Safety and effectiveness of RBD-specific polyclonal equine F(ab´)2 fragments for the treatment of hospitalized patients with severe Covid-19 disease: A retrospective cohort study.

BACKGROUND: Passive immunotherapy has been evaluated as a therapeutic alternative for patients with COVID-19 disease. Equine polyclonal immunotherapy for COVID-19 (EPIC) showed adequate safety and potential efficacy in a clinical trial setting and obtained emergency use authorization in Argentina. We studied its utility in a real world setting with a larger population. METHODS: We conducted a retrospective cohort study at "Hospital de Campaña Escuela-Hogar" (HCEH) in Corrientes, Argentina, to assess safety and effectiveness of EPIC in hospitalized adults with severe COVID-19 pneumonia. Primary endpoints were 28-days all-cause mortality and safety. Mortality and improvement in modified WHO clinical scale at 14 and 21 days were secondary endpoints. Potential confounder adjustment was made by logistic regression weighted by the inverse of the probability of receiving the treatment (IPTW) and doubly robust approach. FINDINGS: Subsequent clinical records of 446 non-exposed (Controls) and 395 exposed (EPIC) patients admitted between November 2020 and April 2021 were analyzed. Median age was 58 years and 56.8% were males. Mortality at 28 days was 15.7% (EPIC) vs. 21.5% (Control). After IPTW adjustment the OR was 0.66 (95% CI: 0.46-0.96) P = 0.03. The effect was more evident in the subgroup who received two EPIC doses (complete treatment, n = 379), OR 0.58 (95% CI 0.39 to 0.85) P = 0.005. Overall and serious adverse events were not significantly different between groups. CONCLUSIONS: In this retrospective cohort study, EPIC showed adequate safety and effectiveness in the treatment of hospitalized patients with severe SARS-CoV-2 disease.

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients. OBJECTIVE: To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19. DESIGN, SETTING AND PARTICIPANTS: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021. INTERVENTION: Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient's weight, for 2 days. MAIN OUTCOMES AND MEASURES: The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points. RESULTS: The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3-6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32-1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes. LIMITATIONS: Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population. CONCLUSION: Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04529525 .

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19): a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: To assess the efficacy of ivermectin in addition to standard treatment compared to standard treatment alone in reducing hospitalizations in the COVID-19 patient population. TRIAL DESIGN: IVERCOR-COVID19 will be a single-center, prospective, randomized, double-blind, parallel group (1:1 ratio), placebo-controlled study. PARTICIPANTS: Patients who meet the following criteria will be invited to participate: Inclusion criteria: (1) Over 18 years of age who reside in the province of Corrientes at the time of diagnosis. (2) Confirmed diagnosis of COVID-19 by polymerase chain reaction (PCR) test for detection of SARS-CoV2 in the last 48 h. (3) In the case of women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study and for the entire period of time for the duration of the study and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study). (4) Weight at the time of inclusion greater than 48 kg. (5) That they sign the informed consent for participation in the study. EXCLUSION CRITERIA: (1) pregnant or breastfeeding women; (2) known allergy to ivermectin or some of the components of ivermectin tablets or placebo; (3) current use of home oxygen; (4) require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19; (5) presence of mal-absorptive syndrome; (6) presence of any other concomitant acute infectious disease; (7) known history of severe liver disease, for example liver cirrhosis; (8) need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19; (9) need or use of hydroxychloroquine or chloroquine; (10) use of ivermectin up to 7 days prior to randomization; (11) patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months; and (12) current participation or in the last 30 days in a research study that has included the administration of a drug (Table 1). Table 1 Ivermectin/placebo dose according to patient weight Patient weight Ivermectin/placebo dose Total dose (mg) Equal to or greater than 48 kg and less than 80 kg 2 tablets of 6 mg each at the time of inclusion and 2 tablets 24 h after the first intake 24 Equal or greater than 80 kg and less than 110 kg 3 tablets of 6 mg each at the time of inclusion and 3 tablets 24 h after the first intake 36 Equal or greater than 110 kg 4 tablets of 6 mg each at the time of inclusion and 4 tablets 24 h after the first intake 48 The study will be carried out by the Ministry of Public Health of the Province of Corrientes (Argentina) in coordination with the Institute of Cardiology of Corrientes in the Province of Corrientes, Argentina. INTERVENTION AND COMPARATOR: Intervention group: patients who are randomized to ivermectin will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg ivermectin; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of ivermectin; patients weighing more than 110 kg will receive 4 tablets of 6 mg ivermectin) the day they enter the study and the same dose 24 h after the first dose. CONTROL GROUP: patients who are randomized to placebo will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg placebo; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of placebo; patients weighing more than 110 kg will receive 4 tablets of 6 mg placebo) on the day they enter the study and the same dose 24 h after the first dose (Table 2). Table 2 Inclusion and exclusion criteria Inclusion criteria Exclusion criteria 1. Over 18 years of age who reside in the province of Corrientes at the time of diagnosis 1. Pregnant or breastfeeding women 2.Confirmed diagnosis of COVID-19 by polymerase chain reaction test for detection of SARS-CoV2 in the last 48 h 2. Known allergy to ivermectin or some of the components of ivermectin tablets or placebo 3. In case of being women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study, during the entire period of time for the duration of the study, and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study) 3. Current use of home oxygen 4. Weight at the time of inclusion equal to or greater than 48 kg 4. That require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19 5. That they sign the informed consent for participation in the study 5. Presence of mal-absorptive syndrome 6. Presence of any other concomitant acute infectious disease 7. Known history of severe liver disease, for example liver cirrhosis 8. Need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19 9. Need or use of hydroxychloroquine or chloroquine 10. Use of ivermectin up to 7 days prior to randomization 11. Patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months 12. Current participation or in the last 30 days in a research study that has included the administration of a drug MAIN OUTCOMES: Primary outcome will be the percentage of hospitalizations in patients with COVID-19 in the intervention and control groups. SECONDARY OUTCOMES: time to hospitalization in each of the arms of the study: number of days elapsed from the inclusion in the study until the hospitalization of the patient; percentage of use of invasive mechanical ventilation in each of the study arms: every patient who is connected to invasive mechanical ventilation after signing the informed consent and before the final study visit; time to invasive mechanical ventilation in each of the arms of the study: number of days elapsed from inclusion in the study to connection to invasive mechanical ventilation of the patient; percentage of patients requiring dialysis in each of the study arms: all patients who require renal replacement therapy of any kind, temporary or permanent, and which begins after signing the informed consent and before the final visit; mortality from all causes in each of the two trial groups: death of the patient, from any cause. Negative PCR swab at 3 ± 1 and 12 ± 2 days after entering the study. Ivermectin safety: it will be analyzed according to the incidence of adverse events that patients present in the intervention and control groups. The end of study (EOS) is recorded as the day the patient is discharged or death. Discharge will be granted according to the current recommendations of the Ministry of Public Health of the Province of Corrientes. A follow-up visit (EOF) will be made by phone 30 days after the EOS when vital status will be verified. RANDOMIZATION: Randomization will be done through a web system with randomly permuted blocks. Randomization will be carried out by one of the investigators who will not participate in the inclusion of patients or in the delivery of medication (Table 3). Table 3 EOS end of study, EOF end of follow-up Visit Basal and randomization, day 0 Day 3 ± 1 Day 12 ± 2 V#1 V#2 V#3 EOS EOF Informed consent X - - - - Inclusion/exclusion criteria X - - - - Demographic data and medical history X - - - - Concomitant medication X - - - - Vital signs* X X - - - Anthropometric data^ X - - - - Basal laboratory X - - - - PCR swab - X X - - Assessment of adverse events - X X X - Final objective evaluation - X X X X Randomization X - - - - Adherence to treatment X X - - - *Includes heart rate, temperature, and oxygen saturation by a digital saturometer ^Includes weight and height BLINDING (MASKING): The participants, investigators, care providers, and outcome assessors will be blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): We will include a total of 500 patients (250 patients in each group). TRIAL STATUS: This is version 1.0, 17 August 2020. The recruitment started on 19 August 2020, and we anticipate the trial will finish recruitment on 31 December 2020. TRIAL REGISTRATION: ClinicalTrials.gov NCT04529525 . Registered on 26 August 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

[Pleural tuberculosis in a hospital in Northeast Argentina]. / Tuberculosis pleural en un hospital del noreste argentino.

Pleural tuberculosis ranks first in extrapulmonary sites. The aim of this study was to estimate the proportion pleural TB among TB cases, and characterize the presentation, diagnostic methods and outcomes of patients hospitalized in the ángela I. de Llano hospital, Corrientes, Argentina, between January 1, 2011 and June 30, 2014. We performed a descriptive and observational study. Ten patients were diagnosed with TB pleural effusion. The mean age was 48.5 ± 16.9 (16-63) years. The average evolution time before the consultation was 21.3 ± 11.6 (7-45) days. All were unilateral, exudates, with cell count of 2152 ± 687 (84-7000) cells; 8 cases had lymphocyte predominance. The average value of adenosine deaminase determination (ADA) was 92.7 ± 27.0 (60-150) IU/l. The pleural effusion smear was positive in 4 cases; development of Mycobacterium tuberculosis was obtained in 3 cases; histologically, three presented caseating granulomas. One death was recorded. Although pleural TB usually occurs in male patients, middle-aged, as a unilateral exudative pleural effusion with lymphocytic predominance, with less than a month's evolution, diagnostic certainty has its limitations, thus clinical suspicion, epidemiology, imaging, pathology and laboratory tests, and determination of adenosine deaminase levels, represent a valuable contribution to diagnosis.

Tuberculosis pleural en un hospital del Noreste Argentino / Pleural tuberculosis in a hospital in Northeast Argentina

La tuberculosis (TB) pleural ocupa el primer lugar dentro de las localizaciones extrapulmonares. El objetivo de este trabajo fue estimar la proporción de TB pleural entre los casos de TB y caracterizar la forma de presentación, métodos de diagnóstico y evolución de los pacientes internados en el Servicio de Clínica Médica del hospital Ángela I. de Llano, Corrientes, Argentina, durante el período enero de 2011 a junio de 2014. Se realizó un estudio observacional y descriptivo. Fueron diagnosticados 10 pacientes con TB pleural. La edad media fue 48.5 ± 16.9 (16-63) años. El tiempo de evolución antes de la consulta fue 21.3 ± 11.6 (7-45) días. Todos fueron exudados unilaterales, con recuento celular de 2152 ± 687 (84-7000) células; 8 casos presentaron predominio linfocitario. El valor promedio de adenosina deaminasa (ADA) fue 92.7 ± 27.0 (60-150) UI/l. La baciloscopia del líquido pleural fue positiva en 4 casos; se obtuvo desarrollo de Mycobacterium tuberculosis en 3 casos. En el estudio histológico 3 presentaron granulomas caseificantes. Se registró un óbito. Si bien suele darse en hombres, de mediana edad, con un tiempo de evolución menor al mes, como un derrame pleural unilateral exudativo a predominio de linfocitos, el diagnóstico de certeza presenta sus limitaciones, por ende la clínica, la epidemiología, los estudios por imágenes, la anatomía patológica y los exámenes de laboratorio, como la determinación de los niveles de ADA, constituyen un aporte valioso para el diagnóstico.

Pleural tuberculosis ranks first in extrapulmonary sites. The aim of this study was to estimate the proportion pleural TB among TB cases, and characterize the presentation, diagnostic methods and outcomes of patients hospitalized in the Ángela I. de Llano hospital, Corrientes, Argentina, between January 1, 2011 and June 30, 2014. We performed a descriptive and observational study. Ten patients were diagnosed with TB pleural effusion. The mean age was 48.5 ± 16.9 (16-63) years. The average evolution time before the consultation was 21.3 ± 11.6 (7-45) days. All were unilateral, exudates, with cell count of 2152 ± 687 (84-7000) cells; 8 cases had lymphocyte predominance. The average value of adenosine deaminase determination (ADA) was 92.7 ± 27.0 (60-150) IU/l. The pleural effusion smear was positive in 4 cases; development of Mycobacterium tuberculosis was obtained in 3 cases; histologically, three presented caseating granulomas. One death was recorded. Although pleural TB usually occurs in male patients, middle-aged, as a unilateral exudative pleural effusion with lymphocytic predominance, with less than a month´s evolution, diagnostic certainty has its limitations, thus clinical suspicion, epidemiology, imaging, pathology and laboratory tests, and determination of adenosine deaminase levels, represent a valuable contribution to diagnosis.

Drug-induced hepatotoxicity and tuberculosis in a hospital from the Argentinian northeast: cross-sectional study.

INTRODUCTION: Hepatotoxicity is a serious adverse effect of tuberculosis treatment. OBJECTIVES: The aim of this study was to estimate the prevalence, forms of presentation and clinical course of patients with hepatotoxicity secondary to antituberculosis drugs. METHODS: We performed a descriptive and observational study using medical records from patients older than 16 years between Jaunary 1, 2011 and June 30, 2014 in the Medical Clinic of the Hospital Angela I. de Llano, Corrientes, Argentina. RESULTS: During the study period 118 patients were diagnosed with tuberculosis; 7.6% (nine patients: six men and three women) developed hepatotoxicity. Six had hepatocellular characteristics and three had cholestatic characteristics. The mean age was 34.6 ± 14.3 years. All patients received triple-association medication plus ethambutol on a daily basis. They were hospitalized for an average of 16 days (range: 4-37). Four were asymptomatic, three had anorexia, nausea and vomiting, and two were jaundiced. The interval between the beginning of treatment and the appearance of clinical manifestations was on average 9.6 days (range 2-23). The interval between the onset and cessation of treatment was on average 15.2 days (range 3-48). No patients required liver transplantation and no deaths were recorded. CONCLUSIONS: Hepatotoxicity of antituberculosis drugs has been associated with factors such as age over 35 years, female gender, pregnancy, malnutrition, alcoholism, human immunodeficiency virus, preexisting liver disease, daily treatment, diabetes, renal failure, and combined treatment. Since we lack a regional registry, this casuistry could be the kickoff for the creation of regional and/or national records of anti-tuberculosis drugs adverse effects and pharmacologic vigilance. Also, there is a need for programs to actively seek this complication, and the development of guidelines for unifying concepts and treatment protocols.

INTRODUCCIÓN : La hepatotoxicidad es un efecto adverso grave debido al tratamiento antituberculoso. OBJETIVOS: El objetivo de este trabajo fue estimar la prevalencia, las formas de presentación y evolución de pacientes con hepatotoxicidad por antifímicos. MÉTODOS: Se realizó un estudio observacional y descriptivo. Se incluyeron historias clínicas de pacientes mayores de 16 años, desde el 1 de enero de 2011 hasta el 30 junio de 2014 en el Servicio de Clínica Médica del Hospital Ángela I. de Llano, de Corrientes, Argentina. RESULTADOS: Durante el período estudiado se diagnosticaron 118 pacientes con tuberculosis. El 7,6% (nueve pacientes, seis hombres y tres mujeres) desarrolló hepatotoxicidad, de carácter hepatocelular en seis y colestásico en tres. La media de edad fue 34,6 años ± 14,3. Todos recibieron triple asociación y etambutol diariamente. Se los internó, en promedio 16 días (rango 4 a 37). Cuatro se encontraban asintomáticos, tres presentaron anorexia, náuseas y vómitos, y dos ictericia. El intervalo entre el inicio del tratamiento y la manifestación clínica fue en promedio de 9,6 días (rango 2 a 23). El intervalo entre el inicio y la suspensión del tratamiento fue en promedio 15,2 días (rango 3 a 48). Ninguno requirió trasplante hepático ni se registró ningún óbito. CONCLUSIONES: La hepatotoxicidad por antifímicos se ha asociado a factores como edad mayor de 35 años, sexo femenino, embarazo, desnutrición, alcoholismo, presencia de virus de la inmunodeficiencia humana, hepatopatía previa, tratamiento diario, diabetes, insuficiencia renal, tratamiento combinado. Debido a la escasez de registros regionales, esta casuística podría ser el inicio para la creación de registros, a nivel regional y/o nacional, de efectos adversos, el establecimiento de programas de farmacovigilancia que contribuyan a la búsqueda activa de esta complicación, y el desarrollo de guías para unificar conceptos y protocolos de tratamiento específicos.