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Rationale: The Southeast Asian tuberculosis burden is high, and it remains unclear if urban indoor air pollution in this setting is exacerbating the epidemic. Objectives: To determine the associations of latent tuberculosis with common urban indoor air pollution sources (secondhand smoke, indoor motorcycle emissions, and cooking) in Southeast Asia. Methods: We enrolled child household contacts of patients with microbiologically confirmed active tuberculosis in Vietnam, from July 2017 to December 2019. We tested children for latent tuberculosis and evaluated air pollution exposures with questionnaires and personal aerosol sampling. We tested hypotheses using generalized estimating equations. Measurements and Main Results: We enrolled 72 patients with tuberculosis (27% with cavitary disease) and 109 of their child household contacts. Latent tuberculosis was diagnosed in 58 (53%) household contacts at baseline visit. Children experienced a 2.56-fold increased odds of latent tuberculosis for each additional household member who smoked (95% confidence interval, 1.27-5.16). Odds were highest among children exposed to indoor smokers and children

Rationale: A central strategy of tuberculosis (TB) control in the United States is reducing the burden of latent TB infection (LTBI) through targeted testing and treatment of persons with untreated LTBI. Objectives: The objective of the study was to provide estimates of and risk factors for engagement in LTBI care in the overall U.S. population and among specific risk groups. Methods: We used nationally representative data from 7,080 participants in the 2011-2012 National Health and Nutrition Examination Survey. Engagement in LTBI care was assessed by estimating the proportion with a history of testing, diagnosis, treatment initiation, and treatment completion. Weighted methods were used to account for the complex survey design and to derive national estimates. Results: Only 1.4 million (10%) of an estimated 14.0 million individuals with an LTBI had previously completed treatment. Of the 12.6 million who did not complete LTBI treatment, 3.7 million (29%) had never been tested and 7.2 million (57%) received testing but had no history of diagnosis. High-risk groups showed low levels of engagement, including contacts of individuals with TB and persons born outside the United States. Conclusions: There is a reservoir of more than 12 million individuals in the United States who may be at risk for progression to TB disease and potential transmission. TB control programs and community providers should consider focused efforts to increase testing, diagnosis, and treatment for LTBI.

The term latent tuberculosis (TB) was coined two centuries ago to describe post-mortem tuberculous pathology in the absence of ante-mortem tuberculosis manifestations. However, the meaning of the term has changed with each passing century, engendering confusion. In the early 20th century, with the advent of microbiological assays for live tubercle bacteria, latent TB switched from the host to refer to the bacteria from post-mortem tissues of nontuberculous hosts. Then in the late 20th century, the definition of latent TB infection returned to the host, this time referring to those with immunoreactivity to Mycobacterium tuberculosis antigens. Based on this new definition, latent TB infection is unique among bacterial infectious diseases, in that supportive evidence of the infection state is sought by the absence of the causative bacterium and its clinical manifestations. The use of indirect bedside and laboratory tests to denote infection creates clinical and research confusion, as the tests for immunoreactivity suffer from recognized limitations in sensitivity and specificity. We propose that the concept of latent TB infection be separated from that of tuberculous immunoreactivity in the interest of correct diagnosis and focused treatment, correct formulation and interpretation of research questions and better allocation of programmatic resources for TB elimination. To this end, we suggest new terminology to course-correct our thinking about tuberculous infection (TBI) which is subdivided into tuberculous infection-no disease (TBInd) and the long-accepted term for the disease, tuberculosis (TB).

Rationale: Most U.S. residents who develop tuberculosis (TB) were born abroad, and U.S. TB incidence is increasingly driven by infection risks in other countries. Objectives: To estimate the potential impact of effective global TB control on health and economic outcomes in the United States. Methods: We estimated outcomes using linked mathematical models of TB epidemiology in the United States and migrants’ birth countries. A base-case scenario extrapolated country-specific TB incidence trends. We compared this with scenarios in which countries achieve 90% TB incidence reductions between 2015 and 2035, as targeted by the World Health Organization’s End TB Strategy (“effective global TB control”). We also considered pessimistic scenarios of flat TB incidence trends in individual countries. Measurements and Main Results: We estimated TB cases, deaths, and costs and the total economic burden of TB in the United States. Compared with the base-case scenario, effective global TB control would avert 40,000 (95% uncertainty interval, 29,000–55,000) TB cases in the United States in 2020–2035. TB incidence rates in 2035 would be 43% (95% uncertainty interval, 34–54%) lower than in the base-case scenario, and 49% (95% uncertainty interval, 44–55%) lower than in 2020. Summed over 2020–2035, this represents 0.8 billion dollars (95% uncertainty interval, 0.6–1.0 billion dollars) in averted healthcare costs and $2.5 billion dollars (95% uncertainty interval, 1.7–3.6 billion dollars) in productivity gains. The total U.S. economic burden of TB (including the value of averted TB deaths) would be 21% (95% uncertainty interval, 16–28%) lower (18 billion dollars [95% uncertainty level, 8–32 billion dollars]). Conclusions: In addition to producing major health benefits for high-burden countries, strengthened efforts to achieve effective global TB control could produce substantial health and economic benefits for the United States.

Rationale: Mathematical modeling is used to understand disease dynamics, forecast trends, and inform public health prioritization. We conducted a comparative analysis of tuberculosis (TB) epidemiology and potential intervention effects in California, using three previously developed epidemiologic models of TB. Objectives: To compare the influence of various modeling methods and assumptions on epidemiologic projections of domestic latent TB infection (LTBI) control interventions in California. Methods: We compared model results between 2005 and 2050 under a base-case scenario representing current TB services and alternative scenarios including: 1) sustained interruption of Mycobacterium tuberculosis (Mtb) transmission, 2) sustained resolution of LTBI and TB prior to entry of new residents, and 3) one-time targeted testing and treatment of LTBI among 25% of non–U.S.-born individuals residing in California. Measurements and Main Results: Model estimates of TB cases and deaths in California were in close agreement over the historical period but diverged for LTBI prevalence and new Mtb infections—outcomes for which definitive data are unavailable. Between 2018 and 2050, models projected average annual declines of 0.58–1.42% in TB cases, without additional interventions. A one-time LTBI testing and treatment intervention among non–U.S.-born residents was projected to produce sustained reductions in TB incidence. Models found prevalent Mtb infection and migration to be more significant drivers of future TB incidence than local transmission. Conclusions: All models projected a stagnation in the decline of TB incidence, highlighting the need for additional interventions including greater access to LTBI diagnosis and treatment for non–U.S.-born individuals. Differences in model results reflect gaps in historical data and uncertainty in the trends of key parameters, demonstrating the need for high-quality, up-to-date data on TB determinants and outcomes.

Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, causing almost 2 million deaths annually. Although this airborne disease has been treatable since 1948, global rates of TB have dropped less than two percent per year; an estimated 10 million incident cases continue to occur annually, including one million in children. While transmission of active disease is an important driver of the epidemic, the seedbed that feeds the epidemic is the more than two billion people estimated to have TB infection, five to ten percent of whom will progress to active disease during their lifetime. While any successful strategy aimed at TB elimination needs to address this reservoir of TB infection worldwide, much remains to be understood about host and pathogen factors that can be used to identify increased risk for progression to disease, and intervened upon to prevent progression from occurring. The Division of AIDS of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA, and the Harvard Medical School Center for Global Health Delivery-Dubai convened a group of scientists and stakeholders on September 28 and 29, 2017, to address knowledge gaps that affect our ability to rapidly find and treat individuals infected with Mycobacterium tuberculosis who are most likely to progress to active disease. The meeting identified a number of efforts underway to address this important gap in the collective ability to stop the global TB epidemic. Here, we review and outline the priority areas for research, diagnosis and treatment of TB infection that emerged from the meeting (Table 1), building on recent reviews in this area.

Introduction For decades, tuberculosis (TB) remained the leading cause of mortality due to a single infectious agent globally. In 2020, mortality due to the coronavirus disease 2019 (COVID-19) pandemic exceeded annual rates of death from TB. The impact of active COVID-19 and TB co-infection remain unclear. We present one of the first documented cases of active TB in the setting of COVID-19 infection in the United States. Case Report A 49-year-old man with a past medical history of mediastinal gray zone lymphoma and hypertension presented to the emergency room with a four-day history of diarrhea and hematochezia. The patient immigrated from Vietnam in 1995. Computed tomography imaging revealed thickening of the sigmoid wall, and bilateral pulmonary ground glass opacities consistent with COVID-19 pneumonia, which was confirmed by polymerase chain reaction (PCR). He was also neutropenic from recent chemotherapy. On admission, he began experiencing worsening hypoxia with exertion, and was started on remdesivir and dexamethasone for COVID-19 infection. Serial chest radiographs revealed worsening bibasilar opacities. He continued to have higher oxygen requirements and maxed out on high-flow nasal cannula and non-rebreather with 88-90% oxygen saturation, requiring transfer to the intensive care unit. A complete infectious workup was performed at this point. Cytomegalovirus PCR was positive at 1486IU and was started on ganciclovir. A bronchoscopy was performed but all testing was negative, including that for acid-fast bacilli (AFB) smear. The patient continued to become increasingly hypoxic, acidotic, and septic, and eventually underwent tracheostomy. Twenty days post-bronchoscopy, cultures from the bronchoalveolar fluid came back positive for Mycobacterium tuberculosis (MTB). A new sputum sample was sent and was found to be smear positive (2+ AFB) and MTB PCR positive. The patient was initiated on rifampin, isoniazid, pyrazinamide, and ethambutol therapy. Unfortunately, the patient continued to decompensate and was unable to be weaned off the ventilator. Comfort care was initiated by the family and the patient passed away on hospital day 68. Discussion The patient had several risk factors for latent TB reactivation, including malignancy, long-term corticosteroid use, and COVID-19 infection. Early research has shown that risk of death and recovery time with COVID-19 may be higher in patients with previous or active TB compared to those without. In patients with severe COVID-19 pneumonia and multiple risk factors for immunosuppression, latent TB reactivation should be considered in addition to secondary superinfection.

BACKGROUND: The objective of the study was to provide estimates of and risk factors for engagement in LTBI care in the overall U.S. population and among specific risk groups. METHODS: We used nationally representative data from 7,080 participants in the 2011-2012 National Health and Nutrition Examination Survey. Engagement in LTBI care was assessed by estimating the proportion with a history of testing, diagnosis, treatment initiation and treatment completion. Weighted methods were used to account for the complex survey design and to derive national estimates. RESULTS: Only 1.4 million (10%) of an estimated 14.0 million individuals with LTBI had previously completed treatment. Of the 12.6 million who did not complete LTBI treatment, 3.7 million (29%) had never been tested and 7.2 million (57%) received testing but had no history of diagnosis. High-risk groups showed low levels of engagement, including TB contacts and persons born outside the United States. CONCLUSIONS AND RELEVANCE: There is a reservoir of more than 12 million individuals in the U.S. who may be at risk for progression to TB disease and potential transmission. TB control programs and community providers should consider focused efforts to increase testing, diagnosis, and treatment for LTBI.

Rationale: Current diagnostic tests fail to identify individuals at higher risk of progression to tuberculosis disease, such as those with recent Mycobacterium tuberculosis infection, who should be prioritized for targeted preventive treatment. Objectives: To define a blood-based biomarker, measured with a simple flow cytometry assay, that can stratify different stages of tuberculosis infection to infer risk of disease. Methods: South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion 1 yr) infection. We defined the ΔHLA-DR median fluorescence intensity biomarker as the difference in HLA-DR expression between IFN-γ+ TNF+ Mycobacterium tuberculosis–specific T cells and total CD3+ T cells. Biomarker performance was assessed by blinded prediction in untouched test cohorts with recent versus persistent infection or tuberculosis disease and by unblinded analysis of asymptomatic adolescents with tuberculosis infection who remained healthy (nonprogressors) or who progressed to microbiologically confirmed disease (progressors). Measurements and Main Results: In the test cohorts, frequencies of Mycobacterium tuberculosis–specific T cells differentiated between QuantiFERON-TB− (n = 25) and QuantiFERON-TB+ (n = 47) individuals (area under the receiver operating characteristic curve, 0.94; 95% confidence interval, 0.87–1.00). ΔHLA-DR significantly discriminated between recent (n = 20) and persistent (n = 22) QuantiFERON-TB+ (0.91; 0.83–1.00); persistent QuantiFERON-TB+ and newly diagnosed tuberculosis (n = 19; 0.99; 0.96–1.00); and tuberculosis progressors (n = 22) and nonprogressors (n = 34; 0.75; 0.63–0.87). However, ΔHLA-DR median fluorescent intensity could not discriminate between recent QuantiFERON-TB+ and tuberculosis (0.67; 0.50–0.84). Conclusions: The ΔHLA-DR biomarker can identify individuals with recent QuantiFERON-TB conversion and those with disease progression, allowing targeted provision of preventive treatment to those at highest risk of tuberculosis. Further validation studies of this novel immune biomarker in various settings and populations at risk are warranted.

RATIONALE: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms but clarity on the optimal dosing approach is lacking. OBJECTIVES: In this individual participant data meta-analysis of rifapentine pharmacokinetics, we characterize rifapentine population pharmacokinetics, including autoinduction, and determine optimal dosing strategies for short-course rifapentine-based regimens for latent tuberculosis infection. METHODS: Rifapentine pharmacokinetic studies were identified though a systematic review of literature. Individual plasma concentrations were pooled, and non-linear mixed effects modeling was performed. A subset of data was reserved for external validation. Simulations were performed under various dosing conditions including current weight-based methods and alternative methods driven by identified covariates. MEASUREMENTS AND MAIN RESULTS: We identified 9 clinical studies with a total of 863 participants with pharmacokinetic data (n=4301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentration. The maximum effect was a 72% increase in clearance and was reached after 21 days. Drug bioavailability decreased by 27% with HIV infection, decreased by 28% with fasting, and increased by 49% with a high-fat meal. Body weight was not a clinically relevant predictor of clearance. Pharmacokinetic simulations showed that current weight-based dosing leads to lower exposures in low weight individuals, which can be overcome with flat dosing. In HIV-positive patients, 30% higher doses are required to match drug exposure in HIV-negative patients. CONCLUSIONS: Weight-based dosing of rifapentine should be removed from clinical guidelines and higher doses for HIV-positive patients should be considered to provide equivalent efficacy.

Rationale: The World Health Organization recommends the use of isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections. The recent rise of drug-resistant tuberculosis has complicated the choice of treatment regimen for latent tuberculosis infection.Objectives: To evaluate the effects of INH preventive therapy on the contacts of patients with multidrug-resistant tuberculosis.Methods: In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index patients with tuberculosis and 14,044 tuberculosis-exposed household contacts who we followed for 1 year for the occurrence of incident tuberculosis disease. Although Peruvian national guidelines specify that INH preventive therapy should be provided to contacts aged 19 years old or younger, only half this group received INH preventive therapy.Measurements and Main Results: Among 4,216 contacts under 19 years of age, 2,106 contacts (50%) initiated INH preventive therapy at enrollment. The protective effect of INH was more extreme in contacts exposed to drug-sensitive tuberculosis (adjusted hazard ratio, 0.30; 95% confidence interval, 0.18-0.48) and to multidrug-resistant tuberculosis (adjusted hazard ratio, 0.19; 95% confidence interval, 0.05-0.66) compared with those exposed to mono-INH-resistant tuberculosis (adjusted hazard ratio, 0.80; 95% confidence interval, 0.23-2.80). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received INH preventive therapy compared with 3% (8 of 273) of those who did not.Conclusions: Household contacts who received INH preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. INH may have a role in the management of latent multidrug-resistant tuberculosis infection.

RATIONALE: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. OBJECTIVES: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the tuberculin skin test (TST) might improve prediction of incident TB. METHODS: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by re-linkage to national TB surveillance records (median follow-up 4.7 years). Incidence rates and rate ratios, sensitivities, specificities and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior BCG). MEASUREMENTS AND MAIN RESULTS: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (p

RATIONALE: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy. OBJECTIVES: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H). METHODS: Data from reproductive-age (15–51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. RESULTS: Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13%–14%=−1%; 95% confidence interval = −17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% −5% = −5%; 95% confidence interval = −18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. CONCLUSIONS: Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Many aspects of pathogenic granuloma formation are poorly understood, requiring new relevant laboratory models that represent the complexity (genetics and diversity) of human disease. To address this need, we developed an in vitro model of granuloma formation using human peripheral blood mononuclear cells (PBMCs) derived from patients with active sarcoidosis, latent tuberculosis (TB) infection (LTBI), or normal healthy control subjects. PBMCs were incubated for 7 days with uncoated polystyrene beads or beads coated with purified protein derivative (PPD) or human serum albumin. In response to PPD-coated beads, PBMCs from donors with sarcoidosis and LTBI formed robust multicellular aggregates resembling granulomas, displaying a typical T-helper cell type 1 immune response, as assessed by cytokine analyses. In contrast, minimal PBMC aggregation occurred when control PBMCs were incubated with PPD-coated beads, whereas the response to uncoated beads was negligible in all groups. Sarcoidosis PBMCs responded to human serum albumin-coated beads with modest cellular aggregation and inflammatory cytokine release. Whereas the granuloma-like aggregates formed in response to PPD-coated beads were similar for sarcoidosis and LTBI, molecular profiles differed significantly. mRNA expression patterns revealed distinct pathways engaged in early granuloma formation in sarcoidosis and LTBI, and they resemble molecular patterns reported in diseased human tissues. This novel in vitro human granuloma model is proposed as a tool to investigate mechanisms of early granuloma formation and for preclinical drug discovery research of human granulomatous disorders. Clinical trial registered with www.clinicaltrials.gov (NCT01857401).

Immune cells of the distal airways serve as “first responders” of host immunity to the airborne pathogen Mycobacterium tuberculosis (Mtb). Mtb infection of cynomolgus macaques recapitulates the range of human outcomes from clinically silent latent tuberculosis infection (LTBI) to active tuberculosis of various degrees of severity. To further advance the application of this model to human studies, we compared profiles of bronchoalveolar lavage (BAL) cells of humans and cynomolgus macaques before and after Mtb infection. A simple gating strategy effectively defined BAL T-cell and phagocyte populations in both species. BAL from Mtb-naive humans and macaques showed similar differential cell counts. BAL T cells of macaques were composed of fewer CD4+cells but more CD8+ and CD4+CD8+ double-positive cells than were BAL T cells of humans. The most common mononuclear phagocyte population in BAL of both species displayed coexpression of HLA-DR, CD206, CD11b, and CD11c; however, multiple phagocyte subsets displaying only some of these markers were observed as well. Macaques with LTBI displayed a marked BAL lymphocytosis that was not observed in humans with LTBI. In macaques, the prevalence of specific mononuclear phagocyte subsets in baseline BAL correlated with ultimate outcomes of Mtb infection (i.e., LTBI versus active disease). Overall, these findings demonstrate the comparability of studies of pulmonary immunity to Mtb in humans and macaques. They also indicate a previously undescribed complexity of airway mononuclear phagocyte populations that suggests further lines of investigation relevant to understanding the mechanisms of both protection from and susceptibility to the development of active tuberculosis within the lung.