Economic evaluation of microbiological and host biomarker-based tests for the diagnosis of pleural tuberculosis in a high burden setting.

Background: Pleural tuberculosis (TB) remains difficult to diagnose. Tests measuring host biomarkers, such as adenosine deaminase (ADA) and unstimulated interferon-gamma, perform better than conventional microbiological tests for TB diagnosis using pleural fluid. However, there is no data on the cost-effectiveness of these diagnostic approaches. Methods: A cost-consequence analysis was performed from the South African healthcare provider perspective to determine the cost-effectiveness of the following strategies for the diagnosis of pleural TB: (I) Smear microscopy (SM); (II) Mycobacterial-Growth-In-Tube liquid culture (MGIT); (III) adenosine deaminase (ADA); (IV) Xpert ULTRA (Xpert); (V) unstimulated interferon-gamma using IRISA-TB™ (IRISA-TB). Costs (2019 USD) were derived from national sources and outcomes from published literature. Cost-effectiveness was expressed as the cost per pleural TB case diagnosed and initiated on treatment (per 1,000 patients screened). Sensitivity analyses were performed. Results: Total strategy costs ranged from $354,632 (SM) to $390,363 (ADA). Strategies incorporating highly specific tests, including IRISA-TB and Xpert, had the lowest costs associated with unnecessary treatment. In terms of outcomes (per 1,000 screened), IRISA-TB and ADA correctly identified the most pleural TB cases (8.4 and 8.0 cases, respectively), almost double that of MGIT (4.2 cases) and Xpert ULTRA (3.7 cases). IRISA-TB was the most cost-effective strategy, as the cost per pleural TB patient diagnosed and initiated on treatment was $44,084, ~$5,000 less than ADA (the second most cost-effective strategy; $49,065). These values were most sensitive to changes in pleural TB prevalence, treatment costs, and empirical treatment rates. The cost difference, compared to ADA, equated to a potential saving of ~US$45 million per year in South Africa. Conclusions: IRISA-TB offers good value for money and is a potentially more cost-effective alternative to ADA for pleural TB diagnosis.

Interleukin-4 Responsive Dendritic Cells Are Dispensable to Host Resistance Against Leishmania mexicana Infection.

IL-4 and IL-13 cytokines have been associated with a non-healing phenotype in murine leishmaniasis in L. mexicana -infected BALB/c mice as demonstrated in IL-4-/-, IL-13-/- and IL-4Rα-/- global knockout mouse studies. However, it is unclear from the studies which cell-type-specific IL-4/IL-13 signaling mediates protection to L. mexicana. Previous studies have ruled out a role for IL-4-mediated protection on CD4+ T cells during L. mexicana infections. A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4Rα on CD11c+ DCs (CD11ccreIL-4Rα-/lox) were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control. Our results show that CL disease progression in BALB/c mice is independent of IL-4Rα signaling on DCs as CD11ccreIL-4Rα-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-γ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, surprisingly, IL-4 production in CD11ccreIL-4Rα-/lox mice was significantly increased with an increasing trend of IL-13 when compared to littermate controls. Moreover, the absence of IL-4Rα signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4Rα-/lox mice due to greater total cell infiltration into the lymph node. A similar trend was observed for B cells whereas the recruitment of myeloid populations (macrophages, DCs, neutrophils, and Mo-DCs) into LN was comparable to littermate IL-4Rα-/lox mice. Interestingly, IL-4Rα-deficient bone marrow-derived dendritic cells (BMDCs), stimulated with LPS or L. mexicana promastigotes in presence of IL-4, showed similar levels of IL-12p70 and IL-10 to littermate controls highlighting that IL-4-mediated DC instruction was not impaired in response to L. mexicana. Similarly, IL-4 stimulation did not affect the maturation or activation of IL-4Rα-deficient BMDCs during L. mexicana infection nor their effector functions in production of nitrite and arginine-derived metabolite (urea). Together, this study suggests that IL-4 Rα signaling on DCs is not key in the regulation of immune-mediated protection in mice against L. mexicana infection.

Evaluation of Berberine as an Adjunct to TB Treatment.

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.