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Cardiovascular Safety of Azithromycin in Patients Hospitalized With COVID-19: A Prespecified Pooled Analysis of the COALITION I and COALITION II Randomized Clinical Trials.
Furtado, RHM, Barros E Silva, PGM, Fonseca, HAR, Serpa-Neto, A, Correa, TD, Guimarães, HP, Pereira, AJ, Olivato, GB, Zampieri, FG, Lisboa, T, et al
The American journal of cardiology. 2024;:18-24
Abstract
The cardiovascular safety from azithromycin in the treatment of several infectious diseases has been challenged. In this prespecified pooled analysis of 2 multicenter randomized clinical trials, we aimed to assess whether the use of azithromycin might lead to corrected QT (QTc) interval prolongation or clinically relevant ventricular arrhythmias. In the COALITION COVID Brazil I trial, 667 patients admitted with moderate COVID-19 were randomly allocated to hydroxychloroquine, hydroxychloroquine plus azithromycin, or standard of care. In the COALITION COVID Brazil II trial, 447 patients with severe COVID-19 were randomly allocated to hydroxychloroquine alone versus hydroxychloroquine plus azithromycin. The principal end point for the present analysis was the composite of death, resuscitated cardiac arrest, or ventricular arrhythmias. The addition of azithromycin to hydroxychloroquine did not result in any prolongation of the QTc interval (425.8 ± 3.6 ms vs 427.9 ± 3.9 ms, respectively, mean difference -2.1 ms, 95% confidence interval -12.5 to 8.4 ms, p = 0.70). The combination of azithromycin plus hydroxychloroquine compared with hydroxychloroquine alone did not result in increased risk of the primary end point (proportion of patients with events at 15 days 17.2% vs 16.0%, respectively, hazard ratio 1.08, 95% confidence interval 0.78 to 1.49, p = 0.65). In conclusion, in patients hospitalized with COVID-19 already receiving standard-of-care management (including hydroxychloroquine), the addition of azithromycin did not result in the prolongation of the QTc interval or increase in cardiovascular adverse events. Because azithromycin is among the most commonly prescribed antimicrobial agents, our results may inform clinical practice. Clinical Trial Registration: NCT04322123, NCT04321278.
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Anti-spike antibody durability after SARS-CoV-2 vaccination in adolescent solid organ transplant recipients.
McAteer, J, Kalluri, DD, Abedon, RR, Qin, CX, Auerbach, SR, Charnaya, O, Danziger-Isakov, LA, Ebel, NH, Feldman, AG, Hsu, EK, et al
Pediatric transplantation. 2024;(1):e14671
Abstract
BACKGROUND Adolescent solid organ transplant recipients (aSOTRs) who received three doses of the COVID-19 mRNA vaccine experience high seroconversion rates and antibody persistence for up to 3 months. Long-term antibody durability beyond this timeframe following three doses of the SARS-CoV-2 mRNA vaccine remains unknown. We describe antibody responses 6 months following the third vaccine dose (D3) of the BNT162b2 mRNA vaccination among aSOTRs. METHODS Participants in a multi-center, observational cohort who received the third dose of the vaccine were analyzed for antibodies to the SARS-CoV-2 spike protein receptor-binding domain (Roche Elecsys anti-SARS-CoV-2-S positive: ≥0.8, maximum: >2500 U/mL). Samples were collected at 1-, 3-, and 6-months post-D3. Participants were surveyed at each timepoint and at 12-months post-D3. RESULTS All 34 participants had positive anti-RBD antibody titers 6 months post-D3. Variations in titers occurred between 3 and 6 months post-D3, with 8/28 (29%) having decreased antibody levels at 6 months compared to 3 months and 2/28 (7%) reporting increased titers at 6 months. The remaining 18/28 (64%) had unchanged antibody titers compared to 3-month post-D3 levels. A total of 4/34 (12%) reported breakthrough infection within 6 months and 3/32 (9%) reported infection after 6-12 months following the third dose of the SARS-CoV-2 mRNA vaccine. CONCLUSIONS The results suggest that antibody durability persists up to 6 months following three doses of the SARS-CoV-2 mRNA in aSOTRs. Demography and transplant characteristics did not differ for those who experienced antibody weaning. Breakthrough infections did occur, reflecting immune-evasive nature of novel variants such as Omicron.
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Abnormal Iron Status and Adverse Outcome After Elective Cardiac Surgery: A Prospective, Observational Multicenter Study.
Hazen, YJJM, Noordzij, PG, Geuzebroek, GSC, Koets, J, Somers, T, Gerritse, BM, Scohy, TV, Vernooij, LM, van Gammeren, A, Thelen, MHM, et al
Journal of cardiothoracic and vascular anesthesia. 2024;(3):667-674
Abstract
OBJECTIVES To investigate the incidence of preoperative abnormal iron status and its association with packed red blood cell (PRBC) transfusion, postoperative major complications, and new onset of clinically significant disability in patients undergoing elective cardiac surgery. DESIGN A prospective, observational multicenter cohort study. SETTING Three cardiac surgical centers in the Netherlands between 2019 and 2021. Recruitment was on hold between March and May 2020 due to COVID-19. PATIENTS A total of 427 patients aged 60 years and older who underwent elective on-pump cardiac surgery. MEASUREMENTS AND MAIN RESULTS The primary endpoint was a 30-day PRBC transfusion. Secondary endpoints were postoperative major complications within 30 days (eg, acute kidney injury, sepsis), and new onset of clinically significant disability within 120 days of surgery. Iron status was evaluated before surgery. Abnormal iron status was present in 45.2% of patients (n = 193), and most frequently the result of iron deficiency (27.4%, n = 117). An abnormal iron status was not associated with PRBC transfusion (adjusted relative risk [ARR] 1.2; 95% CI 0.9-1.8: p = 0.227) or new onset of clinically significant disability (ARR 2.0; 95% CI 0.9-4.6: p = 0.098). However, the risk of postoperative major complications was increased in patients with an abnormal iron status (ARR 1.7; 95% CI 1.1-2.5: p = 0.012). CONCLUSIONS An abnormal iron status before elective cardiac surgery was associated with an increased risk of postoperative major complications but not with PRBC transfusion or a new onset of clinically significant disability.
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Melatonin, vitamins and minerals supplements for the treatment of Covid-19 and Covid-like illness: A prospective, randomized, double-blind multicenter study.
Mahjoub, L, Youssef, R, Yaakoubi, H, Salah, HB, Jaballah, R, Mejri, M, Sekma, A, Trabelsi, I, Nouira, S, Khrouf, M, et al
Explore (New York, N.Y.). 2024;(1):95-100
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Abstract
BACKGROUND Melatonin, zinc, and multivitamins are among most recommended supplements in the fight against coronavirus disease 2019 (COVID-19). We aimed to examine the efficacy and safety of this association in the treatment of COVID-19 and COVID-like illnesses. METHODS We conducted a multicenter prospective, randomized, double-blind, controlled trial. Patients with no medical history consulting the emergency department for covid and covid-like illness and who were not hospitalized were included. Patients were assigned in a 1:1 ratio to the treatment or the placebo group. The primary outcome was studying the effectiveness of zinc multivitamin supplement and melatonin in the treatment of COVID and -like illnesses symptoms' according to the time from randomization to clinical improvement. The pre-specified secondary outcomes were date of disappearance of symptoms present on admission, appearance of an adverse effect due to the administration of the treatment, number of patients developing complications, requiring hospitalization, requiring respiratory support. RESULTS One hundred sixty four patients were eligible for the study and were randomized to either the treatment group or the placebo group. Overall, 128 of the 164 patients had a PCR for SARS-CoV-2, yielding a positive PCR result in 49.1% of them. Regarding the disappearance of all initial presenting symptoms: on the 5th day of the follow-up, there was a significant difference between the two groups with a p value 0.04;On the 10th day, there was a significant difference too with p value of 0.038. There were no significant differences between the two groups in recovery during the 15th day of follow-up p>0.5. Finally, 100% of patients fully recovered in the treatment group vs 98.8% in the placebo group. No severe adverse events were reported throughout the trial. CONCLUSIONS Our results showed that daily doses of Melatonin, zinc and vitamins did significantly reduce the duration of symptoms accelerating its disappearance among patients consulting with COVID-19 or COVID-19 like illness.
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Intranasal Versus Intravenous Dexamethasone to Treat Hospitalized COVID-19 Patients: A Randomized Multicenter Clinical Trial.
Cárdenas, G, Chávez-Canales, M, Espinosa, AM, Jordán-Ríos, A, Malagon, DA, Murillo, MFM, Araujo, LVT, Campos, RLB, Wong-Chew, RM, González, LER, et al
Archives of medical research. 2024;(2):102960
Abstract
BACKGROUND SARS-CoV2 induces flu-like symptoms that can rapidly progress to severe acute lung injury and even death. The virus also invades the central nervous system (CNS), causing neuroinflammation and death from central failure. Intravenous (IV) or oral dexamethasone (DXM) reduced 28 d mortality in patients who required supplemental oxygen compared to those who received conventional care alone. Through these routes, DMX fails to reach therapeutic levels in the CNS. In contrast, the intranasal (IN) route produces therapeutic levels of DXM in the CNS, even at low doses, with similar systemic bioavailability. AIMS To compare IN vs. IV DXM treatment in hospitalized patients with COVID-19. METHODS A controlled, multicenter, open-label trial. Patients with COVID-19 (69) were randomly assigned to receive IN-DXM (0.12 mg/kg for three days, followed by 0.6 mg/kg for up to seven days) or IV-DXM (6 mg/d for 10 d). The primary outcome was clinical improvement, as defined by the National Early Warning Score (NEWS) ordinal scale. The secondary outcome was death at 28 d between IV and IN patients. Effects of both treatments on biochemical and immunoinflammatory profiles were also recorded. RESULTS Initially, no significant differences in clinical severity, biometrics, and immunoinflammatory parameters were found between both groups. The NEWS-2 score was reduced, in 23 IN-DXM treated patients, with no significant variations in the 46 IV-DXM treated ones. Ten IV-DXM-treated patients and only one IN-DXM patient died. CONCLUSIONS IN-DMX reduced NEWS-2 and mortality more efficiently than IV-DXM, suggesting that IN is a more efficient route of DXM administration.
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Survival and Long-Term Functional Status of COVID-19 Patients Requiring Prolonged Extracorporeal Membrane Oxygenation Support.
Martínez-Martínez, M, Schmidt, M, Broman, LM, Roncon-Albuquerque, R, Langouet, E, Campos, I, Argudo, E, Domènech Vila, JM, Sastre, SM, Gallart, E, et al
Annals of the American Thoracic Society. 2024;(3):449-455
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Abstract
Rationale: Severe cases of acute respiratory distress syndrome (ARDS) may require prolonged (>28 d) extracorporeal membrane oxygenation (ECMO). In nonresolving disease, recovery is uncertain, and lung transplant may be proposed. Objectives: This study aims to identify the variables influencing survival and to describe the functional status of these patients at 6 months. Methods: This was a retrospective, multicenter, observational cohort study including patients requiring ECMO support for coronavirus disease (COVID-19)-related ARDS for >28 days. Multivariate analysis was performed using Cox regression in preselected variables and in least absolute shrinkage and selection operator selected variables. In a post hoc analysis to account for confounders and differences in awake strategy use by centers, treatment effects of the awake strategy were estimated using an augmented inverse probability weighting estimator with robust standard errors clustered by center. Results: Between March 15, 2020 and March 15, 2021, 120 patients required ECMO for >28 days. Sixty-four patients (53.3%) survived decannulation, 62 (51.7%) were alive at hospital discharge, and 61 (50.8%) were alive at 6-month follow-up. In the multivariate analysis, age (1.09; 95% confidence interval [CI], 1.03-1.15; P = 0.002) and an awake ECMO strategy (defined as the patient being awake, cooperative, and performing rehabilitation and physiotherapy with or without invasive mechanical ventilation at any time during the extracorporeal support) (0.14; 95% CI, 0.03-0.47; P = 0.003) were found to be predictors of hospital survival. At 6 months, 51 (42.5%) patients were at home, 42 (84.3%) of them without oxygen therapy. A cutoff point of 47 ECMO days had a 100% (95% CI, 76.8-100%) sensitivity and 60% (95% CI, 44.3-73.6%) specificity for oxygen therapy at 6 months, with 100% specificity being found in 97 days. Conclusions: Patients with COVID-19 who require ECMO for >28 days can survive with nonlimiting lung impairment. Age and an awake ECMO strategy may be associated with survival. Longer duration of support correlates with need for oxygen therapy at 6 months.
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Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study.
Cornelissen, MEB, Bloemsma, LD, Vaes, AW, Baalbaki, N, Deng, Q, Beijers, RJHCG, Noij, LCE, Houweling, L, Bazdar, S, Spruit, MA, et al
Journal of translational medicine. 2024;(1):191
Abstract
BACKGROUND In the Netherlands, the prevalence of post COVID-19 condition is estimated at 12.7% at 90-150 days after SARS-CoV-2 infection. This study aimed to determine the occurrence of fatigue and other symptoms, to assess how many patients meet the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) criteria, to identify symptom-based clusters within the P4O2 COVID-19 cohort and to compare these clusters with clusters in a ME/CFS cohort. METHODS In this multicentre, prospective, observational cohort in the Netherlands, 95 post COVID-19 patients aged 40-65 years were included. Data collection at 3-6 months after infection included demographics, medical history, questionnaires, and a medical examination. Follow-up assessments occurred 9-12 months later, where the same data were collected. Fatigue was determined with the Fatigue Severity Scale (FSS), a score of ≥ 4 means moderate to high fatigue. The frequency and severity of other symptoms and the percentage of patients that meet the ME/CFS criteria were assessed using the DePaul Symptom Questionnaire-2 (DSQ-2). A self-organizing map was used to visualize the clustering of patients based on severity and frequency of 79 symptoms. In a previous study, 337 Dutch ME/CFS patients were clustered based on their symptom scores. The symptom scores of post COVID-19 patients were applied to these clusters to examine whether the same or different clusters were found. RESULTS According to the FSS, fatigue was reported by 75.9% of the patients at 3-6 months after infection and by 57.1% of the patients 9-12 months later. Post-exertional malaise, sleep disturbances, pain, and neurocognitive symptoms were also frequently reported, according to the DSQ-2. Over half of the patients (52.7%) met the Fukuda criteria for ME/CFS, while fewer patients met other ME/CFS definitions. Clustering revealed specific symptom patterns and showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort, where 2 clusters had > 10 patients. CONCLUSIONS This study shows persistent fatigue and diverse symptomatology in post COVID-19 patients, up to 12-18 months after SARS-CoV-2 infection. Clustering showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort.
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The influence of propolis plus Hyoscyamus niger L. against COVID-19: A phase II, multicenter, placebo-controlled, randomized trial.
Kosari, M, Khorvash, F, Sayyah, MK, Ansari Chaharsoughi, M, Najafi, A, Momen-Heravi, M, Karimian, M, Akbari, H, Noureddini, M, Salami, M, et al
Phytotherapy research : PTR. 2024;(1):400-410
Abstract
The incubation period of COVID-19 symptoms, along with the proliferation and high transmission rate of the SARS-CoV-2 virus, is the cause of an uncontrolled epidemic worldwide. Vaccination is the front line of prevention, and antiinflammatory and antiviral drugs are the treatment of this disease. In addition, some herbal therapy approaches can be a good way to deal with this disease. The aim of this study was to evaluate the effect of propolis syrup with Hyoscyamus niger L. extract in hospitalized patients with COVID-19 with acute disease conditions in a double-blinded approach. The study was performed on 140 patients with COVID-19 in a double-blind, randomized, and multicentral approach. The main inclusion criterion was the presence of a severe type of COVID-19 disease. The duration of treatment with syrup was 6 days and 30 CC per day in the form of three meals. On Days 0, 2, 4, and 6, arterial blood oxygen levels, C-reactive protein (CRP), erythrocyte sedimentation rate, and white blood cell, as well as the patient's clinical symptoms such as fever and chills, cough and shortness of breath, chest pain, and other symptoms, were recorded and analyzed. Propolis syrup with H. niger L. significantly reduces cough from the second day, relieving shortness of breath on the fourth day, and significantly reduces CRP, weakness, and lethargy, as well as significantly increased arterial blood oxygen pressure on the sixth day compared to the placebo group (p < 0.05). The results in patients are such that in the most severe conditions of the disease 80% < SpO2 (oxygen saturation), the healing process of the syrup on reducing CRP and increasing arterial blood oxygen pressure from the fourth day is significantly different compared with the placebo group (p < 0.05). The use of syrup is associated with a reduction of 3.6 days in the hospitalization period compared with the placebo group. Propolis syrup with H. niger L. has effectiveness in the viral and inflammatory phases on clinical symptoms and blood parameters and arterial blood oxygen levels of patients with COVID-19. Also, it reduces referrals to the intensive care unit and mortality in hospitalized patients with COVID-19. So, this syrup promises to be an effective treatment in the great challenge of COVID-19.
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Mortality-related risk factors of inpatients with diabetes and COVID-19: A multicenter retrospective study in Belgium.
Servais, T, Laurent, F, Roland, T, Rossi, C, De Groote, E, Godart, V, Repetto, E, Ponchon, M, Chasseur, P, Crenier, L, et al
Annales d'endocrinologie. 2024;(1):36-43
Abstract
BACKGROUND AND AIMS We describe mortality-related risk factors of inpatients with diabetes and coronavirus disease 2019 (COVID-19) in Belgium. METHODS We conducted a multicenter retrospective study from March to May, 2020, in 8 Belgian centers. Data on admission of patients with diabetes and COVID-19 were collected. Survivors were compared to non-survivors to identify prognostic risk factors for in-hospital death using multivariate analysis in both the total population and in the subgroup of patients admitted in the intensive care unit (ICU). RESULTS The study included 375 patients. The mortality rate was 26.4% (99/375) in the total population and 40% (27/67) in the ICU. Multivariate analysis identified older age (HR 1.05 [CI 1.03-1.07], P<0.0001) and male gender (HR 2.01 [1.31-3.07], P=0.0013) as main independent risk factors for in-hospital death in the total population. Metformin (HR 0.51 [0.34-0.78], P=0.0018) and renin-angiotensin-aldosterone system blockers (HR 0.56 [0.36-0.86], P=0.0088) use before admission were independent protective factors. In the ICU, chronic kidney disease (CKD) was identified as an independent risk factor for death (HR 4.96 [2.14-11.5], P<0.001). CONCLUSION In-hospital mortality due to the first wave of COVID-19 pandemic in Belgium was high in patients with diabetes. We found that advanced age and male gender were independent risk factors for in-hospital death. We also showed that metformin use before admission was associated with a significant reduction of COVID-19-related in-hospital mortality. Finally, we showed that CKD is a COVID-19-related mortality risk factor in patients with diabetes admitted in the ICU.
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PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial.
Koren, MJ, Descamps, O, Hata, Y, Hengeveld, EM, Hovingh, GK, Ikonomidis, I, Radu Juul Jensen, MD, Langbakke, IH, Martens, FMAC, Søndergaard, AL, et al
The lancet. Diabetes & endocrinology. 2024;(3):174-183
Abstract
BACKGROUND Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy. METHODS In this randomised, double-blind, placebo-controlled and active-controlled trial, 42 research sites across seven countries (Belgium, Germany, Greece, Japan, the Netherlands, Poland, and the USA) recruited individuals with established atherosclerotic cardiovascular disease (aged ≥40 years) or at high risk of atherosclerotic cardiovascular disease (aged >50 years), who had LDL cholesterol concentration of at least 1·8 mmol/L and were receiving maximum tolerated statins and stable lipid-lowering therapy. The study randomly allocated participants (3:1) with an interactive web response system to receive either NNC0385-0434 (15 mg, 40 mg, or 100 mg) once a day co-formulated with the oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (500 mg); placebo; or open-label evolocumab (140 mg) every 2 weeks administered subcutaneously. Blinding was performed within each dose level. The primary endpoint was percentage change from baseline in LDL cholesterol measured by β quantification at week 12. All randomly assigned participants received at least one dose of treatment and were included in both safety and efficacy analyses. The trial was registered on ClinicalTrials.gov, NCT04992065, and is completed. FINDINGS Between Aug 16, 2021, and Jan 28, 2022, we randomly assigned 267 patients to one of the three NNC0385-0434 dose cohorts (n=53 per cohort), matching placebo (n=54), or open-label evolocumab (n=54). The study population comprised 82 (31%) women and 185 (69%) men; mean age was 64·3 years (SD 9·0). Baseline mean LDL cholesterol concentration was 2·7 mmol/L (SD 0·8). Treatment with NNC0385-0434 resulted in reductions in LDL cholesterol from baseline to week 12, of 32·0 percentage points (95% CI 20·9 to 43·0) in the 15 mg cohort, 44·9 percentage points (33·8 to 56·0) in the 40 mg cohort, and 61·8 percentage points (50·7 to 72·9) in the 100 mg cohort, compared with the placebo group (p<0·0001 for each). Patients treated with evolocumab had similar LDL cholesterol reductions (59·6% [SE 4·1] decrease from baseline) to patients receiving NNC0385-0434 100 mg (56·2% [4·0]). The estimated treatment difference between NNC0385-0434 100 mg and evolocumab 140 mg was 3·4 percentage points [95% CI -7·8 to 14·7]. The most frequently reported adverse event was COVID-19, which affected 31 (12%) of 267 patients, with similar numbers across treatment groups. Investigative sites reported gastrointestinal disorders as the most frequent treatment-related adverse event (26 patients and 35 events total in the three NNC0385 cohorts and one patient and one event each in the placebo and evolocumab cohorts). No deaths or treatment-related serious adverse events occurred. INTERPRETATION This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations. FUNDING Novo Nordisk.