Abordaje integral de infecciones respiratorias agudas virales y coqueluche / Comprehensive approach to acute viral respiratory infections and whooping cough

Informe sobre el objetivo del abordaje de estas patologías, desde el Ministerio de Salud de la Ciudad de Buenos Aires: Medidas de prevención; Priorización de diagnóstico; Estrategia integrada de vigilancia de la Infecciones Respiratorias Agudas de posible origen viral; Vigilancia Universal; Vigilancia epidemiológica de coqueluche (tos convulsa); y Recomendaciones sobre el uso de antivirales para influenza; (AU)

Recurrence of hepatitis C virus after treatment with pegylated interferon and direct acting antivirals in Punjab Pakistan / Recorrência do vírus da hepatite C após tratamento com interferon peguilado e antivirais de ação direta em Punjab, Paquistão

Although increased response rates concomitant in hepatitis C virus but relapse after treatment is threatened. Therefore, it is terrible requirement to evaluate the response of Pegylated interferon and direct acting antivirals in Punjab Pakistan. The study was conducted to find the rate of recurrence of HCV infection after treatment with Pegylated Interferon and Direct Acting Antivirals in Punjab Pakistan. This study was conducted at Department of Pathology, Nawaz Sharif Medical College Gujrat, while treatment effects monitored in different Government and Private Hospitals of Punjab, Pakistan. Total 973 patients who administered the recommended dose and divided in two groups (i) Interferon based therapy (ii) direct acting antivirals (DAAs).Other parameters like ALT and viral load studied. The rate of recurrence was higher in female infected with genotype 2b and in male with mixed genotype 3a/2b after six month of antiviral therapy. Genotype 3a showed significant response to therapy after three month. 32 among 374 (8.5%) were positive after 24 weeks of treatment with interferon, 29 (7.7%) patients have same genotype while 3 patients were re-infected with different HCV strains. With DAAs, only 27 (4.8%) patients were positive among 558 after 2 weeks and one patient re-infected with different genotype. Early and sustained virological response noted in DAAs. ALT and viral load decreased faster with DAAs that not achieved after 4 weeks with pegylated interferon. Sustained virological response appears in DAAs and recurrence rate is high in interferon therapy compared to DAAs. Therefore, reinfection has implications for correct treatment efficiency and to select strategies for retreatment cases.

Embora aumentem as taxas de resposta concomitantes no vírus da hepatite C (HCV), há risco de recidiva após o tratamento. Portanto, é um requisito terrível avaliar a resposta do interferon peguilado e antivirais de ação direta em Punjab, Paquistão. O estudo foi conduzido para encontrar a taxa de recorrência da infecção por HCV após o tratamento com interferon peguilado e antivirais de ação direta em Punjab, Paquistão. Este estudo foi conduzido no Departamento de Patologia Nawaz Sharif Medical College Gujrat, enquanto os efeitos do tratamento foram monitorados em diferentes hospitais públicos e privados de Punjab, Paquistão. Total de 973 pacientes que administraram a dose recomendada foram divididos em dois grupos: (i) Terapia baseada em interferon, (ii) antivirais de ação direta (DAAs). Outros parâmetros como ALT e carga viral foram estudados. A taxa de recorrência foi maior em mulheres infectadas com o genótipo 2b e em homens com genótipo misto 3a / 2b após seis meses de terapia antiviral. O genótipo 3a mostrou resposta significativa à terapia após três meses. 32 entre 374 (8,5%) foram positivos após 24 semanas de tratamento com interferon, 29 (7,7%) pacientes têm o mesmo genótipo, enquanto 3 pacientes foram reinfectados com diferentes cepas de HCV. Com DAAs, apenas 27 (4,8%) pacientes foram positivos entre 558 após duas semanas e um paciente reinfectado com genótipo diferente. Resposta virológica precoce e sustentada observada em DAAs. ALT e carga viral diminuíram mais rapidamente com DAAs, que não alcançou após 4 semanas com interferon peguilado. A resposta virológica sustentada aparece em DAAs, e a taxa de recorrência é alta na terapia com interferon em comparação com DAAs. Portanto, a reinfecção tem implicações para a eficiência do tratamento correto e para selecionar estratégias para casos de retratamento.

Impact of supplemental vitamins and natural honey for treatment of COVID-19: A review

Abstract The main aim of the paper is to assess whether vitamin C, vitamin D, and natural honey can be administered in the course of the COVID-19 pandemic for promising in line methods with recent evidence. Both systematic literature and clinical trial identification were conducted by searching various databases. A total 58 articles and 29 clinical trials were selected wherein 11 for vitamin C, 16 for vitamin D, and 2 for natural honey were identified for analysis. The high doses of vitamin C (i.e. '200 mg/kg body weight/day, divided into 4 doses') has been found to reduce COVID-19 lung damage, various flu infections. Additionally, the high doses of vitamin C can shorten around 7.8% stay in the intensive care unit. At the same time, vitamin D can effectively protect from lung injury and acute respiratory infections whereas vitamin D deficiency severely affects 75% of the institutionalized people (serum 25(OH) D < 25 nmol/L). Meanwhile, natural honey which contains proteins (0.1-0.4%); ash (0.2%); water (15-17%) has potential antiviral effects and the ability to improve immunity. Therefore, the administration of vitamins and honey is the promising evidence-based approach for reducing fatalities, saving lives, and bringing the COVID-19 pandemic to a rapid end. It is believed that the utilization of vitamin C, vitamin D, and natural honey with the current treatment may be effective in treating COVID-19-caused fatal complications such as pneumonia. Therefore, high-level clinical studies are required on COVID-19 to administrate the effects of vitamins and natural honey

Tratamiento simplificado para pacientes con Hepatitis C / Simplified treatment for hepatitis C patients

El nuevo tratamiento simplificado con antivirales orales para pacientes con Hepatitis C puede ser abordado desde la atención primaria, lo que facilita el acceso de la población afectada por esta infección crónica. En este artículo se repasan los aspectos claves del diagnóstico, el esquema de tratamiento simplificado y los candidatos a recibirlo. (AU)

The new simplified treatment with oral antivirals for hepatitis C patients can be approached at the primary care level, facilitating access for the population affected by this chronic infection. This article reviews the key aspects of the diagnosis, the simplified treatment scheme, and the eligible candidates for the treatment. (AU)

Optimization of glycerol-based medium composition for antifungal metabolites production by Bacillus subtilis

Abstract Bacillus species are promising producers of various compounds that have pronounced antimicrobial, antiviral and antitumor activities. Due to its GRAS status, Bacillus subtilis represents an excellent candidate for the usage in plant pathogens biocontrol. In this research, evaluation of antifungal metabolites biosynthesis by Bacillus subtilis ATCC 6633 and optimization of glycerol-based medium composition, using response surface methodology, for the production of compounds effective against Neurospora crassa were investigated. The results of disc-diffusion method indicate that applied Bacillus strain produces compounds with antifungal activity against tested fungus. In order to find optimal cultivation medium composition, the experiments were carried out in accordance with Box-Behnken design, and optimization was performed using the concept of desirability function combined with previously defined mathematical equation, which describes examined bioprocess. The optimization model predicts that maximum inhibition zone diameter against Neurospora crassa of 32.24 mm is achieved when initial content of glycerol, NaNO2 and K2HPO4 were 49.68 g/L, 2.90 g/L and 6.49 g/L, respectively. Additionally, the second optimization set was made to minimize the consumption of medium components and costs of medium preparation. The obtained results are the basis for further research aimed to develop medium appropriate for economically justified production of bioactive compounds at industrial scale.

Mecanismos de acción de agentes propuestos para el tratamiento farmacológico específico de la infección por SARS-CoV-2 / Mechanisms of action of proposed agents for the specific pharmacological treatment of SARS-CoV-2 infection

Resumen Desde la notificación de la pandemia por SARS-CoV-2, agente patógeno responsable del COVID-19, muchos de los tratamientos dirigidos a su manejo han estado sometidos a estudios de manera constante, con el fin de comprobar su eficacia y seguridad. El conocimiento de su virología y etiopatogenia posibilitaría objetivar los pasos moleculares específicos que puedan ser blancos terapéuticos de variados fármacos actualmente disponibles. Esta experiencia proviene principalmente de las infecciones por SARS-CoV y MERS-CoV, con resultados variados 'in vitro' en el SARS-CoV-2, sin evidencia clínica que demuestre efectividad y seguridad de dichos tratamientos. A la fecha, no se ha podido concretar con claridad un esquema de tratamiento específico, debido a que la evidencia surgida ha puesto en jaque cada uno de los fármacos propuestos. Esto ha motivado a continuar en la búsqueda de una estrategia efectiva que permita manejar esta pandemia con la seguridad y eficacia necesaria para que el beneficio terapéutico esté por sobre los posibles efectos adversos que estos esquemas farmacológicos pudiesen presentar. La siguiente revisión pretende mostrar la evidencia disponible a la fecha, definiendo la actividad de cada fármaco en función de su mecanismo de acción.

Since the beginning of the pandemic by SARS-CoV-2, the pathogen responsible for COVID-19, many of the therapeutic options for its management have been under constant revision, in order to verify their safety and efficiency. Knowledge of the viral structure and pathogenesis make it possible to determine the molecular pathways that may be targeted with current available drugs. The experience with these drugs comes mainly from infections caused by SARS-CoV and MERS-CoV, in vitro studies with SARS-CoV-2 that yield variable results, and clinical experience that does not ensure effectiveness and safety of such drugs. To date, it has not been possible to elucidate a specific treatment scheme, because of the constant release of evidence that challenges the usefulness of the proposed drugs. This has motived us to continue seeking for an effective strategy that allows to manage this pandemic in a safe and efficient manner, so that therapeutic benefit surpasses the related adverse drug reactions that can occur. The following review aims to showcase the evidence available to date by defining the activity of each drug based on its mechanism of action.

COVID-19: enfoque básico para entender sus tratamientos / COVID-19: a basic approach to understanding potential treatments

Resumen El virus SARS-CoV-2 ha sido identificado como el agente patológico causante de la pandemia de COVID-19. Aun cuando no se cuenta con un tratamiento estándar, se han probado antivirales como remdesivir y otros fármacos como cloroquina e ivermectina, que interfieren con la replicación del virus. También se han intentado algunas estrategias encaminadas a disminuir los mecanismos inmunitarios, como el uso de tocilizumab y antioxidantes naturales. Los fármacos relacionados con el sistema renina-angiotensina han resultado controversiales. Aún se debe estudiar con detalle los mecanismos de patogenicidad, así como los tratamientos controlados para proponer alguna opción terapéutica viable que evite la entrada y replicación del virus o que aumente los sistemas inmunitarios del huésped.

Abstract SARS-CoV-2 virus has been identified as the causative agent of the COVID-19 pandemic. Even when no standard treatment is available, antivirals such as remdesivir and other drugs such as chloroquine and ivermectin, which interfere with viral replication, have been assayed. Some strategies aimed to reduce immune mechanisms, such as the use of tocilizumab and natural antioxidants, have also been tested. The use of drugs related to the renin-angiotensin system has been controversial. Pathogenicity mechanisms, as well as controlled treatments, still have to be studied in detail in order to propose a viable therapeutic option that prevents the entry and replication of the virus or enhances the host immune system.

COVID-19 pandemic: challenges ahead / Pandemia de COVID-19: retos por enfrentar

Abstract Since December 2019, health systems worldwide have faced the pandemic caused by the new severe acute respiratory syndrome coronavirus 2. The pandemic began in China and has spread throughout the world. This new coronavirus has a high transmission capacity and elevated lethality in people over 60 years old and in those with risk factors (obesity, diabetes, and systemic arterial hypertension); those characteristics have a different proportion in each country. At present, there is no specific, effective, and safe treatment to treat this virus. In this review, an analysis is made on the differences in epidemiological aspects of the disease and its presentation in pediatric patients; the poorly-based recommendation for using an empirical combination of antimalarials plus antimicrobials as antiviral treatment; the indication of intravenous steroids; and the possible influence of antihypertensive drugs on the course of the disease.

Resumen A partir de diciembre de 2019, los sistemas de salud de todos los países se han enfrentado a la pandemia causada por un nuevo coronavirus (SARS-CoV-2), el cual fue notificado por primera vez en China y se ha esparcido por todo el mundo. Este nuevo coronavirus posee una alta capacidad para transmitirse. A escala mundial la letalidad ha sido más alta en la población mayor de 60 años y en aquellos que tienen factores de riesgo (obesidad, diabetes e hipertensión arterial sistémica). Sin embargo, estas características varían en proporción en cada país. Hasta el momento no hay un tratamiento específico, eficaz y seguro para combatir este virus. En este artículo se realiza un análisis sobre las diferencias globales en los aspectos epidemiológicos y con relación a su presentación en pacientes pediátricos, así como de la recomendación, con pobre fundamento, del uso de la combinación de antimaláricos y antimicrobianos empíricos como antivirales. También se analizan la indicación de esteroides intravenosos y la posible influencia de los fármacos antihipertensivos en el curso de la enfermedad.

SARS-CoV-2 and influenza: a comparative overview and treatment implications / SARS-CoV-2 e influenza: revisión comparativa e implicaciones del tratamiento

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Alphainfluenzavirus are RNA viruses that cause coronavirus disease-19 and influenza, respectively. Both viruses infect the respiratory tract, show similar symptoms, and use surface proteins to infect the host. Influenza requires hemagglutinin and neuraminidase to infect, whereas SARS-CoV-2 uses protein S. Both viruses depend on a viral RNA polymerase to express their proteins, but only SARS-CoV-2 has a proofreading mechanism, which results in a low mutation rate compared to influenza. E1KC4 and camostat mesylate are potential inhibitors of SARS-CoV-2 S protein, achieving an effect similar to oseltamivir. Due to the SARS-CoV-2 low mutation rate, nucleoside analogs have been developed (such as EIDD-2801), which insert lethal mutations in the viral RNA. Furthermore, the SARS-CoV-2 low mutation rate suggests that a vaccine, as well as the immunity developed in recovered patients, could provide long-lasting protection compared to vaccines against influenza, which are rendered obsolete as the virus mutates.

Resumen La enfermedad por coronavirus de 2019 y la influenza son causadas por virus ARN: coronavirus tipo 2 del síndrome respiratorio agudo grave (SARS-CoV-2) y Alphainfluenzavirus, respectivamente. Ambos virus infectan el tracto respiratorio, presentan síntomas similares y emplean proteínas de superficie para infectar al huésped. El virus de la influenza requiere de hemaglutinina y neuraminidasa para infectar, mientras que el SARS-CoV-2 utiliza la proteína S. Ambos virus dependen de la ARN polimerasa viral para expresar sus proteínas, pero solo el SARS-CoV-2 cuenta con un mecanismo de corrección de errores, por lo que presenta una baja tasa de mutaciones en comparación con el virus de la influenza. E1KC4 y el mesilato de camostat son inhibidores potenciales de la proteína S del SARS-CoV-2, obteniendo un efecto similar al de oseltamivir. Aprovechando la baja tasa de mutación del SARS-CoV-2, se han desarrollado análogos de nucleósidos (como el fármaco EIDD-2801) que insertan mutaciones letales en el ARN viral. Además, la baja tasa de mutación del SARS-CoV-2, obteniendo un efecto similar al de oseltamivir sugiere que las vacunas desarrolladas, así como la inmunidad generada en pacientes recuperados, podrían brindar protección prolongada, en comparación con las vacunas desarrolladas contra la influenza, que resultan obsoletas frente a una cepa mutada.

Lopinavir/ritonavir for COVID-19: a living systematic review / Lopinavir/ritonavir para COVID-19: una revisión sistemática viva

Objective: Provide a timely, rigorous, and continuously updated summary of the evidence on the role of lopinavir/ritonavir in the treatment of patients with COVID-19. Methods: We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in PubMed, Embase, CENTRAL, and other 33 sources. We searched for randomized trials and non-randomized studies evaluating the effect of lopinavir/ritonavir versus placebo or no treatment in patients with COVID-19. Two reviewers independently evaluated potentially eligible studies, according to predefined selection criteria, and extracted data using a predesigned standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. Results: Our search strategy yielded 862 references. Finally, we identified 12 studies, including two randomized trials, evaluating lopinavir/ritonavir, in addition to standard care versus standard care alone in 250 adult inpatients with COVID-19. The evidence from randomized trials shows lopinavir/ritonavir may reduce mortality (relative risk: 0.77; 95% confidence interval: 0.45 to 1.3; low certainty evidence), but the anticipated magnitude of the absolute reduction in mortality, varies across different risk groups. Lopinavir/ritonavir also had a slight reduction in the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. However, it did not lead to any difference in the duration of hospitalization and may lead to an increase in the number of total adverse effects. The overall certainty of the evidence was low or very low. Conclusions: For severe and critical patients with COVID-19, lopinavir/ritonavir might play a role in improving outcomes, but the available evidence is still limited. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon.

Objetivo: Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y constantemente actualizado de la evidencia disponible sobre los efectos de lopinavir/ritonavir en pacientes con COVID-19. Métodos: Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) y otras 33 fuentes. Se buscaron ensayos aleatorios y estudios no aleatorios que evaluaran el uso de lopinavir/ritonavir versus placebo o ningún tratamiento en pacientes con COVID-19. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará disponible durante la pandemia de COVID-19. Resultados: La búsqueda inicial arrojó 862 referencias. Finalmente, identificamos 12 estudios incluyendo 2 ensayos aleatorios, que evaluaban lopinavir/ritonavir adicionado al tratamiento estándar versus tratamiento estándar en 250 pacientes adultos hospitalizados con COVID-19. Los resultados provenientes de los ensayos aleatorios muestran que el uso de lopinavir/ritonavir puede reducir la mortalidad (riesgo relativo: 0,77; intervalo de confianza 95%: 0,45 a 1,3; certeza de evidencia baja), pero la magnitud de la reducción absoluta de la mortalidad varía según los diferentes grupos de riesgo. El uso de lopinavir/ritonavir mostró además una ligera reducción en el riesgo de requerir ventilación mecánica invasiva, desarrollar insuficiencia respiratoria o síndrome de dificultad respiratoria aguda. No se observó diferencias en la duración de la hospitalización y su uso puede producir un aumento en el número de efectos adversos totales. La certeza global de la evidencia fue baja o muy baja. Conclusiones: Para pacientes graves y críticos con COVID-19, el uso de lopinavir/ritonavir podría desempeñar un papel en la mejora de los resultados, pero la evidencia disponible aún es limitada. La gran cantidad de estudios en curso deberían proporcionar evidencia valiosa para informar a los investigadores y los tomadores de decisiones en el futuro cercano.

Respuestas rápidas a la pandemia de COVID-19 a través de la ciencia y la colaboración global: el ensayo clínico Solidaridad

RESUMEN La COVID-19 representa una crisis global. La realización rápida de un ensayo clínico con la rigurosidad necesaria para obtener resultados confiables requiere la colaboración de diversos actores que participan en el desarrollo, evaluación y autorización de los ensayos clínicos (EC), como el patrocinador del ensayo, los investigadores, la autoridad regulatoria y el comité de ética (CE). Llevar a cabo estos estudios no solo es científicamente apropiado, sino una obligación ética y moral para ofrecer a las personas infectadas con COVID-19 un tratamiento efectivo. Solidaridad es un megaensayo clínico que reclutará miles de sujetos de investigación con enfermedad moderada a grave, a quienes se les asignará aleatoriamente a uno de los grupos de tratamiento en evaluación incluyendo hidroxicloroquina, lopinavir/ritonavir asociado o no a interferón; o remdesivir en comparación con el manejo estándar. El Perú se ha sumado a la lista de países donde se reproducirá el ensayo, mediante el cual se podrá identificar rápidamente si alguno de estos fármacos ofrece un beneficio real a los pacientes.

ABSTRACT COVID-19 represents a global crisis. Rapidly conducting a clinical trial with the rigor necessary to obtain reliable results requires the collaboration of various participants involved in the development, evaluation and authorization of clinical trials (CT) such as the trial sponsor, researchers, regulatory authority and the ethics committee (EC). Carrying out these studies is not only scientifically appropriate, but an ethical and moral obligation to guarantee our patients effective treatment. SOLIDARITY is a mega clinical trial that recruited thousands of subjects with moderate to severe disease, who were randomly assigned to one of the treatment groups under evaluation, including hydroxychloroquine, lopinavir/ritonavir associated or not with interferon; or remdesivir compared to standard therapy. Peru has joined the list of countries where the trial will be reproduced, through which it will be possible to quickly identify if any of these drugs offers a real benefit to patients.

COVID-19: la pandemia por el nuevo virus SARS-CoV-2

RESUMEN Durante las primeras semanas de 2020 se comenzaron a informar casos de personas con SARS-CoV-2 fuera de China, con un rápido aumento de casos y muertes en todo el mundo. El SARS-CoV-2 es un virus ARN monocatenario positivo, envuelto en una bicapa lipídica derivada de la membrana celular del huésped y constituido por cuatro proteínas estructurales (S, M, E y N), además de una hemaglutinina-esterasa. La unión de la proteína S con el receptor de enzima convertidora de angiotensina 2 (ECA2) permite la entrada del virus a la célula huésped y es una potencial diana terapéutica. El 81% de los enfermos hace cuadro leve; el 14%, grave; y el 5% requiere cuidados intensivos. La fiebre es el síntoma más frecuente, seguido de tos y disnea. La mayoría de los pacientes no presentan leucocitosis pero sí linfopenia, con cultivos de esputo que no muestran otros patógenos. En las biopsias de pulmón de pacientes graves el hallazgo más llamativo es el daño alveolar difuso. Radiológicamente se aprecian patrones de vidrio esmerilado y alveolar, siendo las lesiones de predominio basal, subpleural y posterior, con una distribución periférica multifocal, afectando más el lóbulo inferior derecho. Hay una marcada respuesta inflamatoria, que llega hasta la tormenta de citoquinas, en la que el tratamiento antiinflamatorio con terapia de pulso con metilprednisolona estaría indicado. Aunque no existan estudios en gran escala respecto al uso de cloroquina/hidroxicloroquina, debido a la situación mundial se ha autorizado su uso por su efecto anti SARS-CoV-2 y anti-inflamatorio, el cual puede ser potenciado con el uso de azitromicina.

ABSTRACT During the first weeks of 2020, cases of SARS-CoV-2 began to be reported outside of China, with a rapid increase in cases and deaths worldwide. SARS-CoV-2 is a positive single-stranded RNA virus, encased in a lipid bilayer derived from the host cell membrane and consists of four structural proteins (S, M, E and N), plus a haemagglutinin-sterase. The binding of the S protein to the ECA2 receptor allows the entry of the virus into the host cell and is a potential therapeutic target. 81% of patients develop mild symptoms, 14% have severe symptoms and 5% require intensive care management. Fever is the most frequent symptom, followed by cough and dyspnea. Most patients do not present leukocytosis, but they do present lymphopenia with sputum cultures that do not show other pathogens. In lung biopsies of severe patients, the most noticeable finding is diffuse alveolar damage. Radiologically, ground glass and alveolar patterns are observed; the lesions being predominantly basal, subpleural, and posterior, with a multifocal peripheral distribution, more affecting the right lower lobe. There is a marked inflammatory response, up to the cytokine storm, in which anti-inflammatory treatment with pulse therapy with methylprednisolone would be indicated. Although there are no large-scale studies regarding the use of chloroquine / hydroxychloroquine, due to the global situation, its use has been authorized for its anti-SARS-CoV-2 and anti-inflammatory effect, which can be potentiated with the use of azithromycin.

COVID-19: respuesta inmune y perspectivas terapéuticas

RESUMEN La enfermedad causada por el nuevo coronavirus (COVID-19) se caracteriza por presentar fiebre y tos, afectar el tracto respiratorio inferior y estar asociada con la edad, comorbilidades y un sistema inmune debilitado. Típicamente se ha evidenciado linfopenias en los casos graves y una desmedida producción de citocinas inflamatorias (tormenta de citocinas), lo que explicaría el rol de la respuesta hiperinflamatoria en la patogénesis de la COVID-19. Las respuestas inflamatorias secundarias por reinfecciones del virus podrían inducir el aumento o la mejora dependiente de anticuerpos (ADE, por sus siglas en inglés), un fenómeno virémico que podría ser un mecanismo alternativo de infección celular y que se deberá tener en cuenta cuando se diseñen vacunas o inmunoterapias que involucren el estímulo de anticuerpos neutralizantes o el uso de anticuerpos monoclonales. Actualmente no existen vacunas ni tratamientos que demuestren seguridad y eficacia en pacientes con COVID-19; sin embargo, se espera la conclusión de los resultados de la aplicación de una vacuna de ácidos nucleicos ARNm (mensajero del ácido ribonucleico) y de un fármaco antiviral (remdisivir) que se encuentran en ensayos clínicos fase III. Por el momento la mejor medida para evitar la propagación de la infección es el aislamiento social exhaustivo y viene siendo adoptado por varios países según recomendación de la Organización Mundial de la Salud (OMS).

ABSTRACT Disease caused by the new coronavirus (COVID-19) is characterized by fever, cough, and affection of the lower respiratory tract. It is associated with age, comorbidities and a weakened immune system. Typically, lymphopenias have been evidenced in severe cases and an excessive production of inflammatory cytokines (cytokine storm), which would explain the role of the hyperinflammatory response in the pathogenesis of COVID-19. Secondary inflammatory responses from virus reinfections may induce antibody-dependent enhancement (ADE), a viremic phenomenon that may be an alternative mechanism of cellular infection and should be considered when designing vaccines or immunotherapies involving the stimulation of neutralizing antibodies or the use of monoclonal antibodies. Currently, no vaccines or treatments demonstrate safety and efficacy in patients with COVID-19. However, the results from phase III clinical trials which involve the application of an mRNA (messenger ribonucleic acid) nucleic acid vaccine and an antiviral drug (remdisivir), are yet to be concluded. For the time being, the best measure to prevent the spread of COVID-19 is by implementing social isolation, this measure has been adopted by several countries as recommended by the World Health Organization (WHO).

Agentes potencialmente terapéuticos contra el SARS-CoV-2: revisión rápida de la evidencia

RESUMEN El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) del Seguro Social de Salud (EsSalud) ha desarrollado siete informes breves mediante revisiones rápidas de evidencia sobre los agentes potencialmente terapéuticos contra el SARS-CoV-2 con la finalidad de brindar información actual y relevante para los decisores, clínicos, investigadores y la comunidad académica en el Perú. Los agentes terapéuticos evaluados incluyeron cloroquina/hidroxicloroquina, lopinavir/ritonavir, tocilizumab, oseltamivir, interferón, atazanavir y plasma anti-SARS-CoV-2. La identificación de evidencia incluyó la revisión de las bases electrónicas PubMed y Cochrane Library. Adicionalmente, se realizó una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud, así como, en las principales sociedades o instituciones especializadas, como la Organización Mundial de la Salud (OMS) y los Centros para el Control y la Prevención de Enfermedades (CDC, por sus siglas en inglés). Asimismo, para disminuir el sesgo de publicación, se buscó en las páginas web www.clinicaltrials.gov y http://apps.who.int/trialsearch, para identificar ensayos clínicos en desarrollo o que no hayan sido publicados aún. Finalmente, se consideró extraer información con una estrategia de «bola de nieve¼ mediante la revisión de las listas de referencias de las revisiones sistemáticas, estudios primarios y revisiones narrativas que sean de relevancia. A la fecha de la última revisión (27 de marzo de 2020), no se dispone de evidencia para recomendar un medicamento específico para el tratamiento de pacientes con COVID-19. Se necesita de mayor evidencia, preferentemente ensayos clínicos de buena calidad, para la toma de decisiones terapéuticas contra el SARS-CoV-2.

ABSTRACT The Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) of the Seguro Social de Salud (EsSalud) has completed seven brief reports by means of rapid reviews of evidence regarding the potentially effective therapies against SARS-CoV-2 in order to provide current and relevant information for decision makers, clinicians, researchers and the academic community in Peru. The therapeutic agents evaluated were chloroquine/hydroxychloroquine, lopinavir/ritonavir, tocilizumab, oseltamivir, interferon, atazanavir and anti SARS-CoV-2 serum. Evidence identification included the review of PubMed and Cochrane Library electronic databases. Additionally, manual search was carried out on websites from groups dedicated to research and education on health, as well as in the main specialized societies or institutions, such as, the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC). Furthermore, in order to reduce publication bias, the websites: www.clinicaltrials.gov and http://apps.who.int/trialsearch were searched to identify in-progress or unpublished clinical trials. Finally, a "snowball" strategy was performed by reviewing the reference lists of the systematic reviews, primary studies and selected narrative reviews to identify relevant information. The latest review (March 27, 2020) showed that there is no evidence to recommend any medication for patients´ treatment with COVID-19. More evidence, preferably high-quality randomized clinical trials, is needed for decision-making against SARS-CoV-2.

Influenza A (H1N1): outbreak management in a dialysis unit and clinical outcomes of infection in chronic hemodialysis patients / Influenza A (H1N1): controle de surto em unidade de diálise e desfechos clínicos da infecção em pacientes em hemodiálise crônica

ABSTRACT Introduction: Chronic hemodialysis (HD) patients are considered to be at high risk for infection. Here, we describe the clinical outcomes of chronic HD patients with influenza A (H1N1) infection and the strategies adopted to control an outbreak of influenza A in a dialysis unit. Methods: Among a total of 62 chronic HD patients, H1N1 infection was identified in 12 (19.4%). Of the 32 staff members, four (12.5%) were found to be infected with the H1N1 virus. Outcomes included symptoms at presentation, comorbidities, occurrence of hypoxemia, hospital admission, and clinical evaluation. Infection was confirmed by real-time reverse transcriptase polymerase chain reaction. Results: The 12 patients who had H1N1 infection did not differ significantly from the other 50 non-infected patients with respect to age, sex, dialysis vintage, dialysis modality, or proportion of comorbidities. Obesity was higher in the H1N1-infected group (41.5 vs. 4%, p<0.002). The most common symptoms were fever (92%), cough (92%), and rhinorrhea (83%). Early empirical antiviral treatment with oseltamivir was started in symptomatic patients and infection control measures, including the intensification of contact-reduction measures by the staff members, antiviral chemoprophylaxis to asymptomatic patients undergoing HD in the same shift of infected patients, and dismiss of staff members suspected of being infected, were implemented to control the spread of infection in the dialysis unit. Conclusion: The clinical course of infection with H1N1 in our patients was favorable. None of the patients developed severe disease and the strategies adopted to control the outbreak were successful.

RESUMO Introdução: Pacientes em hemodiálise (HD) crônica apresentam risco elevado para infecções. O presente estudo descreve os desfechos clínicos de pacientes em HD crônica com infecção pelo vírus influenza A (H1N1) e as estratégias adotadas para controlar um surto de influenza A numa unidade de diálise. Métodos: Doze (19,4%) de 62 pacientes em HD crônica e quatro (12,5%) de 32 funcionários desta unidade de diálise apresentaram infecção pelo vírus H1N1. Os desfechos incluíram sintomas à apresentação, comorbidades, ocorrência de hipoxemia, internação hospitalar e avaliação clínica. A presença de infecção foi confirmada por reação em cadeia da polimerase via transcriptase reversa (RT-PCR) em tempo real. Resultados: Os 12 pacientes com infecção por H1N1 não diferiram significativamente dos 50 pacientes sem infecção no tocante a idade, sexo, tempo em diálise, modalidade de diálise e percentual de comorbidades. O percentual de obesidade foi mais elevado no grupo com infecção por H1N1 (41,5% vs. 4%, p<0,002). Os sintomas mais comuns foram febre (92%), tosse (92%) e rinorreia (83%). Os pacientes foram submetidos a tratamento antiviral com oseltamivir e medidas de controle (intensificação das medidas de redução de contato pelos funcionários da clínica, quimioprofilaxia com antiviral para pacientes assintomáticos em HD na mesma sala dos pacientes com infecção e afastamento de funcionários da clínica com suspeita de infecção) para controlar a disseminação da infecção pela unidade de diálise. Conclusão: O curso clínico da infecção por H1N1 em nossos pacientes foi favorável. Nenhum evoluiu para doença grave e as estratégias adotadas foram efetivas no controle do surto.

Queratoplastia penetrante con y sin terapia antiviral en la queratopatía herpética / Penetrating keratoplasty with and without antiviral therapy in herpetic keratopathy

RESUMEN Objetivo: Identificar el resultado óptico o terapéutico de la queratoplastia penetrante en pacientes con queratopatía herpética. Métodos: Se realizó una investigación descriptiva, transversal, donde se expusieron los resultados del alcance de la queratoplastia penetrante por queratopatía herpética, operados en el Hospital Clínico Quirúrgico "Hermanos Ameijeiras", de La Habana. Resultados: La muestra fue de 33 queratoplastias penetrantes. Con fines ópticos sumaron 24 (72,7 por ciento) y tectónicas 9 (27,3 por ciento). En 5 de estas la agudeza visual fue menor o igual a 0,3. En el total de la muestra, 9 opacificaron, 11 sufrieron complicaciones posquirúrgicas, 8 recurrieron en queratoplastias penetrantes ópticas y 6 en queratoplastias penetrantes terapéuticas. Se rechazaron 7 queratoplastias penetrantes ópticas (33,3 por ciento) y 4 queratoplastias penetrantes terapéuticas (4 por ciento). Presentaron complicaciones 5 (25 por ciento) con queratoplastias penetrantes ópticas y 6 (55,6 por ciento) con queratoplastias penetrantes terapéuticas. En el posquirúrgico 22 (66,6 por ciento) tenían agudeza visual mayor o igual a 0,3 (p= 0,0000). Conclusiones: La inactividad de la enfermedad viral corneal beneficia el pronóstico del injerto por queratopatía herpética en las opacidades de las queratoplastias con fines ópticos. Queda demostrado que el uso de antivirales pre y posoperatorios disminuye la recidiva de la enfermedad herpética sobre el injerto y el rechazo, al lograr mejor agudeza visual y mayor viabilidad. La severidad inflamatoria posquirúrgica se asocia con la enfermedad viral activa o afección de origen inmune al realizar el trasplante, conexos a las complicaciones post queratoplastia(AU)

ABSTRACT Objective: Identify the optical or therapeutic outcome of penetrating keratoplasty in patients with herpetic keratopathy. Methods: A descriptive cross-sectional study was conducted in which a presentation was made of the results of the scope of penetrating keratoplasties for herpetic keratopathy performed at Hermanos Ameijeiras Clinical Surgical Hospital in Havana. Results: The sample was 33 penetrating keratoplasties: 24 optical (72.7 percent) and 9 tectonic (27.3 percent). Visual acuity was lower than or equal to 0.3 in 5 of them. Of the total sample, 9 opacified, 11 had postoperative complications, 8 recurred in optical penetrating keratoplasties, and 6 in therapeutic penetrating keratoplasties. Rejection occurred in 7 optical penetrating keratoplasties (33.3 percent) and 4 therapeutic penetrating keratoplasties (4%). Complications were observed in 5 (25 percent) optical penetrating keratoplasties and 6 (55.6 percent) therapeutic penetrating keratoplasties. In the postoperative period 22 (66.6 percent) had a visual acuity greater than or equal to 0.3 (p= 0.0000). Conclusions: Inactivity of corneal viral disease benefits the prognosis of grafting due to herpetic keratopathy in opacities of optical keratoplasties. Pre- and postoperative antivirals were found to reduce the recurrence of herpetic disease on the graft and rejection, achieving better visual acuity and greater viability. Postoperative inflammatory severity is associated to an active viral disease or an immune disorder at the time of the grafting resulting in post keratoplasty complications(AU)

Tratamento da hepatite C em pacientes com doença renal crônica e pós-tranplante renal: eficácia e segurança dos esquemas de antivirais de ação direta contendo sofosbuvir / Hepatitis c treatment of renal transplant and chronic kidney disease patients: efficacy and safety of direct-acting antiviral regimens containing sofosbuvir

ABSTRACT BACKGROUND: Direct-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min. OBJECTIVE: To evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients. METHODS: All patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively. CONCLUSION: The direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.

RESUMO CONTEXTO: Os antivirais de ação direta revolucionaram o tratamento da hepatite C, inclusive para os pacientes com doença renal crônica (DRC), porém ainda há divergências no emprego do sofosbuvir (SOF) quando taxa de filtração glomerular (TFG) <30 mL/min. OBJETIVO: Avaliar a eficácia e segurança desses esquemas no tratamento da hepatite C em pacientes com DRC e pós-transplante renal, além de avaliar o impacto do SOF sobre a função renal dos não-dialíticos. MÉTODOS: Todos os pacientes com hepatite C e DRC ou transplante renal que realizaram tratamento com antivirais de ação direta em centro referenciado do Brasil no período de janeiro/2016 a agosto/2017 foram incluídos. A eficácia foi avaliada por meio da carga viral (HCV-RNA), considerando-se cura uma resposta virológica sustentada (RVS) com resultado indetectável após 12 e/ou 24 semanas do término do tratamento (RVS12 e RVS24). A segurança foi determinada pelos eventos adversos e a ribavirina, quando associada, foi introduzida de forma escalonada em todos os pacientes com TFG <60 mL/min. Para determinação do impacto do SOF sobre a função renal, foram observadas as dosagens de creatinina basal, durante e após término do tratamento com seu incremento avaliado por meio da classificação de AKIN (acute kidney injury network). RESULTADOS: Foram incluídos 241 pacientes, sendo 52,7% do sexo feminino, com média de idade de 60,72±10,47 anos. A associação de SOF+daclatasvir predominou em 75,6% dos casos e anemia esteve presente em 28% dos pacientes que utilizaram ribavirina (P=0,040). As taxas de RVS12 e RVS24 foram de 99,3% e 97,1%. O tratamento foi bem tolerado, com eventos adversos pouco relevantes, sendo os mais prevalentes: astenia (57,7%), prurido (41,1%), cefaleia (40,7%) e irritabilidade (40,2%). Entre os pacientes em tratamento conservador e transplantados renais, os valores de creatinina sofreram oscilações AKIN I em 12,5% dos casos, durante o tratamento, persistindo em apenas 8,5% da amostra após o término, dos quais 2,0% apresentavam TFG <30 mL/min inicialmente, com queda para 1,1% após uso do SOF. Apenas 0,5% e 1,6% evoluíram com elevação AKIN II e AKIN III. CONCLUSÃO: Os antivirais de ação direta foram seguros e eficazes em pacientes com DRC tratados com esquemas contendo SOF, apresentando altas taxas de RVS, boa tolerabilidade e poucos eventos adversos graves. A associação com ribavirina aumentou o risco de anemia, portanto sua introdução de forma escalonada parece ser útil nos pacientes com TFG <60 mL/min. Em pacientes com TFG <30 mL/min o SOF não apresentou impacto renal significativo, com creatinina sérica retornando a valores próximos ao basal após o tratamento.

Combined ns5a & ns5b nucleotide inhibitor therapy for patients with chronic hepatitis c with stage 5 chronic kidney disease on hemodialysis / Terapia inibidora de nucleotídeo NS5A& NS5B combinada para pacientes com hepatite C crônica com doença renal crônica em estágio 5, em hemodiálise

ABSTRACT BACKGROUND: Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. OBJECTIVE: Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. METHODS: We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). RESULTS: Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. CONCLUSION: Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.

RESUMO CONTEXTO: A infecção pelo vírus da hepatite C (HCV) é a infecção viral hepática mais comum que afeta pacientes em hemodiálise de manutenção. O tratamento da infecção crônica por HCV no estágio 4 e 5 da doença renal crônica inclui uma combinação de elbasvir/grazoprevir e glecaprevir/pibrentasvir, que não estão disponíveis em muitos países. OBJETIVO: Portanto, realizamos este estudo para procurar a segurança e eficácia da terapia combinada de sofosbuvir nesta população de difícil tratamento. MÉTODOS: Realizamos um estudo de centro único, prospectivo e aberto, no qual pacientes com doença renal crônica em estágio 5 em hemodiálise de manutenção com infecção por HCV. Um total de 18 pacientes foi incluído. Sofosbuvir com daclatasvir ou ledipasvir foi usado de acordo com o genótipo por 12 semanas. O HCV RNA, genótipo, elastografia transitória foi considerado para cada paciente. O HCV RNA foi quantificado na 4ª semana, 12ª semana e 12 semanas após o tratamento para procurar uma resposta virológica sustentada. RESULTADOS: A infecção por genótipo 1 foi observada em 12 (66,7%) pacientes, seguido pelo genótipo 3 em 4 (22,3%), em um paciente do genótipo 2 e em outro, 5. O valor mediano do HCV RNA foi de 2.35.000 IU/mL. Na elastografia transitória, todos tinham rigidez hepática de <9.4 KPa. Todos os pacientes tinham RNA HCV <15 IU/mL na 4ª e 12ª semana de tratamento e 12 semanas após o tratamento. Não foi observada nenhuma alteração significativa na hemoglobina, eGFR e rigidez hepática. CONCLUSÃO: A dose completa sofosbuvir ou seja, 400 mg, em combinação com inibidores NS5A daclatasvir ou ledipasvir foi considerada segura e eficaz em pacientes com doença renal em estágio final, que estão em manutenção hemodiálise.

Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues / Uso off label, compassivo e irracional de medicamentos na pandemia de Covid-19, consequências para a saúde e questões éticas

Abstract When Covid-19 emerged in December last year, there was no vaccine nor was there specific effective treatment for this fast-spreading and life-threatening viral respiratory infection. Clinical trials were planned and are in progress to investigate whether drugs used for influenza, HIV and other viruses, and also anthelmintics (ivermectin, nitazoxanide, niclosamide), and antimalarials (chloroquine, hydroxychloroquine) showing antiviral activity in in vitro assays, are effective and safe for Covid-19. So far there is no convincing evidence that these antiviral and antiparasitic drugs are of any benefit for Covid-19. Notwithsanding the absence of evidence of clinical efficacy, these drugs are widely used outside of clinical trials (off label) for prophylaxis and treatment of this viral infection. The rationale behind the prescription of macrolide antibiotics (azithromycin) for Covid-19 is obscure as well. The widespread prescription and use of drugs of unproven efficacy and safety for Covid-19 is at odds with the rational use of medicines, a cornerstone principle of pharmacotherapy advanced by WHO in 1985. This irrational use of drugs is cause for concern because some of them are associated with serious heart disorders and deaths.

Resumo Quando a Covid-19 surgiu em dezembro do ano passado, não havia vacina nem tratamento eficaz específico para esta infecção respiratória viral de rápida disseminação e risco de vida. Ensaios clínicos foram planejados e estão em andamento para investigar se os medicamentos usados para influenza, HIV e outros vírus e também anti-helmínticos (ivermectina, nitazoxanida, niclosamida) e antimaláricos (cloroquina, hidroxicloroquina) mostrando atividade antiviral em ensaios in vitro são eficazes e seguros para Covid-19. Até o momento, não há evidências convincentes de que esses medicamentos antivirais e antiparasitários sejam benéficos para a Covid-19. Não obstante a ausência de evidência de eficácia clínica, esses medicamentos são amplamente utilizados fora dos ensaios clínicos (off label) para profilaxia e tratamento dessa infecção viral. A lógica por trás da prescrição de antibióticos macrolídeos (azitromicina) para a Covid-19 também é obscura. A ampla prescrição e uso de medicamentos de eficácia e segurança não comprovadas para a Covid-19 está em desacordo com o uso racional de medicamentos, um princípio fundamental da farmacoterapia promovido pela OMS em 1985. Esse uso irracional de medicamentos é motivo de preocupação, porque alguns deles estão associados a graves doenças cardíacas e mortes.