Comparison of Tuberculin Skin Testing and Interferon-γ Release Assays in Predicting Tuberculosis Disease.

Importance: Elimination of tuberculosis (TB) disease in the US hinges on the ability of tests to detect individual risk of developing disease to inform prevention. The relative performance of 3 available TB tests-the tuberculin skin test (TST) and 2 interferon-γ release assays (IGRAs; QuantiFERON-TB Gold In-Tube [QFT-GIT] and SPOT.TB [TSPOT])-in predicting TB disease development in the US remains unknown. Objective: To compare the performance of the TST with the QFT-GIT and TSPOT IGRAs in predicting TB disease in high-risk populations. Design, Setting, and Participants: This prospective diagnostic study included participants at high risk of TB infection (TBI) or progression to TB disease at 10 US sites between 2012 and 2020. Participants of any age who had close contact with a case patient with infectious TB, were born in a country with medium or high TB incidence, had traveled recently to a high-incidence country, were living with HIV infection, or were from a population with a high local prevalence were enrolled from July 12, 2012, through May 5, 2017. Participants were assessed for 2 years after enrollment and through registry matches until the study end date (November 15, 2020). Data analysis was performed in June 2023. Exposures: At enrollment, participants were concurrently tested with 2 IGRAs (QFT-GIT from Qiagen and TSPOT from Oxford Immunotec) and the TST. Participants were classified as case patients with incident TB disease when diagnosed more than 30 days from enrollment. Main Outcomes and Measures: Estimated positive predictive value (PPV) ratios from generalized estimating equation models were used to compare test performance in predicting incident TB. Incremental changes in PPV were estimated to determine whether predictive performance significantly improved with the addition of a second test. Case patients with prevalent TB were examined in sensitivity analysis. Results: A total of 22 020 eligible participants were included in this study. Their median age was 32 (range, 0-102) years, more than half (51.2%) were male, and the median follow-up was 6.4 (range, 0.2-8.3) years. Most participants (82.0%) were born outside the US, and 9.6% were close contacts. Tuberculosis disease was identified in 129 case patients (0.6%): 42 (0.2%) had incident TB and 87 (0.4%) had prevalent TB. The TSPOT and QFT-GIT assays performed significantly better than the TST (PPV ratio, 1.65 [95% CI, 1.35-2.02] and 1.47 [95% CI, 1.22-1.77], respectively). The incremental gain in PPV, given a positive TST result, was statistically significant for positive QFT-GIT and TSPOT results (1.64 [95% CI, 1.40-1.93] and 1.94 [95% CI, 1.65-2.27], respectively). Conclusions and Relevance: In this diagnostic study assessing predictive value, IGRAs demonstrated superior performance for predicting incident TB compared with the TST. Interferon-γ release assays provided a statistically significant incremental improvement in PPV when a positive TST result was known. These findings suggest that IGRA performance may enhance decisions to treat TBI and prevent TB.

TB-free Ebeye: Results from integrated TB and noncommunicable disease case finding in Ebeye, Marshall Islands.

Background: Tuberculosis (TB) incidence rates in the Republic of the Marshall Islands are among the highest in the world, 480/100,000 in 2017. In response, the Health Ministry completed islandwide screening in Ebeye Island in 2017. Methods: Participants were interviewed to obtain TB history, exposures, and symptoms. TB assessment included chest radiography with sputum collection for GeneXpert® MTB-RIF if indicated. TB diagnosis was made by consensus of visiting TB experts. Participants were also screened for Hansen's disease (HD) and diabetes mellitus (DM). For persons aged ≥21 years, blood pressure, cholesterol, and blood glucose were assessed. Results: A total of 5,166 persons (90.0 % of target population) completed screening leading to the identification of 39 new cases of TB (755/100,000) and 14 persons with HD (270/100,000). DM was detected in 1,096 persons (27 %), including in 351 persons not previously diagnosed. The rate of hypertension was 61 % and of hypercholesterolemia was 15 %. New or prevalent TB diagnosis was associated with newly diagnosed or history of DM (aOR 4.68, 2.15-10.20). Conclusions: In Ebeye, an integrated TB screening campaign found TB, HD, DM, and hypertension. TB and DM were strongly associated.

Outbreak of Multidrug-Resistant Tuberculosis - Kansas, 2021-2022.

An outbreak of multidrug-resistant (MDR) tuberculosis (TB) involved 13 persons in four households in a low-income, under-resourced urban Kansas community during November 2021-November 2022. A majority of the seven adults identified in the Kansas outbreak were born outside the United States in a country that had experienced an MDR TB outbreak with the same genotype during 2007-2009, whereas most of the six children in the Kansas outbreak were U.S.-born. Prompt identification, evaluation, and treatment of persons with MDR TB and their contacts is essential to limiting transmission.

COVID-19 in the US-affiliated Pacific Islands: A timeline of events and lessons learned from March 2020-November 2022.

The US-Affiliated Pacific Islands (USAPIs) experience many health disparities, including high rates of non-communicable disease and limited health resources, making them particularly vulnerable when SARS-CoV-2 began circulating globally in early 2020. Therefore, many USAPIs closed their borders early during the COVID-19 pandemic to give them more time to prepare for community transmission. Routine virtual meetings were established and maintained throughout the pandemic to support preparedness and response efforts and to share information among USAPIs and support partners. Data collected from these regular virtual meetings were gathered and disseminated through routine regional situational reports. These situational reports from March 27, 2020 to November 25, 2022 were reviewed to develop a quantitative dataset with qualitative notes that were used to summarize the COVID-19 response in the USAPIs. The initial surges of COVID-19 in the USAPIs ranged from August 2020 in Guam to August 2022 in the Federated States of Micronesia. This prolonged time between initial surges in the region was due to varying approaches regarding travel requirements, including fully closed borders, repatriation efforts requiring pre-travel quarantine and testing, quarantine requirements upon arrival only, and vaccine mandates. Delaying community transmission allowed USAPIs to establish testing capacity, immunize large proportions of their populations, and use novel COVID-19 therapeutics to reduce severe disease and mortality. Other essential components to support the USAPI regional COVID-19 response efforts included strong partnership and collaboration, regional information sharing and communication efforts, and trust in health leadership among community members. Valuable lessons learned from the USAPIs during the COVID-19 pandemic can be used to continue to strengthen systems within the region and better prepare for future public health emergencies.

Patient Characteristics During Early Transmission of SARS-CoV-2, Palau, January 13-February 24, 2022.

Palau had no reported evidence of COVID-19 community spread until January 2022. We chart reviewed hospitalized patients who had a positive SARS-CoV-2 test result during early community transmission. Booster vaccinations and early outpatient treatment decreased hospitalizations. Inadequate hospital infection control practices contributed to iatrogenic COVID-19 and preventable deaths.

Tuberculosis Among Native Hawaiian and Other Pacific Islander Persons: United States and U.S.-Affiliated Pacific Islands, 2010-2019.

Background: In recent years, tuberculosis (TB) incidence in the United States has declined overall but remained high among Native Hawaiian and Other Pacific Islander (NH/PI) persons. Few studies have examined the epidemiology of TB among NH/PI persons, particularly in the U.S.-Affiliated Pacific Islands (USAPI). We describe TB incidence and characteristics of NH/PI patients during 2010-2019. Methods: We used data from the National Tuberculosis Surveillance System to characterize TB cases reported among NH/PI persons born in the 50 U.S. states (defined to include District of Columbia) and the USAPI. We calculated annual TB incidence among NH/PI patients, stratified by place of birth (U.S. states or USAPI). Using Asian persons born outside the United States-persons historically grouped with NH/PI persons as one racial category-as the reference, we compared demographic, clinical, and socio-behavioral characteristics of NH/PI TB patients. Results: During 2010-2019, 4359 TB cases were reported among NH/PI patients born in the U.S. states (n=205) or the USAPI (n=4154). Median annual incidence per 100,000 persons was 6.5 cases (persons born in the U.S. states) and 150.7 cases (persons born in the USAPI). The proportion of TB patients aged <15 years was higher among NH/PI persons (U.S. states: 54%, USAPI: 24%) than among Asian persons born outside the United States (1%). Conclusions: TB incidence among NH/PI persons is high, particularly among persons born in the USAPI, emphasizing the need to enhance TB prevention strategies in these communities. Interventions should be tailored toward those who experience the highest risk, including NH/PI children and adolescents.

US Postarrival Evaluation of Immigrant and Refugee Children with Latent Tuberculosis Infection Diagnosed Overseas, 2007-2019.

OBJECTIVE: To assess outcomes from the US postarrival evaluation of newly arrived immigrant and refugee children aged 2-14 years who were diagnosed with latent tuberculosis infection (LTBI) during a required overseas medical examination. STUDY DESIGN: We compared overseas and US interferon-γ release assay (IGRA)/tuberculin skin test (TST) results and LTBI diagnosis; assessed postarrival LTBI treatment initiation and completion; and evaluated the impact of switching from TST to IGRA to detect Mycobacterium tuberculosis infection overseas. RESULTS: In total, 73 014 children were diagnosed with LTBI overseas and arrived in the US during 2007-2019. In the US, 45 939 (62.9%) completed, and 1985 (2.7%) initiated but did not complete a postarrival evaluation. Among these 47 924 children, 30 360 (63.4%) were retested for M tuberculosis infection. For 17 996 children with a positive overseas TST, 73.8% were negative when retested by IGRA. For 1051 children with a positive overseas IGRA, 58.0% were negative when retested by IGRA. Overall, among children who completed a postarrival evaluation, 18 544 (40.4%) were evaluated as having no evidence of TB infection, and 25 919 (56.4%) had their overseas LTBI diagnosis confirmed. Among the latter, 17 229 (66.5%) initiated and 9185 (35.4%) completed LTBI treatment. CONCLUSIONS: Requiring IGRA testing overseas could more effectively identify children who will benefit from LTBI treatment. However, IGRA reversions may occur, highlighting the need for individualized assessment for risk of infection, progression, and poor outcome when making diagnostic and treatment decisions. Strategies are needed to increase the proportions receiving a postarrival evaluation and completing LTBI treatment.

Impact of T-Cell Xtend on T-SPOT.TB Assay in High-Risk Individuals after Delayed Blood Sample Processing.

T-SPOT.TB (T-SPOT) is an interferon gamma release assay (IGRA) used to detect infection with Mycobacterium tuberculosis based on the number of spot-forming T cells; however, delays in sample processing have been shown to reduce the number of these spots that are detected following laboratory processing. Adding T-Cell Xtend (XT) into blood samples before processing reportedly extends the amount of time allowed between blood collection and processing up to 32 h. In this study, paired blood samples from 306 adolescents and adults at high risk for latent tuberculosis (TB) infection (LTBI) or progression to TB disease were divided into three groups: (i) early processing (∼4.5 h after collection) with and without XT, (ii) delayed processing (∼24 h after collection) with and without XT, and (iii) early processing without XT and delayed processing with XT. The participants' paired samples were processed at a local laboratory and agreement of qualitative and quantitative results was assessed. The addition of XT did not consistently increase or decrease the number of spots. In groups 1, 2, and 3, samples processed with XT had 13% (10/77), 28.0% (30/107), and 24.6% (30/122), respectively, more spots, while 33.8% (26/77), 26.2% (28/107), and 38.5% (47/122) had fewer spots than samples processed without XT. The findings suggest that XT does not reliably mitigate the loss of spot-forming T cells in samples with processing delay.

Introduction and evaluation of multidrug-resistant tuberculosis supplemental surveillance in the United States.

The current tuberculosis (TB) case reporting system for the United States, the Report of Verified Case of TB (RVCT), has minimal capture of multidrug-resistant (MDR) TB treatment and adverse events. Data were abstracted in five states using the form for 13 MDR TB patients during 2012-2015. The Centers for Disease Control and Prevention Guidelines for Evaluating Public Health Surveillance Systems were used to evaluate attributes of the form. Unstructured interviews with pilot sites and stakeholders provided qualitative feedback. The form was acceptable, simple, stable, representative, and provided high-quality data but was not flexible or timely. For the 13 patients on whom data were collected, the median duration of treatment with an injectable medication was 216 days (IQR 203-252). Six (46%) patients reported a side effect requiring a medication change and eight (62%) had a side effect present at treatment completion. A standardized MDR TB supplemental surveillance form was well received by stakeholders whose feedback was critical to making modifications. The finalized form will be implemented nationally in 2020 and will provide MDR TB treatment and morbidity data in the United States to help ensure patients with MDR TB receive the most effective treatment regimens with the least toxic drugs.

Higher Rates of Tuberculosis Among Class B1 Filipino Immigrants to Hawaii Compared to Nationwide, 2010-2014.

BACKGROUND: Immigrants to the United States from countries with a high burden of tuberculosis (TB) who have abnormal chest radiographs but negative sputum cultures during pre-immigration screening (TB Class B1) have a high risk of being diagnosed with TB disease within 1 year of arrival. METHODS: Using 2010-2014 national surveillance data, we compared proportions of Class B1 Filipino immigrants who received a diagnosis of TB disease within 1 year of arrival to Hawaii to proportions in other U.S. states (not including Hawaii) using chi-squared tests. RESULTS: In Hawaii, 40/1190 (3.4%) of Class B1 Filipino immigrants to Hawaii received a diagnosis of TB disease within 1 year of arrival compared with 220/16,035 (1.4%) nationwide (P < .01). CONCLUSIONS: During 2010-2014, the percentage of recent Class B1 Filipino immigrants in Hawaii with TB disease diagnosed within 1 year of arrival was over twice that as nationwide.

Increasing Prevalence of Nontuberculous Mycobacteria in Respiratory Specimens from US-Affiliated Pacific Island Jurisdictions1.

Nontuberculous mycobacteria (NTM) respiratory infections represent a growing public health problem in many countries. However, there are limited published epidemiologic studies for the Western Pacific region. We reviewed respiratory specimens submitted to Diagnostic Laboratory Services in Hawaii, USA, for culture of Mycobacterium tuberculosis during August 2007-December 2011 to determine the NTM isolation rate. We observed a statistically significant increase in the rate of specimens with NTM isolated in respiratory culture (adjusted rate ratio per year 1.65, 95% CI 1.54-1.77; p<0.01). In contrast, the number of patients with respiratory cultures positive for M. tuberculosis showed no increase (adjusted rate ratio per year 0.98, 95% CI 0.94-1.01; p = 0.19). A 6-month subset of NTM isolates was identified by using a nucleic acid probe or 16S rRNA sequencing. M. avium complex and M. fortuitum were the most common NTM identified.

Genomic analyses of the ancestral Manila family of Mycobacterium tuberculosis.

With its airborne transmission and prolonged latency period, Mycobacterium tuberculosis spreads worldwide as one of the most successful bacterial pathogens and continues to kill millions of people every year. M. tuberculosis lineage 1 is inferred to originate ancestrally based on the presence of the 52-bp TbD1 sequence and analysis of single nucleotide polymorphisms. Previously, we briefly reported the complete genome sequencing of M. tuberculosis strains 96121 and 96075, which belong to the ancient Manila family and modern Beijing family respectively. Here we present the comprehensive genomic analyses of the Manila family in lineage 1 compared to complete genomes in lineages 2-4. Principal component analysis of the presence and absence of CRISPR spacers suggests that Manila isolate 96121 is distinctly distant from lineages 2-4. We further identify a truncated whiB5 gene and a putative operon consisting of genes encoding a putative serine/threonine kinase PknH and a putative ABC transporter, which are only found in the genomes of Manila family isolates. Six single nucleotide polymorphisms are uniquely conserved in 38 Manila strains. Moreover, when compared to M. tuberculosis H37Rv, 59 proteins are under positive selection in Manila family isolate 96121 but not in Beijing family isolate 96075. The unique features further serve as biomarkers for Manila strains and may shed light on the limited transmission of this ancestral lineage outside of its Filipino host population.

Pharmacokinetics and Dosing of Levofloxacin in Children Treated for Active or Latent Multidrug-resistant Tuberculosis, Federated States of Micronesia and Republic of the Marshall Islands.

BACKGROUND: In the Federated States of Micronesia and then the Republic of the Marshall Islands (RMI), levofloxacin pharmacokinetics were studied in children receiving directly observed once-daily regimens (10 mg/kg, age >5 years; 15-20 mg/kg, age ≤5 years) for either multidrug-resistant tuberculosis disease or latent infection after multidrug-resistant tuberculosis exposure, to inform future dosing strategies. METHODS: Blood samples were collected at 0 (RMI only), 1, 2 and 6 hours (50 children, aged 6 months to 15 years) after oral levofloxacin at >6 weeks of treatment. Clinical characteristics and maximal drug concentration (Cmax) of levofloxacin, elimination half-life and area under the curve from 0 to 24 hours (AUC0-24 hours × µg/mL) were correlated to determine the optimal dosage and to examine associations. Population pharmacokinetics and target attainment were modeled. With results from the Federated States of Micronesia, dosages were increased in RMI toward the target Cmax for Mycobacterium tuberculosis, 8-12 µg/mL. RESULTS: Cmax correlated linearly with per-weight dosage. Neither Cmax nor half-life was associated with gender, age, body mass index, concurrent medications or predose meals. At levofloxacin dosage of 15-20 mg/kg, Cmax ≥8 µg/mL was observed, and modeling corroborated a high target attainment across the ratio of the area under the free concentration versus time curve to minimum inhibitory concentration (fAUCss,0-24/MIC) values. CONCLUSIONS: Levofloxacin dosage should be 15-20 mg/kg for Cmax ≥8 µg/mL and a high target attainment across fAUCss,0-24/MIC values in children ≥2 years of age.

Islands of hope: building local capacity to manage an outbreak of multidrug-resistant tuberculosis in the Pacific.

A single case of multidrug-resistant tuberculosis (MDR-TB) can overwhelm the technical and financial capacity of small TB programs. In May 2008, the island state of Chuuk requested assistance for their first cases of MDR-TB. Second-line drugs and isolation rooms were unavailable, lab capacity was limited, and clinicians lacked experience. Delayed response caused prolonged transmission among household contacts. Several agencies responded with technical assistance and resources. Subsequent evaluations identified 16 additional MDR-TB cases and 124 infected contacts. Within six months, the local TB program gained remarkable capacity to manage MDR-TB cases and contacts, and greatly improve care for all TB patients. The Chuuk outbreak demonstrates the importance of establishing MDR-TB readiness in smaller jurisdictions and maintaining an essential TB control infrastructure.

Defining the research agenda to reduce the joint burden of disease from diabetes mellitus and tuberculosis.

The steadily growing epidemic of diabetes mellitus poses a threat for global tuberculosis (TB) control. Previous studies have identified an important association between diabetes mellitus and TB. However, these studies have limitations: very few were carried out in low-income countries, with none in Africa, raising uncertainty about the strength of the diabetes mellitus-TB association in these settings, and many critical questions remain unanswered. An expert meeting was held in November 2009 to discuss where there was sufficient evidence to make firm recommendations about joint management of both diseases, to address research gaps and to develop a research agenda. Ten key research questions were identified, of which 4 were selected as high priority: (i) whether, when and how to screen for TB in patients with diabetes mellitus and vice versa; (ii) the impact of diabetes mellitus and non-diabetes mellitus hyperglycaemia on TB treatment outcomes and deaths, and the development of strategies to improve outcomes; (iii) implementation and evaluation of the tuberculosis 'DOTS' model for diabetes mellitus management; and (iv) the development and evaluation of better point-of-care diagnostic and monitoring tests, including measurements of blood glucose and glycated haemoglobin A(1c) (HbA(1c)) for patients with diabetes mellitus. Implementation of this research agenda will benefit the control of both diseases.