TBC and COVID: an interplay between two infections.

INTRODUCTION: In a historical era dominated by the SARS-CoV-2 pandemic, a fact of growing interest emerges regarding co-infection with Mycobacterium tuberculosis (M. tuberculosis). This represents today an important clinical and diagnostic challenge, as the two pathogens are capable, through specific immunopathological mechanisms, of interacting with each other, determining a severe respiratory condition with a severe prognosis. AREAS COVERED: With this review, we wanted to collect and analyze the latest scientific evidence concerning the main immunopathogenetic mechanisms shared by these two respiratory pathogens, with particular interest in the possible iatrogenic factors favoring coinfection and the need to define multidisciplinary and standardized screening tools aimed to identify coinfection early, ensuring the best clinical and therapeutic management. EXPERT OPINION: The existence of a direct immunopathogenetic link between COVID-19 and TB indirectly contributes to mutual morbidity and mortality. The identification and application of early and standardized screening tools aimed at the identification of this condition is essential, in addition to vaccine prevention.

Impact of SARS-CoV-2 infection on tuberculosis outcome and follow-up in Italy during the first COVID-19 pandemic wave: a nationwide online survey.

Background: SARS-CoV-2 pandemic affected tuberculosis (TB) management. This Italian nationwide survey assessed COVID-19 impact on TB care and outcomes. Materials and methods: Twenty-one hospitals or referral centres fulfilled an online survey. Primary objective was to describe clinical features, outcomes and retention in care in subjects with latent TB infection (LTBI) or disease over the first wave of COVID-19 pandemic. Secondary objectives were the assessment of risk factors, co-morbidities, diagnostics, radiological findings, and outcomes of COVID-19 in the study population. Results: 254 patients with LTBI or active TB were included. In co-infected (SARS-CoV-2, LTBI/TB) patients, recovery occurred in 29/32 (90.6%) cases, death in one case. High retention in care was preserved. Conclusion: in our cohort, outcomes did not seem to be adversely conditioned by incident COVID-19.

The Pitfalls of Mining for QuantiFERON Gold in Severely Ill Patients With COVID-19.

Objective: To assess the proportion of indeterminate QuantiFERON-TB Gold Plus (QFT-Plus) results in patients admitted for severe coronavirus disease 2019 (COVID-19) pneumonia and evaluate the factors associated with indeterminate QFT-Plus results. Patients and Methods: Data on COVID-19 admissions at Mayo Clinic in Florida were extracted between October 13, 2020, and September 20, 2021, and data from a prepandemic cohort were extracted between October 13, 2018, and September 20, 2019. A secondary analysis of the COVID-19 cohort was performed using gradient boosting modeling to generate variable importance and SHapley Additive exPlanations plots. Results: Our findings demonstrated more indeterminate QFT-Plus test results in patients hospitalized for severe COVID-19 infection than in patients without COVID-19 (139 of 495, 28.1%). The factors associated with indeterminate QFT-Plus test results included elevated levels of C-reactive protein, ferritin, lactate dehydrogenase and interleukin-6 and included lower levels of leukocyte, lymphocyte, and platelet counts. Conclusion: The patients with severe COVID-19 had a higher likelihood of indeterminate QFT-Plus results, which were associated with elevated levels of inflammatory markers consistent with severe infection. Interferon-gamma release assay screening tests are likely confounded by COVID-19 infection itself, limiting the screening ability for latent tuberculosis infection reactivation. Indeterminate QFT-Plus results may also require follow-up QFT-Plus testing after patient recovery from COVID-19, increasing the cost and complexity of medical decision making and management. Additional risk assessments may be needed in this patient population for screening for latent tuberculosis infection in patients with severe COVID-19.

Higher BCG-induced trained immunity prevalence predicts protection from COVID-19: Implications for ongoing BCG trials.

Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their Bacillus-Calmette-Guérin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous 'trained immunity' (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI in populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (24), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences (r(24): -0.79 to -0.57; p-value < .004), mortality (r(24): -0.63 to -0.45; p-value < .03), and interim case fatality rates (i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing or planned randomized controlled trials should consciously consider including measures of TI as: (a) all individuals immunized do not respond equally, (b) small study groups from higher background TI could fail to indicate any protective effect.

Tuberculosis and COVID-19: A combined global threat to human civilization.

A new era has begun with the discovery of SARS-CoV-2 in a seafood market in Wuhan, China. The SARS-CoV-2 outbreak has wreaked havoc on health systems and generated worldwide attention. The world's attention was diverted from the treatment of the leading chronic infectious illness, Mycobacterium tuberculosis. The similarities in the performance of the two infectious species had obvious repercussions. Administrative efforts to combat SARS-CoV-2 have weakened the tuberculosis control chain. As a result, progress against tuberculosis has slowed. Thus, the goal of this review is to examine the impact of SARS- CoV-2 on a chronic public health issue: tuberculosis.

Effect of SARS-CoV-2 seropositivity on antigen - specific cytokine and chemokine responses in latent tuberculosis.

SARS-CoV-2 and latent Mycobacterium tuberculosis infection are both highly co-prevalent in many parts of the globe. Whether exposure to SARS-CoV-2 influences the antigen specific immune responses in latent tuberculosis has not been investigated. We examined the baseline, mycobacterial antigen and mitogen induced cytokine and chemokine responses in latent tuberculosis (LTBI) individuals with or without SARS-CoV-2 seropositivity, LTBI negative individuals with SARS-CoV-2 seropositivity and healthy control (both LTBI and SARS-CoV-2 negative) individuals. Our results demonstrated that LTBI individuals with SARS-CoV-2 seropositivity (LTBI+/IgG +) were associated with increased levels of unstimulated and TB-antigen stimulated IFNγ, IL-2, TNFα, IL-17, IL-1ß, IL-6, IL-12, IL-4, CXCL1, CXCL9 and CXCL10 when compared to those without seropositivity (LTBI+/IgG-). In contrast, LTBI+/IgG+ individuals were associated with decreased levels of IL-5 and IL-10. No significant difference in the levels of cytokines/chemokines was observed upon mitogen stimulation between the groups. SARS-CoV-2 seropositivity was associated with enhanced unstimulated and TB-antigen stimulated but not mitogen stimulated production of cytokines and chemokines in LTBI+ compared to LTBI negative individuals. Finally, most of these significant differences were not observed when LTBI negative individuals with SARS-CoV-2 seropositivity and controls were examined. Our data clearly demonstrate that both baseline and TB - antigen induced cytokine responses are augmented in the presence of SARS-CoV-2 seropositivity, suggesting an augmenting effect of prior SARS-CoV-2 infection on the immune responses of LTBI individuals.

Impact of Latent Tuberculosis on Severity and Outcomes in Admitted COVID-19 Patients.

Background There is limited data on coronavirus disease 2019 (COVID-19) and latent tuberculosis infection (LTBI). Methodology We analyzed data of admitted COVID-19 patients evaluated for LTBI to examine the impact of LTBI on severity, laboratory parameters, and COVID-19 outcome. Prospectively collected data were analyzed for 60 patients who were administered the Mantoux tuberculosis skin test (TST) using five tuberculin units of purified protein derivative. All patients were administered TST irrespective of Bacille Calmette-Guérin (BCG) vaccination status. Comorbidities, clinical features, radiologic involvement, laboratory parameters, and clinical course were analyzed concerning LTBI. Results The mean age was 45.9 (±15.2) years, and 35 (58.3%) patients had non-severe disease. The vast majority (n = 56/60; 93.3%) had been vaccinated with single-dose BCG in infancy or early childhood, as per national immunization guidelines. LTBI was diagnosed in 15 (25%) patients. LTBI prevalence was lower in severe (n = 1/25; 4%) than non-severe (n = 14/35; 40%) COVID-19 (p = 0.01) patients. LTBI patients had lower percentage neutrophil count, higher lymphocyte percentage, higher monocyte count, lower neutrophil-lymphocyte (NL) ratio, lower alanine aminotransferase, lower C-reactive protein, and lesser radiologic involvement compared to those without LTBI (p < 0.05). Similarly, among the mild COVID-19 subgroup, those with LTBI had higher lymphocyte and monocyte counts and lesser radiologic involvement than those without LTBI (p < 0.05). Conclusions LTBI patients appear to have milder disease, higher lymphocyte and monocyte count, higher NL ratio, and lesser radiographic involvement. This observation needs to be studied in larger studies using interferon release assays.

Latent tuberculosis co-infection is associated with heightened levels of humoral, cytokine and acute phase responses in seropositive SARS-CoV-2 infection.

OBJECTIVES: Latent Tuberculosis infection (LTBI) is postulated to modulate immune responses and alter disease severity in SARS-CoV-2 co-infection. However, no data exist on the effect of LTBI on the immune responses in SARS-CoV-2 co-infected individuals. METHODS: We examined the SARS-CoV-2 specific antibody responses, plasma cytokines, chemokines, acute phase proteins and growth factor levels in LTBI positive and negative individuals with SARS-CoV-2 infection. RESULTS: Our results demonstrated that individuals with LTBI (LTBI+) and seropositive for SARS-CoV-2 infection were associated with elevated SARS-CoV-2 specific IgM, IgG and IgA antibodies, as well as enhanced neutralization activity compared to those negative for LTBI (LTBI-) individuals. Our results also demonstrate that LTBI+ individuals exhibited significantly higher plasma levels of IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IL-6, IL-12, IL-15, IL-17, IL-3, GM-CSF, IL-10, IL-25, IL-33, CCL3 and CXCL10 compared to LTBI- individuals. Finally, our results show that LTBI+ individuals exhibit significantly higher levels of C-reactive protein, alpha-2 macroglobulin, VEGF and TGFα compared to LTBI- individuals. CONCLUSIONS: Thus, our data clearly demonstrates that LTBI+ individuals seropositive for SARS-CoV-2 infection exhibit heightened levels of humoral, cytokine and acute phase responses compared to LTBI- individuals. Thus, LTBI is associated with modulation of antibody and cytokine responses as well as systemic inflammation in individuals seropositive for SARS-CoV-2 infection.

Latent Tuberculosis Infection among Health Workers in Germany-A Retrospective Study on Progression Risk and Use of Preventive Therapy.

Despite the decline in tuberculosis incidence (TB) in Germany, health workers (HW) are at greater risk of becoming infected with Mycobacterium tuberculosis. To date, little is known about the risk of progression of latent tuberculosis infections (LTBI) and the use of Tuberculosis Preventive Therapy (TPT) among HW. Routine data from the German Statutory Institution for Accident Insurance and Prevention for Health and Welfare Services (BGW) were analysed and a retrospective survey was conducted. A self-administered questionnaire was sent to 1711 HW who had received recognition of an LTBI as an occupational disease between the years 2009 and 2018. The response rate was 42.3% after correcting for those with no actual address (20.4%). We included 575 HW in the data analysis of the retrospective survey. The cumulative incidence of progression, the incidence density and the associated 95% confidence interval (95% CI) were calculated. Three progressive cases were identified in the analysis of the routine data. In the survey cohort, three HW developed TB during the observation period of 5.4 years on average (standard deviation: 2.8 years; interquartile range: 5.0 years). The cumulative TB incidence was 0.52% in the survey group (95% CI: 0.14% to 1.65%). The incidence density was 0.97 cases per 1000 person years (95% CI: 0.25 to 3.10). One-third of the respondents underwent TPT. Significant differences were observed between age and activity groups in the use of TPT, but not between the genders, year of diagnosis or the reason for performing the screening. The data indicate that the risk of progression of an LTBI is low for HW. However, one-third of the HW had undergone TPT. Information about the expected progression risk is important so that it can be weighed against the risk of side effects of TPT.

The paradigm shift in the approach to management of latent tuberculosis infection in high tuberculosis burden countries.

Introduction: Addressing the reservoir of Latent Tuberculosis Infection (LTBI) is critical to TB elimination because if left untreated LTBI can progress to active TB disease. This additional burden can prevent achieving the global targets of TB elimination. Management of LTBI has been a low priority target for National TB Elimination Programs (NTEP) due to various challenges in the field settings.Areas covered: This article reviews the most recent advances in the field of LTBI management including newer diagnostics, treatments, vaccines, programmatic challenges, and gaps and suggests a way forward that can be adopted by NTEPs for LTBI. We searched the electronic databases of PubMed, Scopus, and Web of Science for studies published between 2010 to 2020 using MeSH terms: Latent TB Diagnosis, TB preventive therapy, Vaccines, LTBI, and HIV/ COVID.Expert opinion: NTEPs of developing countries should offer a better, point-of-care diagnostic, and effective treatment for LTBI to reduce the number of new TB cases arising from people infected with M.tb. Awareness about LTBI should be increased among the health system staff and the public. More funding is needed to advance research as well as implement the newer findings in the NTEP to achieve the End TB targets by 2035.