Proteomic analysis of lung responses to SARS-CoV-2 infection in aged non-human primates: clinical and research relevance.

With devastating health and socioeconomic impact worldwide, much work is left to understand the Coronavirus Disease 2019 (COVID-19), with emphasis in the severely affected elderly population. Here, we present a proteomics study of lung tissue obtained from aged vs. young rhesus macaques (Macaca mulatta) and olive baboons (Papio Anubis) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using age as a variable, we identified common proteomic profiles in the lungs of aged infected non-human primates (NHPs), including key regulators of immune function, as well as cell and tissue remodeling, and discuss the potential clinical relevance of such parameters. Further, we identified key differences in proteomic profiles between both NHP species, and compared those to what is known about SARS-CoV-2 in humans. Finally, we explored the translatability of these animal models in the context of aging and the human presentation of the COVID-19.

Prevalence of non-communicable diseases among household contacts of people with tuberculosis: A systematic review and individual participant data meta-analysis.

OBJECTIVE: To investigate the prevalence of non-communicable diseases among household contacts of people with tuberculosis. METHODS: We conducted a systematic review and individual participant data meta-analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non-communicable disease among household contacts of people with clinical tuberculosis. We estimated the non-communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta-analyses. Furthermore, we compared age and sex-standardised non-communicable disease prevalence with national-level estimates standardised for age and sex. RESULTS: We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta-analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8% (95% confidence interval [CI], 5.1%-14.9%, four studies). Age-and sex-standardised prevalence was higher in two studies (10.4% vs. 6.9% and 11.5% vs. 8.4%) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self-report or medical records was 3.4% (95% CI 2.6%-4.6%, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta-analysis. There were limited data for other non-communicable diseases. CONCLUSION: The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non-communicable diseases and address shared risk factors.

Antigen specificity shapes antibody functions in tuberculosis.

Tuberculosis (TB) is the number one infectious disease cause of death worldwide due to an incomplete understanding of immunity. Emerging data highlight antibody functions mediated by the Fc domain as immune correlates. However, the mechanisms by which antibody functions impact the causative agent Mycobacterium tuberculosis (Mtb) are unclear. Here, we examine how antigen specificity determined by the Fab domain shapes Fc effector functions against Mtb. Using the critical structural and secreted virulence proteins Mtb cell wall and ESAT-6 & CFP-10, we observe that antigen specificity alters subclass, antibody post-translational glycosylation, and Fc effector functions in TB patients. Moreover, Mtb cell wall IgG3 enhances disease through opsonophagocytosis of extracellular Mtb . In contrast, polyclonal and a human monoclonal IgG1 we generated targeting ESAT-6 & CFP-10 inhibit intracellular Mtb . These data show that antibodies have multiple roles in TB and antigen specificity is a critical determinant of the protective and pathogenic capacity.

High all-cause mortality and increasing proportion of older adults with tuberculosis in Texas, 2008-2020.

Pulmonary tuberculosis (PTB) elimination efforts must consider the global growth of the ageing population. Here we used TB surveillance data from Texas, United States (2008-2020; total n = 10656) to identify unique characteristics and outcomes in older adults (OA, ≥65 years) with PTB, compared to young adults (YA, 18-39 years) or middle-aged adults (40-64 years). We found that the proportion of OA with PTB increased from 15% in 2008 to 24% in 2020 (trend p < 0.05). Diabetes was highly prevalent in OA (32%) but not associated with adverse outcomes. Death was 13-fold higher in OA compared to YA and was 7% at the time of diagnosis which suggests diagnostic delays. However, once TB was suspected, we found no differences in culture, smear, or nucleic acid detection of mycobacteria (although less lung cavitations) in OA. During treatment, OA had less drug-resistant TB, few adverse reactions and adhered with TB treatment. We recommend training healthcare workers to 'think TB' in OA, for prompt treatment initiation to diminish deaths. Furthermore, OA should be added as a priority group to the latent TB treatment guidelines by the World Health Organization, to prevent TB disease in this highly vulnerable group.

Interaction between type 2 diabetes and past COVID-19 on active tuberculosis.

BACKGROUND: The global setback in tuberculosis (TB) prevalence and mortality in the post-COVID-19 era have been partially attributed to pandemic-related disruptions in healthcare systems. The additional biological contribution of COVID-19 to TB is less clear. The goal of this study was to determine if there is an association between COVID-19 in the past 18 months and a new TB episode, and the role played by type 2 diabetes mellitus (DM) comorbidity in this relationship. METHODS: A cross-sectional study was conducted among 112 new active TB patients and 373 non-TB controls, identified between June 2020 and November 2021 in communities along the Mexican border with Texas. Past COVID-19 was based on self-report or positive serology. Bivariable/multivariable analysis were used to evaluate the odds of new TB in hosts with past COVID-19 and/or DM status. RESULTS: The odds of new TB were higher among past COVID-19 cases vs. controls, but only significant among DM patients (aOR 2.3). The odds of TB given DM was 2.7-fold among participants without past COVID-19 and increased to 7.9-fold among those with past COVID-19. CONCLUSION: DM interacts with past COVID-19 synergistically to magnify the risk of TB. Latent TB screening and prophylactic treatment, if positive, is recommended in this COVID-19/DM/latent TB high-risk group.

Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis intracellular growth and translocation into the cytosol of alveolar epithelial cells.

The elderly population is highly susceptible to developing respiratory diseases, including tuberculosis, a devastating disease caused by the airborne pathogen Mycobacterium tuberculosis (M.tb) that kills one person every 18 seconds. Once M.tb reaches the alveolar space, it contacts alveolar lining fluid (ALF), which dictates host-cell interactions. We previously determined that age-associated dysfunction of soluble innate components in human ALF leads to accelerated M.tb growth within human alveolar macrophages. Here we determined the impact of human ALF on M.tb infection of alveolar epithelial type cells (ATs), another critical lung cellular determinant of infection. We observed that elderly ALF (E-ALF)-exposed M.tb had significantly increased intracellular growth with rapid replication in ATs compared to adult ALF (A-ALF)-exposed bacteria, as well as a dampened inflammatory response. A potential mechanism underlying this accelerated growth in ATs was our observation of increased bacterial translocation into the cytosol, a compartment that favors bacterial replication. These findings in the context of our previous studies highlight how the oxidative and dysfunctional status of the elderly lung mucosa determines susceptibility to M.tb infection, including dampening immune responses and favoring bacterial replication within alveolar resident cell populations, including ATs, the most abundant resident cell type within the alveoli.

Tuberculosis presentation and outcomes in older Hispanic adults from Tamaulipas, Mexico.

Older people are at high risk of developing and dying from pulmonary infections like tuberculosis (TB), but there are few studies among them, particularly in Hispanics. To address these gaps, we sought to identify host factors associated with TB and adverse treatment outcomes in older Hispanics by conducting a cross-sectional study of TB surveillance data from Tamaulipas, Mexico (2006-2013; n = 8381). Multivariable logistic regressions were assessed for older adults (OA ≥65 years) when compared to young (YA, 18-39 years) and middle-aged adults (40-64 years). We found that the OA had features associated with a less complicated TB (e.g., lower prevalence of extra-pulmonary TB and less likely to abandon treatment or have drug resistant TB), and yet, were more likely to die during TB treatment (adj-OR 3.9, 95% 2.5, 5.25). Among the OA, excess alcohol use and low body mass index increased their odds of death during TB treatment, while a higher number of reported contacts (social support) was protective. Diabetes was not associated with adverse outcomes in OA. Although older age is a predictor of death during TB disease, OA are not prioritized by the World Health Organization for latent TB infection screening and treatment during contact investigations. With safer, short-course latent TB infection treatment available, we propose the inclusion of OA as a high-risk group in latent TB management guidelines.

Human alveolar macrophage response to Mycobacterium tuberculosis: immune characteristics underlying large inter-individual variability.

Background: Mycobacterium tuberculosis (M.tb), the causative bacterium of tuberculosis (TB), establishes residence and grows in human alveolar macrophages (AMs). Inter-individual variation in M.tb-human AM interactions can indicate TB risk and the efficacy of therapies and vaccines; however, we currently lack an understanding of the gene and protein expression programs that dictate this variation in the lungs. Results: Herein, we systematically analyze interactions of a virulent M.tb strain H37Rv with freshly isolated human AMs from 28 healthy adult donors, measuring host RNA expression and secreted candidate proteins associated with TB pathogenesis over 72h. A large set of genes possessing highly variable inter-individual expression levels are differentially expressed in response to M.tb infection. Eigengene modules link M.tb growth rate with host transcriptional and protein profiles at 24 and 72h. Systems analysis of differential RNA and protein expression identifies a robust network with IL1B, STAT1, and IDO1 as hub genes associated with M.tb growth. RNA time profiles document stimulation towards an M1-type macrophage gene expression followed by emergence of an M2-type profile. Finally, we replicate these results in a cohort from a TB-endemic region, finding a substantial portion of significant differentially expressed genes overlapping between studies. Conclusions: We observe large inter-individual differences in bacterial uptake and growth, with tenfold variation in M.tb load by 72h.The fine-scale resolution of this work enables the identification of genes and gene networks associated with early M.tb growth dynamics in defined donor clusters, an important step in developing potential biological indicators of individual susceptibility to M.tb infection and response to therapies.

Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.

Macrophages are the preeminent phagocytic cells which control multiple infections. Tuberculosis a leading cause of death in mankind and the causative organism Mycobacterium tuberculosis (MTB) infects and persists in macrophages. Macrophages use reactive oxygen and nitrogen species (ROS/RNS) and autophagy to kill and degrade microbes including MTB. Glucose metabolism regulates the macrophage-mediated antimicrobial mechanisms. Whereas glucose is essential for the growth of cells in immune cells, glucose metabolism and its downsteam metabolic pathways generate key mediators which are essential co-substrates for post-translational modifications of histone proteins, which in turn, epigenetically regulate gene expression. Herein, we describe the role of sirtuins which are NAD+-dependent histone histone/protein deacetylases during the epigenetic regulation of autophagy, the production of ROS/RNS, acetyl-CoA, NAD+, and S-adenosine methionine (SAM), and illustrate the cross-talk between immunometabolism and epigenetics on macrophage activation. We highlight sirtuins as emerging therapeutic targets for modifying immunometabolism to alter macrophage phenotype and antimicrobial function.

Differential Role of Type 2 Diabetes as a Risk Factor for Tuberculosis in the Elderly versus Younger Adults.

The elderly are understudied despite their high risk of tuberculosis (TB). We sought to identify factors underlying the lack of an association between TB and type 2 diabetes (T2D) in the elderly, but not adults. We conducted a case-control study in elderly (≥65 years old; ELD) vs. younger adults (young/middle-aged adults (18-44/45-64 years old; YA|MAA) stratified by TB and T2D, using a research study population (n = 1160) and TB surveillance data (n = 8783). In the research study population the adjusted odds ratio (AOR) of TB in T2D was highest in young adults (AOR 6.48) but waned with age becoming non-significant in the elderly. Findings were validated using TB surveillance data. T2D in the elderly (vs. T2D in younger individuals) was characterized by better glucose control (e.g., lower hyperglycemia or HbA1c), lower insulin resistance, more sulphonylureas use, and features of less inflammation (e.g., lower obesity, neutrophils, platelets, anti-inflammatory use). We posit that differences underlying glucose dysregulation and inflammation in elderly vs. younger adults with T2D, contribute to their differential association with TB. Studies in the elderly provide valuable insights into TB-T2D pathogenesis, e.g., here we identified insulin resistance as a novel candidate mechanism by which T2D may increase active TB risk.

Novel Automation of an Enzyme-Linked Immunosorbent Spot Assay Testing Method: Comparable Diagnostic Performance of the T-SPOT.TB Test Using Manual Density Gradient Cell Isolation versus Automated Positive Selection with the T-Cell Select Kit.

The diagnosis of latent tuberculosis (TB) infection (LTBI) is critical to improve TB treatment and control, and the T-SPOT.TB test is a commercial enzyme-linked immunosorbent spot assay used for this purpose. The objective of the study was to increase automation and extend the time between blood collection and processing for the T-SPOT.TB test from 0 to 8 h to 0 to 54 h. The previous maximum time between blood collection and processing for the T-SPOT.TB test is 32 h using T-Cell Xtend. For this, we compared the T-SPOT.TB test using manual peripheral blood mononuclear cell (PBMC) isolation by density gradient separation at 0 to 8 h (reference method, control arm) to an automated PBMC isolation method using magnetic beads (T-Cell Select kit) at 0 to 55 h postcollection. A total of 620 subjects were enrolled from 4 study sites, and blood samples were collected from each volunteer, comprising 1,850 paired samples in total. Overall agreement between both methods was 96.8% (confidence interval [CI], 95.9 to 97.6%), with 95.8% (CI, 93.5 to 97.5%) positive and 97.1% negative agreement (CI, 96.1 to 97.9%). In summary, there was a strong overall agreement between the automated and manual T-SPOT.TB test processing methods. The results suggest that the T-SPOT.TB test can be processed using automated positive selection with magnetic beads using T-Cell Select to decrease hands-on time. Also, this cell isolation method allowed for the time between blood collection and processing to range from 0 to 55 h. Additional studies in larger and diverse patient populations including immunocompromised and pediatric patients are needed.

Multi-OMICs analysis reveals metabolic and epigenetic changes associated with macrophage polarization.

Macrophages (MФ) are an essential immune cell for defense and repair that travel to different tissues and adapt based on local stimuli. A critical factor that may govern their polarization is the crosstalk between metabolism and epigenetics. However, simultaneous measurements of metabolites, epigenetics, and proteins (phenotype) have been a major technical challenge. To address this, we have developed a novel triomics approach using mass spectrometry to comprehensively analyze metabolites, proteins, and histone modifications in a single sample. To demonstrate this technique, we investigated the metabolic-epigenetic-phenotype axis following polarization of human blood-derived monocytes into either 'proinflammatory M1-' or 'anti-inflammatory M2-' MФs. We report here a complex relationship between arginine, tryptophan, glucose, and the citric acid cycle metabolism, protein and histone post-translational modifications, and human macrophage polarization that was previously not described. Surprisingly, M1-MФs had globally reduced histone acetylation levels but high levels of acetylated amino acids. This suggests acetyl-CoA was diverted, in part, toward acetylated amino acids. Consistent with this, stable isotope tracing of glucose revealed reduced usage of acetyl-CoA for histone acetylation in M1-MФs. Furthermore, isotope tracing also revealed MФs uncoupled glycolysis from the tricarboxylic acid cycle, as evidenced by poor isotope enrichment of succinate. M2-MФs had high levels of kynurenine and serotonin, which are reported to have immune-suppressive effects. Kynurenine is upstream of de novo NAD+ metabolism that is a necessary cofactor for Sirtuin-type histone deacetylases. Taken together, we demonstrate a complex interplay between metabolism and epigenetics that may ultimately influence cell phenotype.

The Impact of Aging on the Lung Alveolar Environment, Predetermining Susceptibility to Respiratory Infections.

Respiratory infections are one of the top causes of death in the elderly population, displaying susceptibility factors with increasing age that are potentially amenable to interventions. We posit that with increasing age there are predictable tissue-specific changes that prevent the immune system from working effectively in the lung. This mini-review highlights recent evidence for altered local tissue environment factors as we age focusing on increased tissue oxidative stress with associated immune cell changes, likely driven by the byproducts of age-associated inflammatory disease. Potential intervention points are presented.

Tuberculosis Phenotypic and Genotypic Drug Susceptibility Testing and Immunodiagnostics: A Review.

Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.

Antibody-Mediated LILRB2-Receptor Antagonism Induces Human Myeloid-Derived Suppressor Cells to Kill Mycobacterium tuberculosis.

Tuberculosis is a leading cause of death in mankind due to infectious agents, and Mycobacterium tuberculosis (Mtb) infects and survives in macrophages (MФs). Although MФs are a major niche, myeloid-derived suppressor cells (MDSCs) are an alternative site for pathogen persistence. Both MФs and MDSCs express varying levels of leukocyte immunoglobulin-like receptor B (LILRB), which regulate the myeloid cell suppressive function. Herein, we demonstrate that antagonism of LILRB2 by a monoclonal antibody (mab) induced a switch of human MDSCs towards an M1-macrophage phenotype, increasing the killing of intracellular Mtb. Mab-mediated antagonism of LILRB2 alone and its combination with a pharmacological blockade of SHP1/2 phosphatase increased proinflammatory cytokine responses and phosphorylation of ERK1/2, p38 MAPK, and NF-kB in Mtb-infected MDSCs. LILRB2 antagonism also upregulated anti-mycobacterial iNOS gene expression and an increase in both nitric oxide and reactive oxygen species synthesis. Because genes associated with the anti-mycobacterial function of M1-MФs were enhanced in MDSCs following mab treatment, we propose that LILRB2 antagonism reprograms MDSCs from an immunosuppressive state towards a pro-inflammatory phenotype that kills Mtb. LILRB2 is therefore a novel therapeutic target for eradicating Mtb in MDSCs.

Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis.

Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB.

Human Macrophages Exhibit GM-CSF Dependent Restriction of Mycobacterium tuberculosis Infection via Regulating Their Self-Survival, Differentiation and Metabolism.

GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1ß, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.

The Aging Human Lung Mucosa: A Proteomics Study.

The older adult population, estimated to double by 2050, is at increased risk of respiratory infections and other pulmonary diseases. Biochemical changes in the lung alveolar lining fluid (ALF) and in alveolar compartment cells can alter local immune responses as we age, generating opportunities for invading pathogens to establish successful infections. Indeed, the lung alveolar space of older adults is a pro-inflammatory, pro-oxidative, dysregulated environment that remains understudied. We performed an exploratory, quantitative proteomic profiling of the soluble proteins present in ALF, developing insight into molecular fingerprints, pathways, and regulatory networks that characterize the alveolar space in old age, comparing it to that of younger individuals. We identified 457 proteins that were significantly differentially expressed in older adult ALF, including increased production of matrix metalloproteinases, markers of cellular senescence, antimicrobials, and proteins of neutrophilic granule origin, among others, suggesting that neutrophils in the lungs of older adults could be potential contributors to the dysregulated alveolar environment with increasing age. Finally, we describe a hypothetical regulatory network mediated by the serum response factor that could explain the neutrophilic profile observed in the older adult population.

South to North Migration Patterns of Tuberculosis Patients Diagnosed in the Mexican Border with Texas.

The Mexican state of Tamaulipas serves as a migration waypoint into the US. Here, we determined the contribution of immigrants to TB burden in Tamaulipas. TB surveillance data from Tamaulipas (2006-2013) was used to conduct a cross-sectional characterization of TB immigrants (born outside Tamaulipas) and identify their association with TB treatment outcomes. Immigrants comprised 30.8% of TB patients, with > 99% originating from internal Mexican migration. Most migration was from South to North, with cities adjacent to the US border as destinations. Immigrants had higher odds of risk factors for TB [older age (≥ 65 year old, OR 2.4, 95% CI 2.1, 2.8), low education (OR 1.3, 95% CI 1.2, 1.4), diabetes (OR 1.2, 95% CI 1.1, 1.4)], or abandoning treatment (adjusted OR 1.2, 95% CI 1.0, 1.5). There is a need to identify strategies to prevent TB more effectively in Tamaulipas, a Mexican migration waypoint.

COVID-19 and chronic diabetes: the perfect storm for reactivation tuberculosis?: a case series.

BACKGROUND: The coronavirus disease 2019 pandemic is predicted to have a net negative effect on tuberculosis control, with an estimated excess of 6.3 million tuberculosis cases and 1.4 million deaths by 2025. Programmatic issues such as the lockdown of tuberculosis services affect all patients, while biosocial factors have a differential impact on an individual's risk for tuberculosis or adverse tuberculosis outcomes. CASE PRESENTATION: We report three Hispanic cases of incident tuberculosis (two males, 43 and 44 years old; one female, 49 years old) after resolution of coronavirus disease episodes. Coincidentally, all cases shared a common risk factor: a chronic history poorly controlled diabetes. CONCLUSIONS: Our findings alert to the threat posed by the synergy between coronavirus disease and diabetes, on tuberculosis reactivation. In medium- to high-risk settings for tuberculosis, we recommend implementation of routine screening for latent tuberculosis infection in these cases, and preventive tuberculosis treatment in those who are positive.