from 78.6% to 97.8%, and there were 12 spatial clusters of poor treatment outcomes during the 8-year study period. The best-fit model incorporated spatial factors. Both the random hospital effects and autoregression terms had significant impacts on TB treatment outcomes, ranking 6th and 10th, respectively, in terms of statistical importance among 14 factors. The number of bus stations around the home was the least important variable in the model. CONCLUSIONS: Spatial autocorrelation and hospital effects were associated with TB treatment outcomes in Shanghai. In highly-integrated cities like Shanghai, physical accessibility was not related to treatment outcomes. Governments need to pay more attention to the mobility of patients and different success rates of treatment among hospitals.

Phylogeography and transmission of M. tuberculosis in Moldova: A prospective genomic analysis.

BACKGROUND: The incidence of multidrug-resistant tuberculosis (MDR-TB) remains critically high in countries of the former Soviet Union, where >20% of new cases and >50% of previously treated cases have resistance to rifampin and isoniazid. Transmission of resistant strains, as opposed to resistance selected through inadequate treatment of drug-susceptible tuberculosis (TB), is the main driver of incident MDR-TB in these countries. METHODS AND FINDINGS: We conducted a prospective, genomic analysis of all culture-positive TB cases diagnosed in 2018 and 2019 in the Republic of Moldova. We used phylogenetic methods to identify putative transmission clusters; spatial and demographic data were analyzed to further describe local transmission of Mycobacterium tuberculosis. Of 2,236 participants, 779 (36%) had MDR-TB, of whom 386 (50%) had never been treated previously for TB. Moreover, 92% of multidrug-resistant M. tuberculosis strains belonged to putative transmission clusters. Phylogenetic reconstruction identified 3 large clades that were comprised nearly uniformly of MDR-TB: 2 of these clades were of Beijing lineage, and 1 of Ural lineage, and each had additional distinct clade-specific second-line drug resistance mutations and geographic distributions. Spatial and temporal proximity between pairs of cases within a cluster was associated with greater genomic similarity. Our study lasted for only 2 years, a relatively short duration compared with the natural history of TB, and, thus, the ability to infer the full extent of transmission is limited. CONCLUSIONS: The MDR-TB epidemic in Moldova is associated with the local transmission of multiple M. tuberculosis strains, including distinct clades of highly drug-resistant M. tuberculosis with varying geographic distributions and drug resistance profiles. This study demonstrates the role of comprehensive genomic surveillance for understanding the transmission of M. tuberculosis and highlights the urgency of interventions to interrupt transmission of highly drug-resistant M. tuberculosis.