PGE2 displays immunosuppressive effects during human active tuberculosis.

Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. In fact, manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB). However, very limited information regarding the PGE2 pathway in patients with active TB is currently available. In the present work, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against Mycobacterium tuberculosis (Mtb) infection. Actually, we showed that PGE2 significantly reduced the surface expression of several immunological receptors, the lymphoproliferation and the production of proinflammatory cytokines. In addition, PGE2 promoted autophagy in monocytes and neutrophils cultured with Mtb antigens. These results suggest that PGE2 might be attenuating the excessive inflammatory immune response caused by Mtb, emerging as an attractive therapeutic target. Taken together, our findings contribute to the knowledge of the role of PGE2 in the human host resistance to Mtb and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.

Neutrophil autophagy during human active tuberculosis is modulated by SLAMF1.

Neutrophils infected with Mycobacterium tuberculosis (Mtb) predominate in tuberculosis patients' lungs. Neutrophils phagocytose the pathogen, but the mechanism of pathogen elimination is controversial. Macroautophagy/autophagy, a crucial mechanism for several neutrophil functions, can be modulated by immunological mediators. The costimulatory molecule SLAMF1 can act as a microbial sensor in macrophages being also able to interact with autophagy-related proteins. Here, we demonstrate for the first time that human neutrophils express SLAMF1 upon Mtb-stimulation. Furthermore, SLAMF1 was found colocalizing with LC3B+ vesicles, and activation of SLAMF1 increased neutrophil autophagy induced by Mtb. Finally, tuberculosis patients' neutrophils displayed reduced levels of SLAMF1 and lower levels of autophagy against Mtb as compared to healthy controls. Altogether, these results indicate that SLAMF1 participates in neutrophil autophagy during active tuberculosis.Abbreviations: AFB: acid-fast bacilli; BafA1: bafilomycin A1; CLL: chronic lymphocytic leukemia; DPI: diphenyleneiodonium; EVs: extracellular vesicles; FBS: fetal bovine serum; HD: healthy donors; HR: high responder (tuberculosis patient); IFNG: interferon gamma; IL1B: interleukin 1 beta; IL17A: interleukin 17A; IL8: interleukin 8; LR: low responder (tuberculosis patient); mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK14/p38: mitogen-activated protein kinase 14; Mtb: Mycobacterium tuberculosis; Mtb-Ag: Mycobacterium tuberculosis, Strain H37Rv, whole cell lysate; NETs: neutrophils extracellular traps; PPD: purified protein derivative; ROS: reactive oxygen species; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; SLAMF1: signaling lymphocytic activation molecule family member 1; TB: tuberculosis; TLR: toll like receptor.

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.

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.

Tratamiento de las fracturas homolaterales del fémur en artroplastías totales de cadera

Entre enero de 1977 y junio de 1991, en el Servicio de Ortopedia y Traumatología del Hospital Córdoba y en la práctica privada, se trataron 21 pacientes con fracturas homolaterales del fémur en artroplastías totales de cadera cementadas. Hubo franco predominio del sexo femenino (66,6 por ciento) sobre el masculino (33,3 por ciento) y las edades oscilaron entre 50 y 87 años (TM: 67 años). Cuatro (19,2 por ciento) fueron fracturas intraoperatorias y las 17 restantes (80,8 por ciento) postoperatorias, de las cuales 10 (58,8 por ciento) se produjeron en artroplastías totales de cadera con franco aflojamiento del componente femoral. Se describen los tratamientos realizados. En 4 casos (19,2 por ciento) tratados ortopédicamente la consolidación se obtuvo TM en 9 semanas, pero con 75 por ciento de resultados no satisfactorios. En los 17 casos restantes (80,8 por ciento) se realizó tratamiento quirúrgico precedido en general por tracción esquelética de una y media a dos semanas TM. Consistió en reducción y osteosíntesis con placas y/o cerclajes más injertos óseos, con recambio de componente femoral en los casos de aflojamiento protésico. La consolidación se obtuvo TM en 14 semanas, con resultados satisfactorios en 76,5 por ciento. Las complicaciones fueron responsables del 23,5 por ciento de resultados no satisfactorios. El seguimiento promedio fue de 16 meses con un mínimo de 4 y máximo de 40 meses. Los autores concluyen que la fractura femoral en un artroplastía total de cadera homolateral es una complicación de difícil tratamiento y de pronóstico reservado. Dado el incesante incremento de la longevidad y el número de aflojamientos de las artroplastías en pacientes ancianos y osteoporóticos, el cirujano ortopédico debe estar preparado para prevenir y tratar adecuadamente estas fracturas

Tratamiento de las fracturas homolaterales del fémur en artroplastías totales de cadera

Entre enero de 1977 y junio de 1991, en el Servicio de Ortopedia y Traumatología del Hospital Córdoba y en la práctica privada, se trataron 21 pacientes con fracturas homolaterales del fémur en artroplastías totales de cadera cementadas. Hubo franco predominio del sexo femenino (66,6 por ciento) sobre el masculino (33,3 por ciento) y las edades oscilaron entre 50 y 87 años (TM: 67 años). Cuatro (19,2 por ciento) fueron fracturas intraoperatorias y las 17 restantes (80,8 por ciento) postoperatorias, de las cuales 10 (58,8 por ciento) se produjeron en artroplastías totales de cadera con franco aflojamiento del componente femoral. Se describen los tratamientos realizados. En 4 casos (19,2 por ciento) tratados ortopédicamente la consolidación se obtuvo TM en 9 semanas, pero con 75 por ciento de resultados no satisfactorios. En los 17 casos restantes (80,8 por ciento) se realizó tratamiento quirúrgico precedido en general por tracción esquelética de una y media a dos semanas TM. Consistió en reducción y osteosíntesis con placas y/o cerclajes más injertos óseos, con recambio de componente femoral en los casos de aflojamiento protésico. La consolidación se obtuvo TM en 14 semanas, con resultados satisfactorios en 76,5 por ciento. Las complicaciones fueron responsables del 23,5 por ciento de resultados no satisfactorios. El seguimiento promedio fue de 16 meses con un mínimo de 4 y máximo de 40 meses. Los autores concluyen que la fractura femoral en un artroplastía total de cadera homolateral es una complicación de difícil tratamiento y de pronóstico reservado. Dado el incesante incremento de la longevidad y el número de aflojamientos de las artroplastías en pacientes ancianos y osteoporóticos, el cirujano ortopédico debe estar preparado para prevenir y tratar adecuadamente estas fracturas