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CUBAN RESEARCH ON COVID-19

Safety and efficacy of intranasal recombinant human interferon alfa 2b as prophylaxis for COVID-19 in patients on a hemodialysis program. Abdo-Cuza A, Castellanos-Gutiérrez R, Treto-Ramirez J, Arencibia-Larin S, Gómez-Pariente T, González-Fernández T, et al. J Renal Endocrinol. 2021;7(1):e05.

Introduction Patients diagnosed with end-stage chronic kidney disease on a hemodialysis program (HDP) represent a risk group for COVID-19. Scientific societies have developed guidelines for the prevention of contagion, but there is no prophylactic medicine in them. Objectives To describe the safety and efficacy of recombinant intranasal human Interferon alfa 2b as prophylaxis for COVID-19 in patients in an HDP. Patients and Methods Intervention description through the monitoring of 15 patients in outpatient HDP. Prior to the administration of the drug, clinical, radiological evaluation and hematology and blood chemistry studies were performed. Daily contact was made with each study patient in person or by telephone, asking about the occurrence of adverse events or symptoms of disease. Results In 47% of the patients, there was leukopenia, lymphopenia in 67% and anemia and thrombocytopenia in 33% respectively, prior to the use of the drug. There was no clinical suspicion of COVID-19 in any of them. Adverse events occurred in 3 patients (20%), all were mild and non-severe. All patients were negative for SARS-CoV-2 real-time polymerase chain reaction (rtPCR) and antibody studies 45 days after the study started. Conclusion The use of intranasal recombinant human interferon alfa 2b as prophylaxis of COVID-19 in patients in a HDP at a dose of 1 MIU daily for ten days, as part of a prevention protocol, has an adequate safety profile. None of the patients in the series was infected with SARS-CoV-2 during the surveillance period.

Cardiovascular effects of new coronavirus infection SARS-CoV-2 (COVID-19) Cuban Society of Cardiology. Moreno-Martínez FL, Moreno-López FL,  Pharm B, Oroz Moreno R. CorSalud. 2020 Jan–Mar;12(1):3–17.

CIGB-258 Immunomodulatory Peptide: Compassionate Use for Critical and Severe COVID-19 Patients. Venegas-Rodríguez R, Santana-Sánchez R, Peña-Ruiz R, Bequet-Romero M, Hernández-Cedeño M, Santiesteban-Licea B, et al. Austin J Pharmacol Ther. 2020 Sep 17;8(1):1–6.

CIGB-258 is an immunomodulatory peptide with anti-inflammatory properties derived from Cellular Stress Protein 60 (HSP60). We report the compassionate use of CIGB-258 for patients with COVID-19 in critical or severe conditions. The results presented herein depict the first data of CIGB-258 clinical application in COVID-19 patients. Sixteen patients with COVID-19 in serious (31%) or critical (69%) conditions were included in this report. All critically ill patients were under invasive mechanical ventilation at CIGB-258 treatment start, and received intravenous administration of 1 mg or 2 mg of CIGB-258 every 12 hours until extubation, followed by 1 mg daily for another three days of treatment. Seriously ill patients were treated with oxygen therapy, including nasal cannula or oxygen mask, and received 1 mg of CIGB-258 every 24 hours, until respiration parameters improvement. The peptide was administered intravenously. Patients in the study were included from March 31 to April 22, 2020. CIGB-258 showed a favorable clinical safety profile. All critically ill patients recovered from the respiratory distress condition and were extubated. Two of these patients had a fatal outcome due to nosocomial infections. All seriously ill patients considerably improved. Levels of biomarkers associated with hyperinflammation and Interleukin (IL-6), IL-10 and Tumor Necrosis Factor (TNFα) significantly decreased during treatment. Assessment of efficacy will require continuing the randomized, placebo-controlled trials of the CIGB-258 treatment.

Convalescent plasma therapy prevents acute respiratory distress syndrome in patients with SARS-CoV-2 virus disease. Macías Abraham C, Porto González DE, Legrá Ayala A, Forrellat Barrios M, Lam Díaz RM, Cordoví Rodríguez D, et alRev Cubana Hematol Inmunol Hemoter. 2020;34.

Background SARS-CoV-2 disease 2019 is a pandemic with no specific therapeutic agents and substantial mortality. The success of convalescent plasma therapy is based on the transfused plasma had high concentrations of anti-SARS-CoV-2 antibodies, and on the safe preparation of serum to eliminate potential risk factors, such as the transmission of viruses via transfusion. Study design and Methods Five patients laboratory confirmed COVID-19, diagnosed using reverse transcriptase–polymerase chain reaction (RT-PCR) classified like of care and seriously non-ventilated patients with moderate hypoxemia were received 300 mL convalescent plasma treatment. Each donation was tested for antibody titersIgG class anti-SARS-CoV-2 by UMELISA. The transfused plasma units had an average antibody titer of 836.00 ± 617.155. The time interval between the onset of symptoms and transfusion was 9 days (7.20± 3). Before and after each transfusion, clinical and laboratory parameters were evaluated. Results At 24-hour after the plasma transfusion, oxygen partial pressure increased from medium value of 70.4 to 101.6 mm Hg, C-reactive protein and lactate dehydrogenase enzyme values decreased in 3 of 5 patients; however, the ferritin values increased in all the patients. Post-transfusion hospital discharge time was from 48 hours to 12 days and the SARS-CoV-2 PCR was negative between 3 and 5 days. No adverse transfusion reactions were reported. Conclusion This report emphasis about the efficacy and security of convalescent plasma transfusion to care and seriously non-ventilated patients infected like a preventive therapy for severe respiratory distress for SARS-CoV-2 virus disease.

COVID-19 and cancer in Cuba. Rubio MC, Sánchez L, Abreu-Ruíz G, Bermejo-Bencomo W, Crombet T, Lage A. Sem Oncol. 2020 Aug 7.

The COVID-19 pandemic has called attention to the contribution of comorbidities, including cancer and brought additional challenges to previously existing programs for cancer treatment and control. The COVID-19 pandemic in Cuba was addressed through an integrated all-society action plan that to date has been largely successful with a low incidence of COVID-19 and mortality rates several-fold lower than worldwide averages. Despite downsizing many other health components all oncology services were maintained. Between March 11, when the first case was detected, until July 23, Cuba reported 2,449 cases of COVID-19 that included 28 (1.14%) with a diagnosis of cancer. Distribution among cancer diagnoses did not deviate from that expected according to cancer epidemiology in Cuba. However, although the probability of getting infected with the coronavirus for a cancer patient (0.012%), was not higher than that of the general population (0.020%), 9 of the 28 (32.1%) died, a lethality higher than that of COVID-19 patients without cancer (3.5%) a difference that is statistically significant (P< .001). We argue that going forward scientific research on the relationship of aging, inflammation and cancer, including identification of biomarkers and the development of novel therapeutic interventions, should become one of the priorities in the post-COVID agenda of both oncologists and infectious disease scientists.

COVID pandemic: update from Cuba. An effective response. Salas D. Dialect Anthropol. 2020 Aug 13;44:233–7.

On March 11, 2020, the WHO upgraded the official status of COVID-19 to a pandemic. That same day, Cuba’s public health authorities confirmed the first local cases of the new coronavirus, in connection to European visitors. Within weeks, strings of infections appeared across the island, first among foreigners, visiting emigres and their contacts, and then as a result of local transmission. In late April, Cuba’s COVID-19 curve peaked at 847 active hospitalized cases. By late July, however, as the pandemic sweeps the Americas, Cuba seems to have crushed the first wave of the virus, with a cumulative fatality toll of 87. Still, the fight is far from over and the virus’s resurgence is not out of the question as the country advances into a “new normal.”

Desempeño social del especialista en Medicina General Integral en el enfrentamiento a la COVID-19Cañete Rojas Y, Gallardo Sánchez Y, Rosabal Martínez SY, Peña Peña DM. Rev Hum Médicas. 2020;20(2):297–311. Spanish only

El enfrentamiento a la COVID-19 constituye un desafío para los profesionales de la salud en Cuba esencialmente con los cuidados a la población. El trabajo tiene como objetivo describir el desempeño social del especialista en Medicina General Integral en el enfrentamiento a la COVID-19.Se realizó un estudio que evidenció el desempeño social de este especialista en el enfrentamiento epidemiológico a la COVID-19.

Estimating undocumented COVID-19 infections in Cuba by means of a hybrid mechanistic-statistical approach. Gil G, Lage-Castellanos A. arXiv.org. 2020 Aug 7.

We adapt the hybrid mechanistic-statistical approach of Ref. [1] to estimate the total number of undocumented Covid-19 infections in Cuba. This scheme is based on the maximum likelihood estimation of a SIR-like model parameters for the infected population, assuming that the detection process matches a Bernoulli trial. Our estimations show that (a) 60% of the infections were undocumented, (b) the real epidemics behind the data peaked ten days before the reports suggested, and (c) the reproduction number swiftly vanishes after 80 epidemic days.

Gender and fear of COVID-19 in a Cuban population sample. Broche-Pérez Y, Fernández-Fleites Z, Jiménez-Puig E, Fernández-Castillo E, Rodríguez-Martin BC. J Mental Health Addic. 2020 Jun 12.

The COVID-19 pandemic is a global health emergency that could potentially have a serious impact on public health. Fear has been one of the most frequent psychological reaction in the population during the current pandemic. The aim of this study was to compare fear of COVID-19 between genders and to examine whether the differences between genders may be predictors of fear of COVID-19 scores. A cross-sectional web based survey design was adopted. The sample comprised 772 Cuban participants. The Fear of COVID-19 Scale was used to explore fear reactions in the sample. An independent-samples t test was conducted to compare the fear of COVID-19 scores between genders, and multinomial logistic regression was modeling to identify variables independently associated with fear of coronavirus. In our sample, on average, female participants experienced significantly greater fear of COVID-19 than men. The gender of participants significantly predicted the level of fear of COVID-19. Being female was a predictor of medium and high levels of fear of COVID-19. The odds of a female with middle fear levels compared to low fear was 3.13 times more than for a male, and the odds of a female with high fear levels compared to low fear was 3.45 times more than for a male. Our results corroborate international research that indicate a greater psychological vulnerability in women during the COVID-19 pandemic. This result points to the need to design interventions that reduce the negative impact of the current outbreak on women’s mental health.

How Mathematical Approaches Could Help Decision-Making to Epidemic Control? The Successful Experience against COVID-19 in Cuba. Sánchez L, Lorenzo-Luaces P, Sebrango C, Torres A, Fonte C, Crespo M, et al. SSRN. 2020 Jun 26.

Background There is a gap for the effective use of mathematical models for real-time decision-making. We aimed to illustrate with the Cuban experience to control the COVID-19, how mathematical models can be put in place to answer key decision-makers´ questions. Methods A science-policy partnership was created to mutually define questions, communicate results and facilitate the translation of modeling advice into actions. For forecasting and planning at national level mechanistic models and machine learning based on the epidemic patterns in other countries were used. Statistical models to explain the variability of transmission was used to stratify control actions. The effect of interventions was assessed using branching process models, time varying reproduction number (Rt) and social mixing patterns by location, and by age group. Findings The mathematical approach implemented contribute to successful control of the COVID-19 in Cuba. The urbanization, living conditions and the economic index explain the 73% of the variability of the transmission at provincial level. Increased risk of transmission were identified in 33 municipalities mostly in densely populated urban areas with high aging index. Control intervention reduced the transmission from R0=2.84 (95% CI: 1.52 – 4.76) to Rt=0.6 (95% CI:0.2-2.38). The highest transmission was detected among adolescents and from people older than 60 years. Conclusions Understanding the key questions for decision-making at all times, translating problems into a mathematical language, integrating different approaches to their solution and being able to present the results in an easy-to-understand way is vital to have a timely impact on controlling the epidemic.

Implicaciones de la infección por el nuevo coronavirus SARS-Cov-2 para el sistema digestivoInfante Velázquez M. Arch Cubanos Gastroenterol. 2020 Aug;1(2).  Spanish only

La infección por el nuevo coronavirus SARS-Cov 2 afecta de manera significativa al sistema respiratorio, aunque no deja de tener repercusión sobre otros órganos, aparatos y sistemas de la economía. En el caso específico del sistema digestivo, se ha podido determinar la replicación del virus en células de algunos de sus órganos, elemento este que influye en la aparición de síntomas en los pacientes infectados o modificaciones en la analítica relacionada. Algunos de los fármacos utilizados en el tratamiento se acompañan de manifestaciones digestivas como efectos no deseados. La presencia del virus en la mucosa nasofaríngea hace que los procedimientos endoscópicos sobre el tracto digestivo superior sean altamente riesgosos, lo que ha impuesto necesariamente cambios en los sistemas de trabajo de las unidades de endoscopía.  Finalmente, existe un grupo de pacientes con enfermedades intestinales y hepáticas cuyo mecanismo patogénico o su tratamiento está relacionado con la inmunosupresión, por lo que requieren de una atención especializada y particularizada. En esta revisión se aportarán los conocimientos hasta ahora establecidos sobre estos aspectos, de modo tal que sirva a los profesionales relacionados con el diagnóstico y tratamiento de las enfermedades digestivas.

The impact of COVID-19 on mental health in Hispanic Caribbean region. Llibre-Guerra JJ, Jiménez-Velázquez IZ, Llibre-Rodríguez JJ, Acosta D. Cambridge University Press. 2020 May 20.

The recent global severe acute respiratory syndrome coronavirus 2 pandemic will leave its shadow over mental health in our society, especially among the most vulnerable such as elderly populations and those living with mental health disorders, including Alzheimer’s disease (AD) and related dementias. Cognitive impairment and/or dementia itself does not increase the risk for coronavirus disease 2019 (COVID-19). However, people living with cognitive impairment might have difficulties understanding public health information or remembering safeguard procedures (Wang et al., 2020). New measures taken at country level to prevent the spread of the disease are also likely to increase or worsen other mental-health-related disorders like anxiety, depression, substance abuse, post-traumatic stress disorder, and domestic violence (Galea et al., 2020). In early March 2020 Cuba, Dominican Republic and Puerto Rico reported their first COVID-19 cases, and various strategies are underway to tackle with the raising number of cases. The double hit of COVID-19 in elderly populations and among those with comorbid conditions has raised significant concerns in the Caribbean region. In light of these concerns, health care providers and caregivers should pay extra attention to those in most vulnerable situations. In addition, due to the potential impact of COVID-19 on mental health in the elderly population living in the Caribbean area, immediate efforts focused on prevention and early detection of mental health disorders related with the outbreak are required. On this commentary, we examined current situation and impact of COVID-19 on mental health in the Caribbean Hispanic region (Cuba, Dominican Republic, and Puerto Rico). Furthermore, we provide recommendations to health care providers and caregivers to better cope and manage the impact of COVID-19 in our region.

Therapeutic effectiveness of interferon alpha 2b treatment for COVID-19 patient recovery. Pereda R, González D, Rivero HB, Rivero JC, Pérez A, López LR. medRxiv. 2020 Aug 4.

Background Effective antiviral treatments are required to contain the ongoing coronavirus disease 2019 (COVID-19) pandemic. A previous report in 814 patients COVID-19 positive in Cuba provided preliminary therapeutic efficacy evidence with interferon alpha-2b (IFN alpha-2b) from March 11 to April 14, 2020. This study, re-evaluates the contribution of IFN-α2b on the evolution of all patients, after 98 days of the epidemic, in a period from March 11 to June 17, 2020. Method A prospective observational study was implemented to monitor a therapeutic intervention with IFN alpha-2b used in the national protocol for COVID-19 attending in Cuba. Were included patients with positive throat swab specimens by real time RT-PCR who gave informed consent and had no contraindications for IFN treatment. Patients received therapy as per the Cuban COVID protocol that included a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular or subcutaneous administration of IFN alpha-2b The primary endpoint was the proportion of patients discharged from hospital, secondary was the case fatality rate and several outcomes related to time variables were also evaluated. Results From March 11th until June 17th, 2295 patients had been confirmed SARS-CoV-2 positive in Cuba, 2165 were treated with Heberon Alpha R and 130 received the approved protocol without IFN. The proportion of fully recovered patients was higher in the IFN-treated compared with non-IFN treated group. Prior IFN treatment decreases the likelihood of intensive care and increases the survival after severe or critical diseases. The benefits of IFN were significantly supported by time variables analyzed. Conclusions This second report confirm the preliminary evidences from first for the therapeutic effectiveness of IFN alpha-2b for SARS-Cov-2 infection and postulated that Heberon Alpha R is the main component within the antiviral triad used as a therapeutic intervention in the Cuban protocol COVID-19.

Therapeutic effectiveness of interferon-alpha2b against COVID-19: the Cuban experience. Pereda R, González D, Rivero H, Rivero J, Pérez A, López LR. medRxiv. 2020 Jun 9.

Background Effective therapies are needed to control the SARS-Cov-2 infection pandemic and reduce mortality associated with COVID-19. Several clinical studies have provided evidence for the antiviral effects of type I interferons (IFNs) in patients with respiratory coronaviruses. This study assessed the therapeutic efficacy of IFN-alpha 2b in patients infected with SARS-CoV-2 during the first month after the outbreak began in Cuba. Method This multicenter prospective observational study was conducted in 16 hospitals in 8 Cuban provinces. Participants were patients with confirmed SARS-CoV-2 infection detected from throat swab specimens by real time RT-PCR who gave informed consent and had no contraindications for IFN treatment. Patients received therapy as per the Cuban COVID protocol, that included a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular administration of IFN-alpha 2b (Heberon Alpha R, Center for Genetic Engineering and Biotechnology, Havana), 3 times per week, for 2 weeks. The primary endpoint was the proportion of patients discharged from hospital (without clinical and radiological symptoms and non-detectable virus by RT-PCR). The secondary endpoint was the case fatality rate (CFR), defined as the number of confirmed deaths divided by the number of confirmed cases. Results From March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba, 761 (93.4%) were treated with Heberon Alpha R and 53 received the approved protocol without IFN treatment. The proportion of fully recovered patients was higher in the IFN-treated compared with non-IFN treated group (95.4% vs 26.1%, p<0.01). The CFR for all patients was 2.95%, and for those patients who received IFN-alpha 2b the CFR was reduce to 0.92. The estimated global CFR is 6.34% and 4.05% for the Americas reported by WHO and PAHO, respectively. In this study, 82 patients (10.1%) required intensive care and, of these, 42 (5.5%) were treated with IFN. Conclusions This report provides preliminary evidence for the therapeutic effectiveness of IFN alpha-2b for COVID-19 and suggests that the use of Heberon Alpha R may contribute to complete recovery.

Use of a humanized anti-CD6 monoclonal antibody (itolizumab) in elderly patients with moderate COVID-19. Ramos-Suzarte M, Díaz Y, Martín Y, Calderón NA, Santiago W, Vinet O, et al. medRxiv. 2020 Jul 30.

Introduction The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a recent outbreak of Coronavirus Disease (COVID-19). In Cuba, the first case of COVID-19 was reported on March 11. Elderly with multiple comorbidities are particularly susceptible to adverse clinical outcomes in the course of SARS CoV-2 infection. During the outbreak, a local transmission event took place in a nursing home in Villa Clara province, Cuba, in which nineteen elderly residents were positive for SARS-CoV-2. Methods Based on the increased susceptibility to viral-induced cytokine release syndrome inducing respiratory and systemic complications in this population, the patients were included in an expanded access clinical trial to receive itolizumab, an anti-CD6 monoclonal antibody. Results All the patients had underlying medical conditions. The product was well tolerated. After the first dose, the course of the disease was favorable and 18 out of 19 (94.7%) patients were discharged clinically recovered with negative RT-PCR at 13 days (median). One dose of itolizumab, circulating IL-6 decreased in the first 24-48 hours in patients with high baseline values, whereas in patients with low levels, this concentration remained over low values. To preliminary assess the effect of itolizumab, a control group was selected among the Cuban COVID-19 patients, which did not receive immunomodulatory therapy. Control subjects were well-matched regarding age, comorbidities and severity of the disease. Every three moderately ill patients treated with itolizumab, one admission in intensive care unit (ICU) was prevented. Discussion/Conclusion Itolizumab was well tolerated. Its effect is associated with a reduction and controlling IL-6 serum levels. Moreover, treated patients had a favorable clinical outcome, considering their poor prognosis. This treatment is associated significantly with a decrease the risk to be admitted in ICU and reduced 10 times the risk of death. This study corroborates that the timely use of itolizumab, in combination with other antiviral and anticoagulant therapies, is associated with a reduction the COVID-19 disease worsening and mortality. The humanized antibody itolizumab emerges as a therapeutic alternative for patients with COVID-19 and suggests its possible use in patients with cytokine release syndrome from other pathologies.

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