Uso terapéutico de los inhibidores de la enzima convertidora de angiotensina en pacientes con COVID-19: las «dos caras de la moneda¼ / Therapeutic use of angiotensin converting enzyme inhibitors in patients with COVID-19: the "two sides of the coin"

Resumen La evidencia actual es limitada para determinar el impacto del uso de los inhibidores de la enzima convertidora de angiotensina (IECA) en la predisposición al empeoramiento de la enfermedad del coronavirus 2019 (COVID-19). Inicialmente se reportó que en los pacientes con progresión grave de la COVID-19 existía una mortalidad elevada, los cuales tenían antecedentes de hipertensión arterial, diabetes mellitus, enfermedad cardiovascular y enfermedad renal crónica. Parte de estos pacientes también tenía en común que utilizaban IECA, lo cual alertó a la comunidad médica sobre su riesgo potencial en coexistencia con COVID-19. Sin embargo, estudios más recientes de casos-controles encontraron que los inhibidores del sistema renina-angiotensina, incluyendo los IECA, no incrementan el riesgo de COVID-19 o de requerir admisión hospitalaria por esta causa. Diferentes revistas científicas han facilitado el acceso a reportes preliminares, dejando a discreción de la comunidad médica y científica hacer uso de dicha información para promover el desarrollo de estudios que confirmen experimentalmente dichos hallazgos, preclínicos y epidemiológicos, que finalmente impacten en las decisiones de la práctica clínica para beneficiar a los pacientes con COVID-19. En esta revisión de la literatura se exploran los diferentes efectos mediados por los IECA que podrían estar relacionados con la respuesta inmune durante la infección y la transmisión de COVID-19, compilando evidencia disponible que evalúa si en realidad representan un riesgo o si, por el contrario, confieren un efecto protector.

Abstract There is limited evidence for determining the impact of the use of angiotensin converting enzyme inhibitors (ACE-I) in the tendency to worsening of coronavirus-19 disease (COVID-19). It was initially reported that, in patients with serious progression of COVID-19, there was an increased mortality in those that had a history of suffering arterial hypertension, diabetes mellitus, cardiovascular disease, and chronic kidney disease. A proportion of these patients also had in common that they used ACE-I, which alerted the medical community on the potential risk in coexisting with COVID-19. However, in more recent case-control studies, they found that inhibitors of the renin-angiotensin system, including ACE-I, does not increase the risk of COVID-19 or require hospital admission due to this cause. Several scientific journals have provided access to preliminary reports, leaving the use of such information at the discretion of the medical and scientific community for promoting the development of studies that might confirm these preclinical and epidemiological findings experimentally. These may finally have an impact on the clinical practice decisions, in order to benefit patients with COVID-19. In this literature review, the different effects mediated by ACE-I that could be related to the immune response during the infection and transmission of COVID-19 are examined, gathering available evidence that evaluates whether, in reality, they represent a risk or if on the other hand, they confer a protector effect.

Células T reguladoras en lupus eritematoso generalizado / Regulatory T cells in systemic lupus erythematosus

Resumen El lupus eritematoso generalizado (LEG) es una enfermedad autoinmune crónica caracterizada por la pérdida de la tolerancia a los antígenos propios y la síntesis de diferentes autoanticuerpos con la formación y depósito de complejos inmunes y el daño de múltiples órganos. Las células T reguladoras (Treg) desempeñan un papel esencial en el mantenimiento de la tolerancia periférica, controlan el estado de activación del sistema inmune y limitan las respuestas autoinmunes. El estudio del número y la función de las diferentes subpoblaciones de células Treg en LEG ha sido objeto de una intensa investigación. Dependiendo del fenotipo de las células Treg analizado se ha reportado que la frecuencia de estas células en pacientes con LEG se encuentra disminuida, aumentada o sin alteraciones. Además, diferentes grupos han descrito que la función supresora de las células Treg de los pacientes con LEG se encuentra reducida o no se ve afectada. En conjunto, lo datos reportados sugieren que las células Treg desempeñan un papel relevante en la patogénesis del LEG y que estos linfocitos pueden ser considerados blancos potenciales para el diseño de nuevas estrategias terapéuticas para esta enfermedad.

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a loss of tolerance to self-antigens and synthesis of different autoantibodies, with the formation and deposition of immune complexes and damage to multiple organs. T regulatory cells (Tregs) play a crucial role in maintaining peripheral tolerance, controlling the state of activation of the immune system and limiting autoimmune responses. The study of the number and function of the different Treg cell subpopulations in SLE has been the subject of intense research. Depending on the analyzed Treg cell phenotype, the frequency of these cells has been reported to be reduced, increased or unaltered in patients with SLE. In addition, different groups have described that Treg cells suppressive function is reduced or unaffected in patients with SLE. Taken together, the reported data suggest that Treg cells play a relevant role in the pathogenesis of SLE and that these lymphocytes can be considered potential targets for the design of new therapeutic strategies for this condition.

The effect of inspiratory muscle training on the quality of life, immune response, inspiratory and lower limb muscle strength of older adults: a randomized controlled trial / O efeito do treinamento muscular inspiratório em idosos sobre a qualidade de vida, resposta imune, força muscular inspiratória e de membros inferiores: um ensaio clínico randomizado

Abstract Objective: To evaluate the impact of inspiratory muscle training (IMT) on the quality of life, immune response, inspiratory and lower limb muscle strength of older adults. Method: A randomized clinical trial was conducted with 30 institutionalized older adults. They were allocated into two groups: the IMT group (n=15), which underwent IMT with PowerBreathe Classic, using a load of 60% of maximal inspiratory pressure (MIP). This was performed using a 30 repetition protocol, three times a week, for six weeks. The second group was the control group (n=15) which did not perform any type of therapeutic intervention. In both groups, MIP, lower limb strength by sit-up test, quality of life by the SF-36 questionnaire and C-reactive protein (CRP) were evaluated. Results: The results demonstrated the homogeneity between the groups regarding the demographic and clinical variables. The IMT group showed an increase in the variation of MIP (9.20±7.36 cmH2O) compared to the control (0.93±8.79 cmH2O). Improvement was also observed in the sitting and standing test (p<0.05) (Tukey Test) in the difference between the values ​​before and after the IMT. In terms of quality of life, two of the eight SF-36 domains were influenced by the IMT, namely: functional capacity and limitations due to physical factors. There were no changes in CRP in either group. Conclusion: IMT improved the inspiratory muscle strength, lower limb strength and quality of life of institutionalized older adults. These findings reinforce the contribution of this therapy to reducing the deleterious effects of aging.

Resumo Objetivo: Avaliar o impacto do treinamento muscular inspiratório (TMI) sobre a qualidade de vida, resposta imune, força muscular inspiratória e de membros inferiores de idosos. Método: Trata-se de um ensaio clínico randomizado, realizado com 30 idosos institucionalizados. Eles foram alocados em dois grupos, Grupo TMI (n=15): TMI com o PowerBreathe Classic, usando carga de 60% da pressão inspiratória máxima (PIM). O TMI foi realizado através de um protocolo de 30 repetições, três vezes por semana, durante seis semanas; e Grupo controle (n=15): não realizavam nenhum tipo de intervenção terapêutica. Em ambos os grupos foram avaliadas a PIM, a força de membros inferiores pelo teste de sentar-levantar, a qualidade de vida pelo questionário SF-36 e a proteína C reativa (PCR). Resultados: Os resultados demonstraram a homogeneidade entre os grupos em relação às variáveis demográficas e clínicas. O grupo TMI apresentou um aumento da variação da PIM (9,20±7,36cmH2O) comparado ao controle (0,93±8,79 cmH2O). Foi observada ainda melhora no teste de sentar e levantar (p<0,05) (teste de Tukey) na diferença entre os valores antes e após o TMI. Em relação à qualidade de vida, dois dos oito domínios do SF-36 sofreram influência do TMI, são eles: capacidade funcional e limitações por aspectos físicos. Não ocorreram mudanças na PCR em nenhum dos grupos. Conclusão: o TMI foi capaz de melhorar a força muscular inspiratória, a força de membros inferiores, e a qualidade de vida de idosos institucionalizados. Estes achados reforçam a contribuição desta terapêutica em reduzir os efeitos deletérios do envelhecimento.

Classical and alternative macrophages have impaired function during acute and chronic HIV-1 infection

Abstract Objectives: Three decades after HIV recognition and its association with AIDS development, many advances have emerged – especially related to prevention and treatment. Undoubtedly, the development of Highly Active Antiretroviral Therapy (HAART) dramatically changed the future of the syndrome that we know today. In the present study, we evaluate the impact of Highly Active Antiretroviral Therapy on macrophage function and its relevance to HIV pathogenesis. Methods: PBMCs were isolated from blood samples and monocytes (CD14+ cells) were purified. Monocyte-Derived Macrophages (MDMs) were activated on classical (MGM-CSF+IFN-γ) or alternative (MIL-4+IL13) patterns using human recombinant cytokines for six days. After this period, Monocyte-Derived Macrophages were stimulated with TLR2/Dectin-1 or TLR4 agonists and we evaluated the influence of HIV-1 infection and Highly Active Antiretroviral Therapy on the release of cytokines/chemokines by macrophages. Results: The data were obtained using Monocyte-Derived Macrophages derived from HIV naïve or from patients on regular Highly Active Antiretroviral Therapy. Classically Monocyte-Derived Macrophages obtained from HIV-1 infected patients on Highly Active Antiretroviral Therapy released higher levels of IL-6 and IL-12 even without PAMPs stimuli when compared to control group. On the other hand, alternative Monocyte-Derived Macrophages derived from HIV-1 infected patients on Highly Active Antiretroviral Therapy released lower levels of IL-6, IL-10, TNF-α, IP-10 and RANTES after LPS stimuli when compared to control group. Furthermore, healthy individuals have a complex network of cytokines/chemokines released by Monocyte-Derived Macrophages after PAMP stimuli, which was deeply affected in MDMs obtained from naïve HIV-1 infected patients and only partially restored in MDMs derived from HIV-1 infected patients even on regular Highly Active Antiretroviral Therapy. Conclusion: Our therapy protocols were not effective in restoring the functional alterations induced by HIV, especially those found on macrophages. These findings indicate that we still need to develop new approaches and improve the current therapy protocols, focusing on the reestablishment of cellular functions and prevention/treatment of opportunistic infections.

Inmunodeficiencias primarias en niños gravemente enfermos: a propósito de 3 casos clínicos / Primary immunodeficiencies in seriously ill children: Report of 3 clinical cases

Las inmunodeficiencias primarias (IDP) son enfermedades congénitas causadas por alteraciones cuantitativas o funcionales de la respuesta inmunitaria. Se caracterizan por predisposición a infecciones, autoinmunidad, alergia y enfermedades linfoproliferativas. Objetivo: Reportar 3 casos de lactantes menores con IDP que se manifestaron como infecciones graves de curso inhabitual. Casos clínicos: Se presentan 3 pacientes diagnosticados como IDP en su estadía en la Unidad de Paciente Crítico Pediátrico. El primero corresponde a un lactante de 4 meses con neumonía multifocal extensa a quien se diagnosticó un síndrome de inmunodeficiencia combinada severa ligada a X; el segundo es un lactante de 8 meses que se manifestó como una adenitis mesentérica por Candida lusitaniae y que correspondió a enfermedad granulomatosa crónica, y el tercero se trata de un lactante de 6 meses que se presentó con un ectima por Pseudomona y se diagnosticó una agammaglobulinemia ligada a X. Conclusión: El diagnóstico de IDP debe sospecharse en presencia de una infección de evolución arrastrada que no responde a tratamiento habitual. Se discuten los casos y se presenta una puesta al día de las patologías diagnosticadas.

Primary immunodeficiency diseases (PID) are congenital disorders secondary to an impaired immune response. Infections, autoimmune disorders, atopy, and lymphoproliferative syndromes are commonly associated with this disorder. Objective: To present and discuss 3 infants diagnosed with PID. Clinical cases: The cases are presented of three patients with PID diagnosed during their first admission to a Paediatric Intensive Critical Care Unit. The first patient, a 4-month-old infant affected by a severe pneumonia, and was diagnosed as a Severe Combined Immunodeficiency Disease. The second patient was an 8-month-old infant with Candida lusitaniae mesenteric adenitis, and diagnosed with a Chronic Granulomatous Disease. The last patient, a 6-month-old infant presented with ecthyma gangrenosum and X-linked agammaglobulinaemia. Conclusion: PID should be suspected when an infectious disease does not responde to the appropriate therapy within the expected period. An update of each disease is presented.

Inmunidad celular en la patogénesis de la cardiopatía chagásica crónica / Cell-mediated immunity in the pathogenesis of chronic Chagas cardiomyopathy

Resumen La cardiopatía chagásica crónica se presenta en un 30% de las personas infectadas con Trypanosoma cruzi. Aunque el parásito puede ser controlado por la respuesta inmune después de la fase aguda, su detección se hace difícil en la fase crónica a pesar de la persistencia de éste en los tejidos de los individuos infectados. Dado que solo un porcentaje de estos individuos crónicamente infectados desarrolla el daño tisular, se sugiere la existencia de factores asociados que predicen la aparición de la sintomatología crónica: a) la genética del hospedero (moléculas del HLA), cuyo papel aún no se ha dilucidado, b) factores dependientes del parásito cómo la variabilidad de los genotipos (TcI a TcVI), su asociación con tropismo y daño tisular; y c) otros factores como la cantidad del inóculo, la reexposición constante a vectores infectados, las diferentes vías de infección y el estado inmunológico del hospedero. Varias teorías han sido implicadas en el compromiso cardiaco, como la persistencia del T. cruzi en los tejidos, la autoinmunidad inducida y el daño tisular producido por la respuesta inmune. En esta revisión se pretende emitir una hipótesis respecto a la disfunción celular inmune producida por la persistencia parasitaria en los tejidos y su papel en la patogénesis de la enfermedad. Se consideran aspectos como el pronóstico de los pacientes con cardiopatía chagásica llevados a trasplante de corazón por falla cardiaca avanzada comparado con otras causas de falla que conducen a trasplante y la posible organización de los infiltrados inflamatorios en el tejido cardiaco, el cual podría funcionar como un tejido linfoide terciario.

Abstract Chronic Chagas cardiomyopathy is present in 30% of people infected with Trypanosoma cruzi. Even though the parasite can be controlled by immune response after the acute phase, its detection is hard in the chronic phase despite its persistence in the tissues of infected individuals. Since only a fraction of these chronically infected individuals develop tissue damage, the existence of associated predictive factors for appearance of chronic symptoms is suggested: a) host's genetics (HLA molecules) whose role has not yet been clarified; b) parasitedependent factors such as genotype variability (TcI to TcVI), their association with tropism and tissue damage; and c) other factors like the amount of inoculum, the constant reexposure to infected vectors, the different infection routes and the host's immune status. Several theories have been put forward with regard to cardiac compromise, such as T. cruzi persistence in tissues, induce autoimmunity and tissue damage caused by immune response. This review intends to propose a hypothesis on cellular immune dysfunction produced by parasite persistence in tissues and their role in the pathogenesis of the disease. Aspects such as prognosis of patients with Chagas cardiomyopathy who undergo heart transplant due to advanced heart failure are taken into consideration and compared to other failure causes that lead to transplants, and also the possibly organisation of inflammatory infiltrates in heart tissue, which could function as a tertiary lymphoid tissue.

The TcI and TcII Trypanosoma cruzi experimental infections induce distinct immune responses and cardiac fibrosis in dogs

Trypanosoma cruzi infection may be caused by different strains with distinct discrete typing units (DTUs) that can result in variable clinical forms of chronic Chagas disease. The present study evaluates the immune response and cardiac lesions in dogs experimentally infected with different T. cruzi strains with distinct DTUs, namely, the Colombian (Col) and Y strains of TcI and TcII DTU, respectively. During infection with the Col strain, increased levels of alanine aminotransferase, erythrocytes, haematocrit and haemoglobin were observed. In addition, CD8+ T-lymphocytes isolated from the peripheral blood produced higher levels of interleukin (IL)-4. The latter suggests that during the acute phase, infection with the Col strain may remain unnoticed by circulating mononuclear cells. In the chronic phase, a significant increase in the number of inflammatory cells was detected in the right atrium. Conversely, infection with the Y strain led to leucopoenia, thrombopoenia, inversion of the ratio of CD4+/CD8+ T-lymphocytes and alterations in monocyte number. The Y strain stimulated the production of interferon-γ by CD4+ and CD8+ T-lymphocytes and IL-4 by CD8+ T-cells. In the chronic phase, significant heart inflammation and fibrosis were observed, demonstrating that strains of different DTUs interact differently with the host.

Enfermedades auto inflamatorias (EAI) en pediatría / Autoinflammatory diseases in children

Las enfermedades autoinmunes son un grupo de enfermedades de relativo reciente conocimiento. Muchas de ellas están genéticamente determinadas (excepto el síndrome de PFAPA). Se caracterizan por episodios recurrentes de fiebre asociada a síntomas que generalmente pueden comprometer la piel, sistema músculo esquelético y gastrointestinal. A pesar de su baja prevalencia, el descubrimiento de los genes comprometidos en algunas de ella, ha permitido una mejor comprensión de los mecanismos de la respuesta inmune innata y en especial del rol de los llamados inflamosomas. Estos avances han permitido terapias más específicas, lo que ha llevado a disminuir en forma importante la morbilidad asociada, tanto a corto como a largo plazo. En el área pediátrica, el síndrome de PFAPA debe ser incluido como alternativa en el diagnóstico diferencial.

Autoimmune diseases are an emerging group of genetically determined diseases (except PFAPA) that affect innate immune system. They are characterized by recurrent episodes of fever associated with symptoms affecting skin, musculoskeletal and gastrointestinal system. Although unfrequent, the discovery of affected genes has allowed a better understanding of molecular mechanisms of innate immune response, specially about the role of inflammasomes. Subsequent targeted therapies have allowed a great improvement in short term and long term morbidity of most of these diseases. In children, PFAPA must be included in the analysis of differential diagnosis.

Resposta imune humoral na paracoccidioidomicose experimental em camundongos ddY / Humoral immune response in experimental ddY mice paracoccidioidomycosis

A paracoccidioidomicose (PCM) é uma micose sistêmica, restrita à América Latina, com maior incidência noBrasil. O camundongo ddY tem sido empregado como modelo murino de PCM e, no entanto, não há informaçõesa respeito da resposta imune desse animal frente à infecção. O presente estudo tem como objetivo avaliar aresposta imune humoral específica para o principal antígeno, gp43, do fungo Paracoccidioides brasiliensis,em camundongos ddY infectados com a cepa virulenta Pb 18. Foram realizadas análises da antigenemia ehistopatológico em vários órgãos e em diferentes tempos pós-infecção. Os resultados obtidos demonstraramaumento nos níveis de IgG anti-gp43 nos dias 14, 17, 21, 24, 28 e 56 pós-infecção e aumento no nível de gp43solúvel aos 28 dias pós-infecção. As células fúngicas foram detectadas em todos os órgãos analisados(cérebro, coração, pulmão, fígado, baço e rim) e em todos os períodos. As lesões granulomatosas tornaramsepredominantes 14 dias pós-infecção. Os resultados evidenciaram que o camundongo ddY produz respostaimune humoral frente ao principal antígeno de P. brasiliensis, apresentando-se elevado até 56 dias pósinfecção.A redução do nível de gp43 solúvel na fase crônica, supostamente devido ao início do controle dainfecção, requer estudos complementares adicionais.

Paracoccidioidomycosis (PCM) is a systemic mycosis, restrict to Latin America, with higher incidence inBrazil. ddY mice have been used as experimental PCM model, although there is no data regarding immuneresponse. The aim of the present study was evaluated specific humoral response against the main specificantigen of the fungal Paracoccidioides brasiliensis, the gp43, in ddY mice infected with virulent Pb 18.Antigenemia analysis and histophatological exam in several organs were performed in different time post-infection The results showed increased levels of anti-gp43 IgG on days 14, 17, 21, 24, 28 and 56 post-infectionand increased levels of soluble gp-43 on day 28 post-infection. The fungal cells were detected in all organsanalyzed (brain, heart, lung, liver, spleen and kidney) in all investigated periods. The granulomatous lesionsbecame predominant 14 days after infection. The results evidence that ddY mice produce humoral immuneresponse to main P. brasiliensis antigen, with high levels until 56 days after infection. Further studies areneeded to show that reduction of soluble gp43 in chronic phase correlates with infection control.

Entendiendo la relación entre la infección por Helicobacter pylori y enfermedades alérgicas en niños y adultos / Understanding the relationship between Helicobacter pylori infection and allergies in children and adults

La infección por Helicobacter pylori afecta a más del 50 por ciento de la población mundial, asociándose a gastritis histológica, úlcera duodenal y gástrica, así como también a cáncer gástrico. Abundante literatura reciente sugiere una relación entre H. pylori y las enfermedades alérgicas, las cuales han presentado un sostenido aumento en su incidencia en los últimos años. Considerando que ambas enfermedades (H. pylori y alergias), presentan respuestas Th polarizadas y opuestas, se revisan los aspectos claves de esta infección y su respuesta inmune polarizada a Th1, la cual, siendo inefectiva para erradicar H. pylori, es el elemento característico subyacente de la gastritis crónica histológica. Junto con ésto se analiza la respuesta inmune de tipo Th2 sistémica asociada a alergias cutáneas, respiratorias y alimentarias, para así comprender mejor su posible interacción. Algunos estudios plantean que la erradicación de H. pylori beneficiaría la remisión de enfermedades tales como urticaria crónica,asma y alergias alimentarias entre otras. Por el contrario, una fuerte línea de investigación se apoyanen la teoría de higiene y plantean que la erradicaciónde microrganismos como H. pylori, Toxoplasma gondii y virus de hepatitis A aumentaría la incidencia de alergias por un desbalance hacia Th2. En la mayoría de los estudios, la falta de grupo control o protocolos ciegos dificultan la posibilidad de llegar a una conclusión.

Helicobacter pylori's infection affects more than 50% of the world's population, inducing a histologic chronic gastritis, which can develop to a duodenal and gastric ulceration, as well as gastric cancer. Recent literature suggests a possible relationship between H. pylori and allergic diseases, which have also shown an increase in their incidence these last years. Considering that both diseases, H. pylori and allergies, have polarized and opposite immune responses, we wanted to examine the important aspects of this infection and it's immune response (Th1), which is ineffective in eradicating H. pylori, and is a characteristic element in the histologic chronic gastritis. We also wanted to review the immune response linked to skin, food and respiratory allergies (Th2) so we can understand the interaction between allergic diseases and H. pylori. Many of the studies conclude that the eradication of H. pylori would benefit the remission of chronic urticaria, asthma and food allergies among others. However, other studies mention the hygiene hypothesis where the eradication of microrganisms such as H. pylori, Toxoplasma gondii and hepatitis A virus could increase the incidence of allergic diseases due to a polarized response towards Th2. The lack of control groups and blind studies make difficult to establish a final conclusion