Characteristics of and Deaths among 333 Persons with Tuberculosis and COVID-19 in Cross-Sectional Sample from 25 Jurisdictions, United States.

Little is known about co-occurring tuberculosis (TB) and COVID-19 in low TB incidence settings. We obtained a cross-section of 333 persons in the United States co-diagnosed with TB and COVID-19 within 180 days and compared them to 4,433 persons with TB only in 2020 and 18,898 persons with TB during 2017‒2019. Across both comparison groups, a higher proportion of persons with TB-COVID-19 were Hispanic, were long-term care facility residents, and had diabetes. When adjusted for age, underlying conditions, and TB severity, COVID-19 co-infection was not statistically associated with death compared with TB infection only in 2020 (adjusted prevalence ratio 1.0 [95% CI 0.8‒1.4]). Among TB-COVID-19 patients, death was associated with a shorter interval between TB and COVID-19 diagnoses, older age, and being immunocompromised (non-HIV). TB-COVID-19 deaths in the United States appear to be concentrated in subgroups sharing characteristics known to increase risk for death from either disease alone.

Pulmonary Tuberculosis in Older Adults: Increased Mortality Related to Tuberculosis Within Two Months of Treatment Initiation.

BACKGROUND: The proportion of tuberculosis (TB) patients who are older adults is increasing worldwide. Nearly 60% of TB patients in Japan are 70 years or older, and the TB incidence rate in Japan is one of the highest among high-income countries. The previous TB treatment guidelines prior to 2018 in Japan recommended excluding pyrazinamide (PZA) from the initial regimen for patients aged over 80 years. OBJECTIVES: We aimed to examine differences in TB treatment outcomes among different age groups, and between those who received PZA and those who did not. METHODS: We performed a retrospective cohort study of patients with pulmonary TB who were managed at a single medical center in Japan. We compared treatment outcomes and adverse events that resulted in treatment interruption across the age groups. RESULTS: Of 246 patients, 117 (48%) were aged 75 years or older. Compared with patients aged < 74 years, those ≥ 75 years were less likely to have PZA in the initial regimen (53.0% vs 89.9%; p < 0.0001), more likely to die during treatment (38.5% vs 6.2%; p < 0.0001), and more likely to experience adverse events (30.8% vs 19.4%; p < 0.05). The mortality rate related to TB at 2 months after TB treatment initiation was 28% in those aged ≥ 84 years. Furthermore, among patients aged ≥ 84 years, those who did not receive PZA were significantly more likely to die than those who did (65.8% vs 36.8%; p < 0.05). CONCLUSIONS: Patients aged ≥ 75 years with pulmonary TB experienced increased mortality related to TB during treatment and more frequent adverse events than younger patients, even though PZA was often avoided among older patients.

Applying the 15 Public Health Emergency Preparedness Capabilities to Support Large-Scale Tuberculosis Investigations in Complex Congregate Settings.

Public Health-Seattle and King County, a metropolitan health department in western Washington, experiences rates of tuberculosis (TB) that are 1.6 times higher than are state and national averages. The department's TB Control Program uses public health emergency management tools and capabilities sustained with Centers for Disease Control and Prevention grant funding to manage large-scale complex case investigations. We have described 3 contact investigations in large congregate settings that the TB Control Program conducted in 2015 and 2016. The program managed the investigations using public health emergency management tools, with support from the Preparedness Program. The 3 investigations encompassed medical evaluation of more than 1600 people, used more than 100 workers, identified nearly 30 individuals with latent TB infection, and prevented an estimated 3 cases of active disease. These incidents exemplify how investments in public health emergency preparedness can enhance health outcomes in traditional areas of public health.

HLA-E Presents Glycopeptides from the Mycobacterium tuberculosis Protein MPT32 to Human CD8+ T cells.

Infection with Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis, remains a global health concern. Both classically and non-classically restricted cytotoxic CD8+ T cells are important to the control of Mtb infection. We and others have demonstrated that the non-classical MHC I molecule HLA-E can present pathogen-derived peptides to CD8+ T cells. In this manuscript, we identified the antigen recognized by an HLA-E-restricted CD8+ T cell clone isolated from an Mtb latently infected individual as a peptide from the Mtb protein, MPT32. Recognition by the CD8+ T cell clone required N-terminal O-linked mannosylation of MPT32 by a mannosyltransferase encoded by the Rv1002c gene. This is the first description of a post-translationally modified Mtb-derived protein antigen presented in the context of an HLA-E specific CD8+ T cell immune response. The identification of an immune response that targets a unique mycobacterial modification is novel and may have practical impact in the development of vaccines and diagnostics.

Jail Booking as an Occasion for HIV Care Reengagement: A Surveillance-Based Study.

OBJECTIVES: To examine population and HIV care outcomes of people living with HIV/AIDS (PLWHA) at their first incarceration of 2014 in 2 county jails in King County, Washington. METHODS: Using HIV surveillance data linked with jail booking data, we examined demographic information, viral loads, CD4 counts, and incarceration details for the period prior to jail booking, during incarceration, and year following jail release. RESULTS: In 2014, 202 PLWHA were incarcerated, 51% of whom were virally nonsuppressed at booking. This population represented approximately 3% of all HIV-diagnosed persons and 7% of virally nonsuppressed persons in King County. Within a year of release, 62% were virally suppressed, compared with 79% of the general HIV-diagnosed population in King County. CONCLUSIONS: Incarcerated PLWHA are disproportionately virally nonsuppressed compared with nonincarcerated PLWHA up to a year after release from jail. Public Health Implications. Coordination of health information exchange between the health department and jails could enhance public health efforts to improve the HIV care continuum.

Time From HIV Diagnosis to Viral Load Suppression: 2007-2013.

BACKGROUND: US guidelines now recommend that all HIV-infected persons receive antiretroviral therapy). HIV prevention is increasingly focused on ensuring that infected persons are diagnosed soon after HIV acquisition and quickly link to care and initiate antiretroviral therapy. We examined trends in time from HIV diagnosis to viral load suppression in King County, WA, to gauge improvement in our HIV care continuum over time. METHODS: We used HIV surveillance data and Cox proportional hazards to evaluate how the time from diagnosis to viral suppression changed among persons newly diagnosed as having HIV in King County, WA, between 2007 and 2013. RESULTS: A total of 1490 (84%) of 1766 newly diagnosed persons achieved viral suppression in a median time of 213 days (95% confidence interval, 203-229). Thirty-six percent of all persons diagnosed in 2007 and 77% in 2013 were virally suppressed within 12 months of HIV diagnosis (P < 0.0001). Differences in time to suppression by calendar year persisted when stratifying by CD4 count at diagnosis. Race was not significantly associated with time to viral suppression. CONCLUSIONS: Time from HIV diagnosis to viral suppression dramatically declined between 2007 and 2013, and more than three quarters of recently HIV-diagnosed individuals in King County, WA, now achieve viral suppression within a year of diagnosis. This improvement was evident among all persons newly diagnosed as having HIV, regardless of race/ethnicity or CD4 count at time of diagnosis.

Human lung epithelial cells contain Mycobacterium tuberculosis in a late endosomal vacuole and are efficiently recognized by CD8⁺ T cells.

Mycobacterium tuberculosis (Mtb) is transmitted via inhalation of aerosolized particles. While alveolar macrophages are thought to play a central role in the acquisition and control of this infection, Mtb also has ample opportunity to interact with the airway epithelium. In this regard, we have recently shown that the upper airways are enriched with a population of non-classical, MR1-restricted, Mtb-reactive CD8⁺ T cells (MAIT cells). Additionally, we have demonstrated that Mtb-infected epithelial cells lining the upper airways are capable of stimulating IFNγ production by MAIT cells. In this study, we demonstrate that airway epithelial cells efficiently stimulate IFNγ release by MAIT cells as well as HLA-B45 and HLA-E restricted T cell clones. Characterization of the intracellular localization of Mtb in epithelial cells indicates that the vacuole occupied by Mtb in epithelial cells is distinct from DC in that it acquires Rab7 molecules and does not retain markers of early endosomes such as Rab5. The Mtb vacuole is also heterogeneous as there is a varying degree of association with Lamp1 and HLA-I. Although the Mtb vacuole shares markers associated with the late endosome, it does not acidify, and the bacteria are able to replicate within the cell. This work demonstrates that Mtb infected lung epithelial cells are surprisingly efficient at stimulating IFNγ release by CD8⁺ T cells.

Peripheral CD4(+) T-cell tolerance is induced in vivo by rare antigen-bearing B cells in follicular, marginal zone, and B-1 subsets.

B cells are efficient APCs when they internalize antigen via BCR-mediated uptake. Adoptively transferred antigen-presenting B cells can induce T-cell tolerance to foreign and self antigens; however, it is unknown whether endogenous B cells presenting self-peptides interact with naïve T cells and contribute to peripheral T-cell self-tolerance. Moreover, the relative abilities of mature B-cell subsets to induce T-cell tolerance have not been examined. To address these questions, we created a new mouse model wherein a very small fraction of B cells expresses an antigen transgene that cannot be transferred to other APCs. We limited antigen expression to follicular, marginal zone, or B-1 B-cell subsets and found that small numbers of each subset interacted with naïve antigen-specific T cells. Although antigen expressed by B-1 B cells induced the most T-cell division, divided T cells subsequently disappeared from secondary lymphoid tissues. Independent of which B-cell subset presented antigen, the remaining T cells were rendered hypo-responsive, and this effect was not associated with Foxp3 expression. Our data show that physiologically relevant proportions of B cells can mediate peripheral T-cell tolerance, and suggest that the mechanisms of tolerance induction might differ among follicular, marginal zone, and B-1 B-cell subsets.

NF-κB­inducing kinase plays an essential T cell­intrinsic role in graft-versus-host disease and lethal autoimmunity in mice.

NF-κB­inducing kinase (NIK) is an essential upstream kinase in noncanonical NF-κB signaling. NIK-dependent NF-κB activation downstream of several TNF receptor family members mediates lymphoid organ development and B cell homeostasis. Peripheral T cell populations are normal in the absence of NIK, but the role of NIK during in vivo T cell responses to antigen has been obscured by other developmental defects in NIK-deficient mice. Here, we have identified a T cell­intrinsic requirement for NIK in graft-versus-host disease (GVHD), wherein NIK-deficient mouse T cells transferred into MHC class II mismatched recipients failed to cause GVHD. Although NIK was not necessary for antigen receptor signaling, it was absolutely required for costimulation through the TNF receptor family member OX40 (also known as CD134). When we conditionally overexpressed NIK in T cells, mice suffered rapid and fatal autoimmunity characterized by hyperactive effector T cells and poorly suppressive Foxp3(+) Tregs. Together, these data illuminate a critical T cell­intrinsic role for NIK during immune responses and suggest that its tight regulation is critical for avoiding autoimmunity.