Long-term outcomes of the global tuberculosis and COVID-19 co-infection cohort.

BACKGROUND: Longitudinal cohort data of patients with tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are lacking. In our global study, we describe long-term outcomes of patients affected by TB and COVID-19. METHODS: We collected data from 174 centres in 31 countries on all patients affected by COVID-19 and TB between 1 March 2020 and 30 September 2022. Patients were followed-up until cure, death or end of cohort time. All patients had TB and COVID-19; for analysis purposes, deaths were attributed to TB, COVID-19 or both. Survival analysis was performed using Cox proportional risk-regression models, and the log-rank test was used to compare survival and mortality attributed to TB, COVID-19 or both. RESULTS: Overall, 788 patients with COVID-19 and TB (active or sequelae) were recruited from 31 countries, and 10.8% (n=85) died during the observation period. Survival was significantly lower among patients whose death was attributed to TB and COVID-19 versus those dying because of either TB or COVID-19 alone (p<0.001). Significant adjusted risk factors for TB mortality were higher age (hazard ratio (HR) 1.05, 95% CI 1.03-1.07), HIV infection (HR 2.29, 95% CI 1.02-5.16) and invasive ventilation (HR 4.28, 95% CI 2.34-7.83). For COVID-19 mortality, the adjusted risks were higher age (HR 1.03, 95% CI 1.02-1.04), male sex (HR 2.21, 95% CI 1.24-3.91), oxygen requirement (HR 7.93, 95% CI 3.44-18.26) and invasive ventilation (HR 2.19, 95% CI 1.36-3.53). CONCLUSIONS: In our global cohort, death was the outcome in >10% of patients with TB and COVID-19. A range of demographic and clinical predictors are associated with adverse outcomes.

Circulating Monocyte-Like Myeloid Derived Suppressor Cells and CD16 Positive Monocytes Correlate With Immunological Responsiveness of Tuberculosis Patients.

Alterations of myeloid cell populations have been reported in patients with tuberculosis (TB). In this work, we studied the relationship between myeloid-derived suppressor cells (MDSC) and monocytes subsets with the immunological responsiveness of TB patients. Individuals with active TB were classified as low responders (LR-TB) or high responders (HR-TB) according to their T cell responses against a cell lysate of Mycobacterium tuberculosis (Mtb-Ag). Thus, LR-TB, individuals with severe disease, display a weaker immune response to Mtb compare to HR-TB, subjects with strong immunity against the bacteria. We observed that LR-TB presented higher percentages of CD16 positive monocytes as compared to HR-TB and healthy donors. Moreover, monocyte-like (M-MDSC) and polymorphonuclear-like (PMN-MDSC) MDSC were increased in patients and the proportion of M-MDSC inversely correlated with IFN-γ levels released after Mtb-Ag stimulation in HR-TB. We also found that LR-TB displayed the highest percentages of circulating M-MDSC. These results demonstrate that CD16 positive monocytes and M-MDSC frequencies could be used as another immunological classification parameter. Interestingly, in LR-TB, frequencies of CD16 positive monocytes and M-MDSC were restored after only three weeks of anti-TB treatment. Together, our findings show a link between the immunological status of TB patients and the levels of different circulating myeloid cell populations.

COVID-19 y tuberculosis en 5 hospitales de la Ciudad de Buenos Aires / COVID-19 and Tuberculosis in 5 Hospitals in the City of Buenos Aires

La comorbilidad COVID-19/tuberculosis (TB) es poco mencionada en la bibliografía y en general se considera que existe poca interacción entre ambas enfermedades. Presentamos 23 casos (4 pediátricos) diagnosticados en 5 hospitales de la Ciudad de Buenos Aires entre marzo y junio de 2020. El promedio de edad de los adultos fue de 36,9 años; 78% eran de sexo masculino; 57% fueron extranjeros y 74% pertenecían a poblaciones de barrios vulnerables. En la Institución que más casos reportó, la incidencia de TB entre los pacientes COVID-19 fue tan alta como 1635/100 000. La radiología de las formas pulmonares de TB mostró el predominio de imágenes cavitarias; en cuanto a la infección por SARS-CoV-2 se hallaron opacidades en vidrio esmerilado a predominio periférico y consolidaciones. Ambos tipos de imágenes fueron concomitantes en el 78% de los pacientes. El 65% de los casos no tenía diagnóstico de TB y éste fue efectuado a partir de imágenes radiológicas compatibles, confirmadas luego por la bacteriología. Las comorbilidades más frecuentes fueron las adicciones (tabaquismo y drogas ilícitas) y el VIH. La tuberculosis fue tratada con el esquema estándar, aunque se emplearon drogas de segunda línea en los casos de reacciones adversas graves (4 pacientes) y en los multirresistentes. El período de internación fue más prolongado de lo habitual para pacientes no UTI. La mortalidad superó a la del COVID-19 del país 1.8% vs. 8.7%. Se discuten las implicancias de la pandemia por SARS-CoV-2 sobre la reemergencia de la tuberculosis en la denominada era "postpandemia"

The COVID-19/tuberculosis comorbidity is scarcely mentioned in the literature and it is generally considered that there is little interaction between both diseases. We report 23 cases (4 pediatric) diagnosed in 5 hospitals in the City of Buenos Aires between March and June 2020. The mean age of the adults was 36.9 years: 78% were male, 57% were foreigners and 74% belonged to vulnerable populations. In the institution that reported most cases, the incidence of TB among COVID-19 patients was as high as 1635/100 000. In the radiological presentation of the pulmonary forms, cavitary images of TB predominated; regarding SARS-CoV-2 infection, ground glass opacities with a peripheral predominance and consolidation were found. Both types of images were concomitant in 78% of patients; 65% of the cases did not have a diagnosis of TB and this was made from compatible radiological images, later confirmed by bacteriology. The most frequent comorbidities were addictions (smoking and illicit drugs) and HIV. Tuberculosis was treated with the standard regimen, although second-line drugs were used in cases of serious adverse reactions (4 patients) and in multidrug-resistant TB. The hospitalization period was longer than usual for non-ICU patients. Mortality was higher than that of the country's COVID-19: 1.8% vs. 8.7%. The implications of the SARS-CoV-2 pandemic on the re-emergence of tuberculosis in the so-called "post-pandemic" era are discussed.

The Non-synonymous rs763780 Single-Nucleotide Polymorphism in IL17F Gene Is Associated With Susceptibility to Tuberculosis and Advanced Disease Severity in Argentina.

Th17 lymphocytes, that produce IL17A, IL17F, and IL22, play a crucial role during the immune response against Mycobacterium tuberculosis (Mtb) infection. Whereas, the contribution of IL17A in immunity to tuberculosis is usually accepted, the role of IL17F has been scarcely studied so far. The aim of this work was to evaluate the existence of a potential association of the non-synonymous variant rs763780 SNP of the IL17F gene with human tuberculosis. Accordingly, by comparing healthy donors (HD) and tuberculosis patients (TB) populations we demonstrated an association between the C allele of the SNP and the susceptibility to tuberculosis disease in Argentina. Furthermore, we found that peripheral blood mononuclear cells (PBMCs) from individuals with a more effective immune response against Mtb secreted the highest levels of IL17F when stimulated with a lysate of Mtb (Mtb-Ag). Besides, we evidenced that Mtb-Ag-stimulated PBMCs from HD carrying the C variant of the SNP displayed the lowest IFNG secretion, proliferation index, and SLAM expression as compared to TT carriers. Moreover, Mtb-Ag-stimulated PBMCs from TB carrying the C allele produced the lowest levels of IFNG, the highest level of IL17A, and the minimum proliferation indexes as compared to TT TB, suggesting a relationship between the C allele and tuberculosis severity. In fact, TB carrying the C allele presented a more severe disease, with the highest bacilli burden in sputum. Together, our findings identify the IL17F rs763780 SNP as a biomarker of tuberculosis susceptibility and advanced disease severity in Argentina, suggesting that IL17F could be a critical cytokine in tuberculosis immunity.

The IFNG rs1861494 Single Nucleotide Polymorphism Is Associated with Protection against Tuberculosis Disease in Argentina.

Interferon gamma (IFNG) plays a key role during Mycobacterium tuberculosis (Mtb) infection, and several polymorphisms located in its gene are associated with risk of tuberculosis in diverse populations. Nevertheless, the genetic resistance/susceptibility to tuberculosis in Argentina is unknown. The IFNG rs1861494 polymorphism (G→A) was reported to alter the binding of transcription factors to this region, influencing IFNG production. Using a case-control study, we found an association between the AA and AG genotypes and tuberculosis resistance (AA vs. GG: odds ratio (OR) = 0.235, p-value = 0.012; AG vs. GG: OR = 0.303, p-value = 0.044; AA vs. AG: OR = 0.776, p-value = 0.427; AA + AG vs. GG: OR = 0.270, p-value = 0.022). Moreover, Mtb-antigen stimulated peripheral blood mononuclear cells (PBMCs) from healthy donors and AA carriers secreted the highest amounts of IFNG in culture supernatants (p-value = 0.034) and presented the greatest percentage of CD4⁺IFNG⁺ lymphocytes (p-value = 0.035), in comparison with GG carriers. No association between the polymorphism and clinical parameters of tuberculosis severity was detected. However, our findings indicate that the rs1861494 single nucleotide polymorphism (SNP) could be considered as a biomarker of tuberculosis resistance in the Argentinean population.

Cuando la baciloscopía positiva no es tuberculosis. A propósito de un caso y breve review de la literatura / When smear positive is not tuberculosis. About a case and brief review of the literature

El método gold standar para el diagnóstico de la tuberculosis (TB) es el cultivo en medio sólido de Lowenstein-Jensen. Dado el alto costo y los requerimientos de infraestructura y personal entrenado que exige este método, tanto el programa nacional, como las recomendaciones de la Organización Mundial de la Salud (OMS), establecen que una baciloscopía positiva (BAAR +) confirma el diagnóstico de TB. Si bien el cultivo amplía la sensibilidad diagnóstica, tipifica los bacilos, y permite realizar pruebas de sensibilidad, no es un requisito operativo para la definición de confirmación bacteriológica de TB. En Argentina, el 1% de las BAAR (+) corresponden a otras etiologías3. Presentamos un caso comprendido en ese 1%, en el cual mostramos los problemas a los que se enfrenta un paciente (fundamentalmente demora diagnóstica y exposición innecesaria a drogas potencialmente tóxicas) cuando tiene un diagnóstico de TB de acuerdo con los stándares nacionales e internacionales y sin embargo no es TB.

The method gold standard for the diagnosis of tuberculosis (TB) is the culture in Lowenstein-Jensen’s solid way. In view of the high cost and the requirements of infrastructure and trained personnel that demands this method, both the national program, and the recommendations of the World Health Organization (WHO), they establish that a smear-positive confirms TB’s diagnosis. In addition, the culture increases the diagnostic sensitivity, typifies the bacillus and allows the sensitivity tests to be performed, but it is not an operative requirement for the definition of TB’s bacteriological confirmation. In Argentina, 1% of the BAAR (+) are due to other etiologies3. We present a case included in that 1%, in which we show the problems that a patient faces (basically diagnostic delay and unnecessary exposure to potentially toxic drugs) when it has TB’s diagnosis of agreement to the national and international standards and nevertheless it is not TB.

IL17A augments autophagy in Mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease.

During mycobacterial infection, macroautophagy/autophagy, a process modulated by cytokines, is essential for mounting successful host responses. Autophagy collaborates with human immune responses against Mycobacterium tuberculosis (Mt) in association with specific IFNG secreted against the pathogen. However, IFNG alone is not sufficient to the complete bacterial eradication, and other cytokines might be required. Actually, induction of Th1 and Th17 immune responses are required for protection against Mt. Accordingly, we showed that IL17A and IFNG expression in lymphocytes from tuberculosis patients correlates with disease severity. Here we investigate the role of IFNG and IL17A during autophagy in monocytes infected with Mt H37Rv or the mutant MtΔRD1. Patients with active disease were classified as high responder (HR) or low responder (LR) according to their T cell responses against Mt. IL17A augmented autophagy in infected monocytes from HR patients through a mechanism that activated MAPK1/ERK2-MAPK3/ERK1 but, during infection of monocytes from LR patients, IL17A had no effect on the autophagic response. In contrast, addition of IFNG to infected monocytes, increased autophagy by activating MAPK14/p38 α both in HR and LR patients. Interestingly, proteins codified in the RD1 region did not interfere with IFNG and IL17A autophagy induction. Therefore, in severe tuberculosis patients' monocytes, IL17A was unable to augment autophagy because of a defect in the MAPK1/3 signaling pathway. In contrast, both IFNG and IL17A increased autophagy levels in patients with strong immunity to Mt, promoting mycobacterial killing. Our findings might contribute to recognize new targets for the development of novel therapeutic tools to fight the pathogen.

Inusual presentación infecciosa oportunista en pulmón secuelar: reporte de un caso clínico / A Rare Opportunist Infectious Complication in a Lung with Sequelae; Report of a Clinical Case

El aspergiloma se considera la forma clínica más frecuente y mejor reconocida de la aspergilosis pulmonar, que surge como resultado de la colonización por el hongo de una cavidad, quiste o bulla ya existentes, como consecuencia de enfermedades crónicas tales como tuberculosis, bronquiectasias, enfisema bulloso, fibrosis pulmonar o sarcoidosis en estadios avanzados. La presentación de múltiples aspergilomas es infrecuente, lo más común es la presencia de una sola bola fúngica.

Aspergilloma is considered the most common and best known cause of pulmonary aspergillosis, which arises by the fungal colonization of a lung cavity, a cyst or existing bullae resulting from chronic diseases such as tuberculosis, bronchiectasis, bullous emphysema, pulmonary fibrosis and sarcoidosis in advanced stages. The presentation of multiple aspergillomas is infrequent. A single fungal ball-like mass is the most common presentation.