COVID-19: Clinical Advances and Challenges

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Infectious Diseases".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 75203

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Special Issue Editors


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Guest Editor
Department of Internal Medicine, Division of Hospital Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
Interests: value based care; infectious disease

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Guest Editor
Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
Interests: venous thromboembolism (VTE); deep vein thrombosis (DVT); pulmonary embolism (PE); atrial fibrillation; anticoagulation; thrombosis; stroke; CVA; cardiovascular research; internal medicine; hospital medicine; obesity medicine; COVID-19

Special Issue Information

Dear Colleagues,

The protean nature of the COVID-19 pandemic has necessitated unprecedented global coordination, cooperation, and ingenuity. Eleven variants of SARS CoV-2 and a multitude of sub-variants have been identified, over half a billion humans have been infected, and more than six million people have died. Mirroring the meta-morphology of the virus, the medical and scientific community has proven to be extremely versatile, pushing the bounds of translational medicine further than ever before. Therapeutics, vaccines, and a vast array of data were generated, but perhaps the most impactful consequence has been learning how to produce meaningful research in increasingly shorter periods of time.

In spite of the pressure brought to bear for immediate results, a large volume of the literature produced at the outset of the pandemic withstood the test of time, was implemented in a timely manner, and prevented a significant amount of morbidity and mortality. Randomized clinical trials, observational studies, and high-quality systematic reviews and meta-analyses were all utilized to great effect, resulting in protocols, such as the one regarding steroid use implemented in our institution near the advent of the pandemic, many of which were included in our very own Special Issue of “COVID-19 Therapeutics”.

The fruit of humankind’s collective scientific labors is staggering. Nearly 70% of the Earth’s inhabitants are estimated to have been vaccinated to date, and despite the cycles of new, highly infectious variants, we have undoubtedly turned a corner in facing this pandemic and perhaps even closed a chapter. A generation of physicians has been forged in the crucible of a pandemic and, in the process, have discovered the power of the individual to make a difference on a global scale. The imperative to investigate and research has been extended more solidly to the rank-and-file clinician through adaptive trial platforms, mRNA vaccines have proven their efficacy, and global registries have begun to change the way we approach data collection and processing. COVID-19 has proven to be a chameleonic adversary, but humanity has proven to be just as adaptable and, in the process, gained vital lessons to take into the future.

As the pandemic continues, the focus is now on the emerging new variants and the changing efficacy of the existing armamentarium of drugs and vaccines. The present Topical Collection aims to present real-world experience and high-quality reviews on the efficacy and safety of therapeutics and vaccines, as it pertains to emerging variants, and we would like to kindly invite you to submit your original works.

Cordially,

Dr. Shitij Arora
Dr. Leonidas Palaiodimos
Guest Editors

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Keywords

  • SARS-CoV-2
  • COVID-19
  • Treatment
  • Therapeutics
  • Vaccine
  • Efficacy
  • Safety
  • Adverse events
  • Immunity
  • Mortality

Published Papers (30 papers)

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Editorial

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3 pages, 175 KiB  
Editorial
COVID-19 Therapeutics: Improvise—Adapt—Learn
by Joseph Abraham, Leonidas Palaiodimos and Shitij Arora
J. Clin. Med. 2022, 11(18), 5312; https://doi.org/10.3390/jcm11185312 - 09 Sep 2022
Viewed by 1265
Abstract
“In the midst of chaos, there is also opportunity”—Sun Tzu, The Art of War [...] Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)

Research

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14 pages, 843 KiB  
Article
Neurological Manifestations and Complications of the Central Nervous System as Risk Factors and Predictors of Mortality in Patients Hospitalized with COVID-19: A Cohort Study
by Ana Luisa Corona-Nakamura, Martha Judith Arias-Merino, Rayo Morfín-Otero, Guillermo Rodriguez-Zavala, Alfredo León-Gil, Juan Ramsés Camarillo-Escalera, Idarmis Brisseida Reyes-Cortés, María Gisela Valdovinos-Ortega, Erick René Nava-Escobar, Ana María de la Paz Villaseñor-Corona, Mario Alberto Mireles-Ramírez, Aldo Guadalupe Cisneros-Aréchiga, Ofelia Padilla-De la Torre, Héctor Raúl Pérez-Gómez and Eduardo Rodríguez-Noriega
J. Clin. Med. 2023, 12(12), 4065; https://doi.org/10.3390/jcm12124065 - 15 Jun 2023
Viewed by 1363
Abstract
The aim of this study was to analyze the risk factors and predictors of mortality in a retrospective cohort of patients with coronavirus disease (COVID-19) who presented central nervous system (CNS) manifestations and complications when admitted to hospital. Patients hospitalized from 2020 to [...] Read more.
The aim of this study was to analyze the risk factors and predictors of mortality in a retrospective cohort of patients with coronavirus disease (COVID-19) who presented central nervous system (CNS) manifestations and complications when admitted to hospital. Patients hospitalized from 2020 to 2022 were selected. Demographic variables; history of neurological, cardiological and pulmonary manifestations; comorbidities; prognostic severity scales; and laboratory tests were included. Univariate and adjusted analyses were performed to determine risk factors and predictors of mortality. A forest plot diagram was used to show the strength of the associated risk factors. The cohort included 991 patients; at admission, 463 patients presented CNS damage and of these, 96 hospitalized patients presented de novo CNS manifestations and complications. We estimate a general mortality of 43.7% (433/991) and 77.1% (74/96), for hospitalized patients with de novo CNS manifestations and complications, respectively. The following were identified as risks for the development of hospital CNS manifestations and complications when in hospital: an age of ≥64 years, a history of neurological disease, de novo deep vein thrombosis, D-dimer ≥ 1000 ng/dL, a SOFA ≥ 5, and a CORADS 6. In a multivariable analysis, the mortality predictors were an age of ≥64 years, a SOFA ≥ 5, D-dimer ≥ 1000 ng/mL and hospital CNS manifestations and complications when admitted to hospital. Old age, being hospitalized in critical condition, and having CNS manifestations and complications in hospital are predictors of mortality in hospitalized patients with COVID-19. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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12 pages, 1040 KiB  
Article
Characteristics of Chemosensory Perception in Long COVID and COVID Reinfection
by Mikki Jaramillo, Thankam P. Thyvalikakath, George Eckert and Mythily Srinivasan
J. Clin. Med. 2023, 12(10), 3598; https://doi.org/10.3390/jcm12103598 - 22 May 2023
Viewed by 1235
Abstract
Emerging data suggest an increasing prevalence of persistent symptoms in individuals affected by coronavirus disease-19 (COVID-19). The objective of this study was to determine the relative frequency of altered taste and smell in COVID reinfection (multiple COVID positive tests) and long COVID (one [...] Read more.
Emerging data suggest an increasing prevalence of persistent symptoms in individuals affected by coronavirus disease-19 (COVID-19). The objective of this study was to determine the relative frequency of altered taste and smell in COVID reinfection (multiple COVID positive tests) and long COVID (one COVID positive test). We sent an electronic survey to patients in the Indiana University Health COVID registry with positive COVID test results, querying if they were experiencing symptoms consistent with long COVID including altered chemosensory perceptions. Among the 225 respondents, a greater long COVID burden and COVID reinfection was observed in women. Joint pain was reported as the most common symptom experienced by 18% of individuals in the long COVID cohort. In the COVID reinfection cohort >20% of individuals reported headache, joint pain, and cough. Taste perception worse than pre-COVID was reported by 29% and 42% of individuals in the long COVID and COVID reinfection cohorts, respectively. Smell perception worse than pre-COVID was reported by 37% and 46% of individuals in long COVID and COVID reinfection cohorts, respectively. Further, Chi-square test suggested significant association between pre-COVID severity of taste/smell perception and headache in both cohorts. Our findings highlight the prevalence of persistent chemosensory dysfunction for two years and longer in long COVID and COVID reinfection. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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14 pages, 1684 KiB  
Article
Predictive Attributes for Developing Long COVID—A Study Using Machine Learning and Real-World Data from Primary Care Physicians in Germany
by Roman Kessler, Jos Philipp, Joanna Wilfer and Karel Kostev
J. Clin. Med. 2023, 12(10), 3511; https://doi.org/10.3390/jcm12103511 - 17 May 2023
Cited by 5 | Viewed by 1343
Abstract
(1) In the present study, we used data comprising patient medical histories from a panel of primary care practices in Germany to predict post-COVID-19 conditions in patients after COVID-19 diagnosis and to evaluate the relevant factors associated with these conditions using machine learning [...] Read more.
(1) In the present study, we used data comprising patient medical histories from a panel of primary care practices in Germany to predict post-COVID-19 conditions in patients after COVID-19 diagnosis and to evaluate the relevant factors associated with these conditions using machine learning methods. (2) Methods: Data retrieved from the IQVIATM Disease Analyzer database were used. Patients with at least one COVID-19 diagnosis between January 2020 and July 2022 were selected for inclusion in the study. Age, sex, and the complete history of diagnoses and prescription data before COVID-19 infection at the respective primary care practice were extracted for each patient. A gradient boosting classifier (LGBM) was deployed. The prepared design matrix was randomly divided into train (80%) and test data (20%). After optimizing the hyperparameters of the LGBM classifier by maximizing the F2 score, model performance was evaluated using several test metrics. We calculated SHAP values to evaluate the importance of the individual features, but more importantly, to evaluate the direction of influence of each feature in our dataset, i.e., whether it is positively or negatively associated with a diagnosis of long COVID. (3) Results: In both the train and test data sets, the model showed a high recall (sensitivity) of 81% and 72% and a high specificity of 80% and 80%; this was offset, however, by a moderate precision of 8% and 7% and an F2-score of 0.28 and 0.25. The most common predictive features identified using SHAP included COVID-19 variant, physician practice, age, distinct number of diagnoses and therapies, sick days ratio, sex, vaccination rate, somatoform disorders, migraine, back pain, asthma, malaise and fatigue, as well as cough preparations. (4) Conclusions: The present exploratory study describes an initial investigation of the prediction of potential features increasing the risk of developing long COVID after COVID-19 infection by using the patient history from electronic medical records before COVID-19 infection in primary care practices in Germany using machine learning. Notably, we identified several predictive features for the development of long COVID in patient demographics and their medical histories. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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18 pages, 1615 KiB  
Article
Humoral and Cellular Response and Associated Variables Nine Months following BNT162b2 Vaccination in Healthcare Workers
by Natalia Syrimi, Flora Sourri, Maria-Christina Giannakopoulou, Dimitrios Karamanis, Asterios Pantousas, Persefoni Georgota, Eleni Rokka, Zoe Vladeni, Euaggelia Tsiantoula, Evangelia Soukara, Nikoletta Lavda, Dimitrios Gkaragkanis, Aikaterini Zisaki, Panagiotis Vakalidis, Vasiliki Goula, Evdokia Loupou, Leonidas Palaiodimos and Dimitrios Hatzigeorgiou
J. Clin. Med. 2023, 12(9), 3172; https://doi.org/10.3390/jcm12093172 - 28 Apr 2023
Cited by 3 | Viewed by 1805
Abstract
In this study, we aimed to illustrate the trajectory of humoral and cellular immunity nine months after primary vaccination with the BNT162b2 mRNA vaccine among 189 healthcare workers (HCWs). Additionally, we endeavored to identify correlations between immunity parameters and a number of common [...] Read more.
In this study, we aimed to illustrate the trajectory of humoral and cellular immunity nine months after primary vaccination with the BNT162b2 mRNA vaccine among 189 healthcare workers (HCWs). Additionally, we endeavored to identify correlations between immunity parameters and a number of common variables and comorbidities. A total of 189 healthcare workers (HCWs), vaccinated against COVID-19, were finally included in the study. All of the subjects had received two doses of the BNT162b2 vaccine; had undergone antibody tests one, four and nine months post-vaccination; and had completed a medical questionnaire. Further samples taken at nine months were tested for cellular immunity. No participants had evidence of COVID-19 infection pre- or post-vaccination. An anti-S1 receptor binding domain (RBD) antibody assay was used to assess humoral response, and cellular immunity was estimated with an INF-γ release assay (IGRA). Statistical analysis was performed using STATA. We report a statistically significant antibody drop over time. Being above the age of 40 or a smoker reduces the rise of antibodies by 37% and 28%, respectively. More than half of the participants did not demonstrate T-cell activation at nine months. Female gender and antibody levels at four months predispose detection of cellular immunity at nine months post-immunization. This study furthers the qualitative, quantitative, and temporal understanding of the immune response to the BNT162b2 mRNA vaccine and the effect of correlated factors. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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12 pages, 1592 KiB  
Article
Impact of Age and Sex Interaction on Post-Acute Sequelae of COVID-19: An Italian Cohort Study on Adults and Children
by Matteo Puntoni, Susanna Esposito, Laura Patrizi, Chiara Maria Palo, Michela Deolmi, Giovanni Autore, Valentina Fainardi, Caterina Caminiti and on behalf of the University Hospital of Parma LONG-COVID Research Team
J. Clin. Med. 2023, 12(8), 2924; https://doi.org/10.3390/jcm12082924 - 18 Apr 2023
Cited by 1 | Viewed by 1518
Abstract
Identifying factors predisposing individuals to post-acute sequelae of COVID-19 (PASC) would allow for the timely treatment of those vulnerable. Attention on the role of sex and age is growing, but published studies have shown mixed results. Our objective was to estimate the effect [...] Read more.
Identifying factors predisposing individuals to post-acute sequelae of COVID-19 (PASC) would allow for the timely treatment of those vulnerable. Attention on the role of sex and age is growing, but published studies have shown mixed results. Our objective was to estimate the effect modification of age on sex as a risk factor for PASC. We analyzed data from two longitudinal prospective cohort studies on adult and pediatric subjects positive to SARS-CoV-2 infection that were enrolled between May 2021 and September 2022. Age classes (≤5, 6–11, 12–50, >50 years) were based on the potential role of sex hormones on inflammatory/immune and autoimmune processes. A total of 452 adults and 925 children were analyzed: 46% were female and 42% were adults. After a median follow-up of 7.8 months (IQR: 5.0 to 9.0), 62% of children and 85% of adults reported at least one symptom. Sex and age alone were not significantly associated to PASC, but their interaction was statistically significant (p-value = 0.024): the risk was higher for males aged 0–5 (females vs. males HR: 0.64, 95% CI: 0.45–0.91, p = 0.012) and for females aged 12–50 (HR: 1.39, 95% CI: 1.04–1.86, p = 0.025), especially those in the cardiovascular, neurological, gastrointestinal and sleep categories. Further research on PASC with regard to sex and age is warranted. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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21 pages, 2062 KiB  
Article
Characterizing and Predicting Post-Acute Sequelae of SARS CoV-2 Infection (PASC) in a Large Academic Medical Center in the US
by Lars G. Fritsche, Weijia Jin, Andrew J. Admon and Bhramar Mukherjee
J. Clin. Med. 2023, 12(4), 1328; https://doi.org/10.3390/jcm12041328 - 07 Feb 2023
Cited by 5 | Viewed by 1927
Abstract
Background: A growing number of Coronavirus Disease-2019 (COVID-19) survivors are affected by post-acute sequelae of SARS CoV-2 infection (PACS). Using electronic health record data, we aimed to characterize PASC-associated diagnoses and develop risk prediction models. Methods: In our cohort of 63,675 patients with [...] Read more.
Background: A growing number of Coronavirus Disease-2019 (COVID-19) survivors are affected by post-acute sequelae of SARS CoV-2 infection (PACS). Using electronic health record data, we aimed to characterize PASC-associated diagnoses and develop risk prediction models. Methods: In our cohort of 63,675 patients with a history of COVID-19, 1724 (2.7%) had a recorded PASC diagnosis. We used a case–control study design and phenome-wide scans to characterize PASC-associated phenotypes of the pre-, acute-, and post-COVID-19 periods. We also integrated PASC-associated phenotypes into phenotype risk scores (PheRSs) and evaluated their predictive performance. Results: In the post-COVID-19 period, known PASC symptoms (e.g., shortness of breath, malaise/fatigue) and musculoskeletal, infectious, and digestive disorders were enriched among PASC cases. We found seven phenotypes in the pre-COVID-19 period (e.g., irritable bowel syndrome, concussion, nausea/vomiting) and sixty-nine phenotypes in the acute-COVID-19 period (predominantly respiratory, circulatory, neurological) associated with PASC. The derived pre- and acute-COVID-19 PheRSs stratified risk well, e.g., the combined PheRSs identified a quarter of the cohort with a history of COVID-19 with a 3.5-fold increased risk (95% CI: 2.19, 5.55) for PASC compared to the bottom 50%. Conclusions: The uncovered PASC-associated diagnoses across categories highlighted a complex arrangement of presenting and likely predisposing features, some with potential for risk stratification approaches. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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10 pages, 801 KiB  
Article
A Clinical Prediction Rule for Thrombosis in Critically Ill COVID-19 Patients: Step 1 Results of the Thromcco Study
by Karen L. Ramírez Cervantes, Elianne Mora, Salvador Campillo Morales, Consuelo Huerta Álvarez, Pilar Marcos Neira, Kapil Laxman Nanwani Nanwani, Ainhoa Serrano Lázaro, J. Alberto Silva Obregón and Manuel Quintana Díaz
J. Clin. Med. 2023, 12(4), 1253; https://doi.org/10.3390/jcm12041253 - 04 Feb 2023
Viewed by 1174
Abstract
The incidence of thrombosis in COVID-19 patients is exceptionally high among intensive care unit (ICU)-admitted individuals. We aimed to develop a clinical prediction rule for thrombosis in hospitalized COVID-19 patients. Data were taken from the Thromcco study (TS) database, which contains information on [...] Read more.
The incidence of thrombosis in COVID-19 patients is exceptionally high among intensive care unit (ICU)-admitted individuals. We aimed to develop a clinical prediction rule for thrombosis in hospitalized COVID-19 patients. Data were taken from the Thromcco study (TS) database, which contains information on consecutive adults (aged ≥ 18) admitted to eight Spanish ICUs between March 2020 and October 2021. Diverse logistic regression model analysis, including demographic data, pre-existing conditions, and blood tests collected during the first 24 h of hospitalization, was performed to build a model that predicted thrombosis. Once obtained, the numeric and categorical variables considered were converted to factor variables giving them a score. Out of 2055 patients included in the TS database, 299 subjects with a median age of 62.4 years (IQR 51.5–70) (79% men) were considered in the final model (SE = 83%, SP = 62%, accuracy = 77%). Seven variables with assigned scores were delineated as age 25–40 and ≥70 = 12, age 41–70 = 13, male = 1, D-dimer ≥ 500 ng/mL = 13, leukocytes ≥ 10 × 103/µL = 1, interleukin-6 ≥ 10 pg/mL = 1, and C-reactive protein (CRP) ≥ 50 mg/L = 1. Score values ≥28 had a sensitivity of 88% and specificity of 29% for thrombosis. This score could be helpful in recognizing patients at higher risk for thrombosis, but further research is needed. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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12 pages, 2415 KiB  
Article
Cellular and Humoral Responses to Recombinant and Inactivated SARS-CoV-2 Vaccines in CKD Patients: An Observational Study
by Siliang Zhang, Jiaoxia He, Bin Tang, Qin Zhou, Yudong Hu, Yuan Yu, Jianwei Chen, Yi Liu, Chunmeng Li, Hong Ren and Xiaohui Liao
J. Clin. Med. 2023, 12(3), 1225; https://doi.org/10.3390/jcm12031225 - 03 Feb 2023
Cited by 1 | Viewed by 1898
Abstract
Background: It remains unclear what B cell and humoral responses are mounted by chronic kidney disease (CKD) patients in response to recombinant and inactivated SARS-CoV-2 vaccines. In this study, we aimed to explore the cellular and humoral responses, and the safety of recombinant [...] Read more.
Background: It remains unclear what B cell and humoral responses are mounted by chronic kidney disease (CKD) patients in response to recombinant and inactivated SARS-CoV-2 vaccines. In this study, we aimed to explore the cellular and humoral responses, and the safety of recombinant and inactivated SARS-CoV-2 vaccines in CKD patients. Methods: 79 CKD and 420 non-CKD individuals, who completed a full course of vaccination, were enrolled in the study. Adverse events (AEs) were collected via a questionnaire. Cellular and humoral responses were detected at 1, 3, and 6 months, including IgG antibody against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (anti-RBD-IgG), neutralizing antibodies (NAbs), the positive rate of NAbs and anti-RBD-IgG, RBD-atypical memory B cells (MBCs) (CD3 − CD19 + RBD + CD21 − CD27−), RBD-activated MBCs (CD3 − CD19 + RBD + CD21 − CD27+), RBD-resting MBCs (CD3 − CD19 + RBD + CD21 + CD27+), and RBD-intermediate MBCs (CD3 − CD19 + RBD + CD21 + CD27−). Results: We found no differences in the positivity rates of NAbs (70.89% vs. 79.49%, p = 0.212) and anti-RBD IgG (72.15% vs. 83.33%, p = 0.092) between the CKD and control groups. A total of 22 CKD individuals completed the full follow-up (1, 3, and 6 months). Significant and sustained declines were found at 3 months in anti-RBD IgG (26.64 BAU/mL vs. 9.08 BAU/mL, p < 0.001) and NAbs (161.60 IU/mL vs. 68.45 IU/mL p < 0.001), and at 6 months in anti-RBD IgG (9.08 BAU/mL vs. 5.40 BAU/mL, p = 0.064) and NAbs (68.45 IU/mL vs. 51.03 IU/mL, p = 0.001). Significant differences were identified in MBC subgroups between CKD patients and healthy controls, including RBD-specific atypical MBCs (60.5% vs. 17.9%, p < 0.001), RBD-specific activated MBCs (36.3% vs. 14.8%, p < 0.001), RBD-specific intermediate MBCs (1.24% vs. 42.6%, p < 0.001), and resting MBCs (1.34% vs. 22.4%, p < 0.001). Most AEs in CKD patients were mild (grade 1 and 2) and self-limiting. One patient with CKD presented with a recurrence of nephrotic syndrome after vaccination. Conclusions: The recombinant and inactivated SARS-CoV-2 vaccine was well-tolerated and showed a good response in the CKD cohort. Our study also revealed differences in MBC subtypes after SARS-CoV-2 vaccination between CKD patients and healthy controls. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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14 pages, 1118 KiB  
Article
Efficacy of Bromhexine versus Standard of Care in Reducing Viral Load in Patients with Mild-to-Moderate COVID-19 Disease Attended in Primary Care: A Randomized Open-Label Trial
by María Luz Vila Méndez, Carmen Antón Sanz, Alicia del Rocío Cárdenas García, Amparo Bravo Malo, Francisco Javier Torres Martínez, José María Martín Moros, María Real Torrijos, José Francisco Javier Vendrell Covisa, Olga Guzmán Sierra, Verónica Molina Barcena, Nuria Viejo Pinero, Carlos Fernández Díaz, Purificación Arroyo Burguillo, Ana María Blanco Gallego, Carmen Guirao Sánchez, Aránzazu Montilla Bernabé, María del Pilar Villanueva Morán, Salvador Juárez Antón, Ángela Fernández Rodríguez, María Ángeles Somoza Calvo, Ernesto Cerrada Cerrada, Gemma Pérez Mañas, Antonio Sánchez Calso, Frida Vallejo Somohano, Carmen Cauqui Díaz, Gloria Viñas Fernández, Jesús Molina París, Marina González Godoy, Gonzalo Lumbreras García, Javier Rosado Martín, Aida Rodríguez Hernández, Sara López Antúñez, Gabriel Vázquez Perfecto, María Concepción Marcello Andrés, Nieves Marina Puente García, Carmen Gil, Ana Martínez and Begoña Soler Lópezadd Show full author list remove Hide full author list
J. Clin. Med. 2023, 12(1), 142; https://doi.org/10.3390/jcm12010142 - 24 Dec 2022
Cited by 5 | Viewed by 3542
Abstract
A 28-day randomized open-label multicenter study was conducted to assess the efficacy of bromhexine plus standard of care (SOC) (n = 98) vs. SOC alone (n = 93) in 191 outpatients with mild-to-moderate COVID-19 in the primary health care setting. Bromhexine [...] Read more.
A 28-day randomized open-label multicenter study was conducted to assess the efficacy of bromhexine plus standard of care (SOC) (n = 98) vs. SOC alone (n = 93) in 191 outpatients with mild-to-moderate COVID-19 in the primary health care setting. Bromhexine three daily doses of 10 mL (48 mg/day) were administered for seven days. The primary efficacy endpoint was the reduction of viral load estimated as the cycle thresholds (Ct) to detect ORF1ab, N Protein, and S Protein genes by RT-qPCR in saliva samples on day 4 as compared with baseline. Ct values of the three genes increased from baseline throughout days 4 to 14 (p < 0.001) but significant differences between the study groups were not found. Differences in the percentages of patients with low, medium, and high viral loads at 4, 7, and 14 days were not found either. In summary, treatment with bromhexine plus SCO was associated with a viral load reduction of ORF1ab, N Protein, and S Protein genes at day 4, which was not significantly different than similar viral load reductions observed with SOC alone. The present findings do not seem to favor the use of bromhexine as an antiviral in patients with COVID-19. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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12 pages, 1132 KiB  
Article
Assessing the Efficacy of Early Therapies against SARS-CoV-2 in Hematological Patients: A Real-Life Study from a COVID-19 Referral Centre in Northern Italy
by Marta Colaneri, Teresa Chiara Pieri, Silvia Roda, Alessandra Ricciardi, Manuel Gotti, Jacqueline Ferrari, Luca Arcaini, Sara Rattotti, Antonio Piralla, Federica Giardina, Guglielmo Ferrari, Paolo Sacchi, Valentina Zuccaro, Fausto Baldanti and Raffaele Bruno
J. Clin. Med. 2022, 11(24), 7452; https://doi.org/10.3390/jcm11247452 - 15 Dec 2022
Cited by 1 | Viewed by 1622
Abstract
Early therapies to prevent severe COVID-19 have an unclear impact on patients with hematological malignancies. The aim of this study was to assess their efficacy in this group of high-risk patients with COVID-19 in preventing hospitalizations and reducing the SARS-CoV-2 shedding. This was [...] Read more.
Early therapies to prevent severe COVID-19 have an unclear impact on patients with hematological malignancies. The aim of this study was to assess their efficacy in this group of high-risk patients with COVID-19 in preventing hospitalizations and reducing the SARS-CoV-2 shedding. This was a single-center, retrospective, observational study conducted in the Fondazione IRCSS Policlinico San Matteo of Pavia, Northern Italy. We extracted the data of patients with hematologic malignancies and COVID-19 who received and did not receive early COVID-19 treatment between 23 December 2021, and May 2022. We used a Cox proportional hazard model to assess whether receiving any early treatment was associated with lower rates of hospitalization and reduced viral shedding. Data from 88 patients with hematologic malignancies were extracted. Among the patients, 55 (62%) received any early treatment, whereas 33 (38%) did not. Receiving any early therapy did not significantly reduce the hospitalization rate in patients with hematologic malignancies (HR 0.51; SE 0.63; p-value = 0.28), except in the vaccinated non-responders subgroup of patients with negative anti SARS-CoV-2 antibodies at the time of infection, who benefited from early therapies against SARS-CoV-2 (HR 0.07; SE 1.04; p-value = 0.001). Moreover, no difference on viral load decay was observed. In our cohort of patients with hematologic malignancies infected with SARS-CoV-2, early treatment were not effective in reducing the hospitalization rate due to COVID-19, neither in reducing its viral shedding. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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9 pages, 237 KiB  
Article
Factors Associated with Mortality in Coronavirus-Associated Mucormycosis: Results from Mycotic Infections in COVID-19 (MUNCO) Online Registry
by Shitij Arora, Shivakumar Narayanan, Melissa Fazzari, Kranti Bhavana, Bhartendu Bharti, Shweta Walia, Neetu Kori, Sushila Kataria, Pooja Sharma, Kavya Atluri, Charuta Mandke, Vinod Gite, Neelam Redkar, Mayank Chansoria, Sumit Kumar Rawat, Rajani S. Bhat, Ameet Dravid, Yatin Sethi, Chandan Barnawal, Nirmal Kanti Sarkar, Sunit Jariwala, William Southern and Yoram Puiusadd Show full author list remove Hide full author list
J. Clin. Med. 2022, 11(23), 7015; https://doi.org/10.3390/jcm11237015 - 27 Nov 2022
Cited by 2 | Viewed by 1851
Abstract
Background: COVID-19-associated mucormycosis (CAM) is associated with high morbidity and mortality. MUNCO is an international database used to collect clinical data on cases of CAM in real time. Preliminary data from the Mycotic Infections in COVID-19 (MUNCO) online registry yielded 728 cases from [...] Read more.
Background: COVID-19-associated mucormycosis (CAM) is associated with high morbidity and mortality. MUNCO is an international database used to collect clinical data on cases of CAM in real time. Preliminary data from the Mycotic Infections in COVID-19 (MUNCO) online registry yielded 728 cases from May to September 2021 in four South Asian countries and the United States. A majority of the cases (694; 97.6%) consisted of a mucormycosis infection. The dataset allowed for the analysis of the risk factors for adverse outcomes from CAM and this analysis is presented in this paper. Methods: The submission of cases was aided by a direct solicitation and social media online. The primary endpoints were full recovery or death measured on day 42 of the diagnosis. All patients had histopathologically confirmed CAM. The groups were compared to determine the contribution of each patient characteristic to the outcome. Multivariable logistic regression models were used to model the probability of death after a CAM diagnosis. Results: The registry captured 694 cases of CAM. Within this, 341 could be analyzed as the study excluded patients with an unknown CAM recovery status due to either an interruption or a lack of follow up. The 341 viable cases consisted of 258 patients who survived after the completion of treatment and 83 patients who died during the period of observation. In a multivariable logistic regression model, the factors associated with an increased risk of mortality include old age (OR = 1.04, 95% CI 1.02–1.07, p = 0.001), history of diabetes mellitus (OR 3.5, 95% CI 1.01–11.9, p = 0.02) and a lower BMI (OR 0.9, 95% CI 0.82–0.98, p = 0.03). Mucor localized to sinus disease was associated with 77% reduced odds of death (OR = 0.23, 95% CI 0.09–0.57, p = 0.001), while cerebral mucor was associated with an increased odds of death (OR = 10.96, 95% CI 4.93–24.36, p = ≤0.0001). Conclusion: In patients with CAM, older age, a history of diabetes and a lower body mass index is associated with increased mortality. Disease limited to the sinuses without a cerebral extension is associated with a lower risk of mortality. Interestingly, the use of zinc and azithromycin were not associated with increased mortality in our study. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
14 pages, 2181 KiB  
Article
Characteristics of Hospitalized Pediatric Patients in the First Five Waves of the COVID-19 Pandemic in a Single Center in Poland—1407 Cases
by Lidia Stopyra, Aleksandra Kowalik, Justyna Stala, Ida Majchrzak, Justyna Szebla, Mateusz Jakosz, Karolina Grzywaczewska and Przemko Kwinta
J. Clin. Med. 2022, 11(22), 6806; https://doi.org/10.3390/jcm11226806 - 17 Nov 2022
Cited by 5 | Viewed by 1521
Abstract
This is a single-center, prospective study that compared the clinical presentation and laboratory findings of hospitalized children during the first five waves of the COVID-19 pandemic. Data were collected, according to a standardized questionnaire, from 1407 children from 23 March 2020 to 30 [...] Read more.
This is a single-center, prospective study that compared the clinical presentation and laboratory findings of hospitalized children during the first five waves of the COVID-19 pandemic. Data were collected, according to a standardized questionnaire, from 1407 children from 23 March 2020 to 30 April 2022. Significant differences in clinical courses were found among the five waves probably due to different SARS-CoV-2 variants. The median age was 95.8 months in the first wave versus 14.6–23 months in the others. The number of patients with upper respiratory infection was the highest in the fifth wave (74.4% versus 43.8–56.9% in the others) and for lower respiratory infection in the first wave (50.0% versus 16.4–32.5%). Gastroenterocolitis was more common in the fifth wave (24.4% versus 8.9–16.5%); neurological diagnoses appeared more frequently in the fourth wave (16.6% versus 0.6–9.9%), while anosmia and ageusia were higher in the fifth wave (13% versus 1.5–4%). Life-threatening courses were relatively rare. However, children with pneumonia, dehydration from high fever, gastrointestinal symptoms, loss of smell and taste, and neurological symptoms required hospitalization. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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11 pages, 2573 KiB  
Article
Prediction Value of KREBS Von Den Lungen-6 (KL-6) Biomarker in COVID-19 Patients: A Systematic Review and Meta-Analysis
by Michal Matuszewski, Lukasz Szarpak, Zubaid Rafique, Frank W. Peacock, Michal Pruc, Piotr Szwed, Francesco Chirico, Alla Navolokina, Jerzy R. Ladny and Andrea Denegri
J. Clin. Med. 2022, 11(21), 6600; https://doi.org/10.3390/jcm11216600 - 07 Nov 2022
Cited by 6 | Viewed by 1785
Abstract
The SARS-CoV-2 (COVID-19) pandemic is a major issue that necessitates the use of cutting-edge disease prediction models. The aim of the study was to assess the existing evidence regarding association between Krebs von den Lungen-6 levels and COVID-19 severity. A literature search was [...] Read more.
The SARS-CoV-2 (COVID-19) pandemic is a major issue that necessitates the use of cutting-edge disease prediction models. The aim of the study was to assess the existing evidence regarding association between Krebs von den Lungen-6 levels and COVID-19 severity. A literature search was performed on Web of Science, PubMed, Scopus and Cochrane Central Register of Controlled Trials databases from 1 January 2020 up to 2 August 2022. The electronic database search was supplemented by searching Google Scholar. In addition, reference lists of relative articles were also reviewed. KL-6 levels among COVID-19 positive vs. negative patients varied and amounted to 443.37 ± 249.33 vs. 205.73 ± 86.8 U/mL (MD = 275.33; 95%CI: 144.57 to 406.09; p < 0.001). The KL-6 level was 402.82 ± 261.16 U/mL in the severe group and was statistically significantly higher than in the non-severe group (297.38 ± 90.46 U/mL; MD = 192.45; 95%CI: 118.19 to 266.72; p < 0.001). The KL-6 level in the mild group was 272.28 ± 95.42 U/mL, compared to 268.04 ± 55.04 U/mL in the moderate COVID-19 group (MD = −12.58; 95%CI: −21.59 to −3.57; p = 0.006). Our meta-analysis indicates a significant association between increased KL-6 levels and SARS-CoV-2 infection. Moreover, KL-6 levels are significantly higher in patients with a more severe course of COVID-19, indicating that KL-6 may be a useful predictor to identify patients at risk for severe COVID-19. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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15 pages, 6487 KiB  
Article
Relation of Pulmonary Diffusing Capacity Decline to HRCT and VQ SPECT/CT Findings at Early Follow-Up after COVID-19: A Prospective Cohort Study (The SECURe Study)
by Terese L. Katzenstein, Jan Christensen, Thomas Kromann Lund, Anna Kalhauge, Frederikke Rönsholt, Daria Podlekareva, Elisabeth Arndal, Ronan M. G. Berg, Thora Wesenberg Helt, Anne-Mette Lebech and Jann Mortensen
J. Clin. Med. 2022, 11(19), 5687; https://doi.org/10.3390/jcm11195687 - 26 Sep 2022
Cited by 7 | Viewed by 2088
Abstract
A large proportion of patients exhibit persistently reduced pulmonary diffusion capacity after COVID-19. It is unknown whether this is due to a post-COVID restrictive lung disease and/or pulmonary vascular disease. The aim of the current study was to investigate the association between initial [...] Read more.
A large proportion of patients exhibit persistently reduced pulmonary diffusion capacity after COVID-19. It is unknown whether this is due to a post-COVID restrictive lung disease and/or pulmonary vascular disease. The aim of the current study was to investigate the association between initial COVID-19 severity and haemoglobin-corrected diffusion capacity to carbon monoxide (DLco) reduction at follow-up. Furthermore, to analyse if DLco reduction could be linked to pulmonary fibrosis (PF) and/or thromboembolic disease within the first months after the illness, a total of 67 patients diagnosed with COVID-19 from March to December 2020 were included across three severity groups: 12 not admitted to hospital (Group I), 40 admitted to hospital without intensive care unit (ICU) admission (Group II), and 15 admitted to hospital with ICU admission (Group III). At first follow-up, 5 months post SARS-CoV-2 positive testing/4 months after discharge, lung function testing, including DLco, high-resolution CT chest scan (HRCT) and ventilation-perfusion (VQ) single photon emission computed tomography (SPECT)/CT were conducted. DLco was reduced in 42% of the patients; the prevalence and extent depended on the clinical severity group and was typically observed as part of a restrictive pattern with reduced total lung capacity. Reduced DLco was associated with the extent of ground-glass opacification and signs of PF on HRCT, but not with mismatched perfusion defects on VQ SPECT/CT. The severity-dependent decline in DLco observed early after COVID-19 appears to be caused by restrictive and not pulmonary vascular disease. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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13 pages, 265 KiB  
Article
In-Hospital Antibiotic Use for COVID-19: Facts and Rationales Assessed through a Mixed-Methods Study
by Laura Elena Stoichitoiu, Larisa Pinte, Alexandr Ceasovschih, Roxana Carmen Cernat, Nicoleta Dorina Vlad, Vlad Padureanu, Laurentiu Sorodoc, Adriana Hristea, Adrian Purcarea, Camelia Badea and Cristian Baicus
J. Clin. Med. 2022, 11(11), 3194; https://doi.org/10.3390/jcm11113194 - 02 Jun 2022
Cited by 9 | Viewed by 2291
Abstract
It is well known that during the coronavirus disease 2019 (COVID-19) pandemic, antibiotics were overprescribed. However, less is known regarding the arguments that have led to this overuse. Our aim was to understand the factors associated with in-hospital antibiotic prescription for COVID-19, and [...] Read more.
It is well known that during the coronavirus disease 2019 (COVID-19) pandemic, antibiotics were overprescribed. However, less is known regarding the arguments that have led to this overuse. Our aim was to understand the factors associated with in-hospital antibiotic prescription for COVID-19, and the rationale behind it. We chose a convergent design for this mixed-methods study. Quantitative data was prospectively obtained from 533 adult patients admitted in six hospitals (services of internal medicine, infectious diseases and pneumology). Fifty-six percent of the patients received antibiotics. The qualitative data was obtained from interviewing 14 physicians active in the same departments in which the enrolled patients were hospitalized. Thematic analysis was used for the qualitative approach. Our study revealed that doctors based their decisions to prescribe antibiotics on a complex interplay of factors regarding the simultaneous appearance of consolidation on the chest computer tomography together with a worsening of clinical conditions suggestive of bacterial infection and/or an increase in inflammatory markers. Besides these features which might suggest bacterial co-/suprainfection, doctors also prescribed antibiotics in situations of uncertainty, in patients with severe disease, or with multiple associated comorbidities. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
13 pages, 461 KiB  
Article
Remdesivir in the Treatment of COVID-19: A Propensity Score-Matched Analysis from a Public Hospital in New York City Assessing Renal and Hepatic Safety
by Hyomin Lim, Leonidas Palaiodimos, Cesar G. Berto, Oluwatitomi Tedunjaiye, Paras Malik, Sanjana Nagraj, Hansol Choi, Nang San Hti Lar Seng, Michail Kladas, Amrin Kharawala, Dimitrios Karamanis, Nidhi Varma and Acharya Anjali
J. Clin. Med. 2022, 11(11), 3132; https://doi.org/10.3390/jcm11113132 - 31 May 2022
Cited by 5 | Viewed by 2514
Abstract
While the relative efficacy of remdesivir as a therapeutic agent in selected patients with COVID-19 has been established, safety concerns have been raised regarding potential nephrotoxicity and hepatotoxicity. Our main objective was to investigate the kidney- and liver-related safety outcomes in patients with [...] Read more.
While the relative efficacy of remdesivir as a therapeutic agent in selected patients with COVID-19 has been established, safety concerns have been raised regarding potential nephrotoxicity and hepatotoxicity. Our main objective was to investigate the kidney- and liver-related safety outcomes in patients with COVID-19 treated with remdesivir in a public hospital in New York. A propensity score-matched retrospective study was conducted in hospitalized patients with COVID-19 from 1 June 2020 to 10 March 2021. A total of 927 patients were included in this study (remdesivir: 427, non-remdesivir: 500; women: 51.8%; median age 61 years; median BMI: 28.5 kg/m2). Matching without replacement yielded a cohort of 248 patients (124 in each group). In the matched cohort, the remdesivir group had a significantly lower rate of acute kidney injury (AKI) (12.1% vs. 21.8%, p = 0.042), a lower rate of acute liver injury (ALI) on the verge of statistical significance (7.3% vs. 14.5%, p = 0.067), and non-significantly lower death rate (13.7% vs. 16.1%, p = 0.593) compared to the non-remdesivir group. Multivariable analyses revealed that patients treated with remdesivir were found to be associated with a significantly lower likelihood for AKI (OR: 0.40; 95% CI: 0.24–0.67, p < 0.001), no association was found for ALI (OR: 0.68; 95% CI: 0.35–1.30, p = 0.241), while a trend towards an association of patients treated with remdesivir with a lower likelihood for in-hospital death was observed (OR: 0.57; 95% CI: 0.32–1.01, p = 0.053). In conclusion, no safety concerns with regards to renal and liver outcomes were raised in patients with COVID-19 treated with remdesivir. Instead, there were signals of possible nephroprotection and improved in-hospital mortality. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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14 pages, 7548 KiB  
Article
Lung Aeration in COVID-19 Pneumonia by Ultrasonography and Computed Tomography
by Alexandros Kalkanis, Christophe Schepers, Zafeiris Louvaris, Laurent Godinas, Els Wauters, Dries Testelmans, Natalie Lorent, Pierre Van Mol, Joost Wauters, Walter De Wever and Christophe Dooms
J. Clin. Med. 2022, 11(10), 2718; https://doi.org/10.3390/jcm11102718 - 11 May 2022
Cited by 3 | Viewed by 1999
Abstract
We conducted a prospective single-center observational study to determine lung ultrasound reliability in assessing global lung aeration in 38 hospitalized patients with non-critical COVID-19. On admission, fixed chest CT scans using visual (CTv) and software-based (CTs) analyses along with lung ultrasound imaging protocols [...] Read more.
We conducted a prospective single-center observational study to determine lung ultrasound reliability in assessing global lung aeration in 38 hospitalized patients with non-critical COVID-19. On admission, fixed chest CT scans using visual (CTv) and software-based (CTs) analyses along with lung ultrasound imaging protocols and scoring systems were applied. The primary endpoint was the correlation between global chest CTs score and global lung ultrasound score. The secondary endpoint was the association between radiographic features and clinical disease classification or laboratory indices of inflammation. Bland–Altman analysis between chest CT scores obtained visually (CTv) or using software (CTs) indicated that only 1 of the 38 paired measures was outside the 95% limits of agreement (−4 to +4 score). Global lung ultrasound score was highly and positively correlated with global software-based CTs score (r = 0.74, CI = 0.55–0.86; p < 0.0001). Significantly higher median CTs score (p = 0.01) and lung ultrasound score (p = 0.02) were found in severe compared to moderate COVID-19. Furthermore, we identified significantly lower (p < 0.05) lung ultrasound and CTs scores in those patients with a more severe clinical condition manifested by SpO2 < 92% and C-reactive protein > 58 mg/L. We concluded that lung ultrasound is a reliable bedside clinical tool to assess global lung aeration in hospitalized non-critical care patients with COVID-19 pneumonia. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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9 pages, 246 KiB  
Article
Early Administration of Bamlanivimab in Combination with Etesevimab Increases the Benefits of COVID-19 Treatment: Real-World Experience from the Liguria Region
by Antonio Vena, Giovanni Cenderello, Elisa Balletto, Laura Mezzogori, Alessandro Santagostino Barbone, Marco Berruti, Lorenzo Ball, Denise Battaglini, Alessandro Bonsignore, Chiara Dentone, Daniele Roberto Giacobbe, Tarek Kamal Eldin, Malgorzata Mikulska, Barbara Rebesco, Chiara Robba, Ambra Scintu, Andrea Stimamiglio, Lucia Taramasso, Paolo Pelosi, Stefania Artioli and Matteo Bassettiadd Show full author list remove Hide full author list
J. Clin. Med. 2021, 10(20), 4682; https://doi.org/10.3390/jcm10204682 - 13 Oct 2021
Cited by 6 | Viewed by 3444
Abstract
Monoclonal antibodies, such as bamlanivimab and etesevimab combination (BEC), have been proposed for patients with mild or moderate coronavirus disease 2019 (COVID-19). However, few studies have assessed the factors associated with the early administration of BEC or the impact of early BEC treatment [...] Read more.
Monoclonal antibodies, such as bamlanivimab and etesevimab combination (BEC), have been proposed for patients with mild or moderate coronavirus disease 2019 (COVID-19). However, few studies have assessed the factors associated with the early administration of BEC or the impact of early BEC treatment on the clinical evolution of the patients. We conducted a retrospective cohort study of all adults with COVID-19 who received BEC at three institutions in the Liguria region. The primary endpoint was to investigate the clinical variables associated with early BEC infusion. Secondary endpoints were 30-day overall mortality and the composite endpoint of requirement of hospital admission or need for supplemental oxygen during the 30-day follow-up period. A total of 127 patients (median age 70 years; 56.7% males) received BEC. Of those, 93 (73.2%) received BEC within 5 days from symptoms onset (early BEC). Patients with a higher Charlson comorbidity index were more likely to receive early treatment (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.04–2.45; p = 0.03) in contrast to those reporting fever at presentation (OR 0.26, 0.08–0.82; p = 0.02). Early BEC was associated with lower likelihood of hospital admission or need for supplemental oxygen (OR 0.19, 0.06–0.65; p = 0.008). Five patients who received early BEC died during the follow-up period, but only one of them due to COVID-19-related causes. Early bamlanivimab and etesevimab combination was more frequently administered to patients with a high Charlson comorbidity index. Despite this, early BEC was associated with a lower rate of hospital admission or need for any supplementary oxygen compared to late administration. These results suggest that efforts should focus on encouraging early BEC use in patients with mild–moderate COVID-19 at risk for complications. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
15 pages, 1981 KiB  
Article
Anakinra versus Baricitinib: Different Strategies for Patients Hospitalized with COVID-19
by José A García-García, Marta Pérez-Quintana, Consuelo Ramos-Giráldez, Isabel Cebrián-González, María L Martín-Ponce, José del Valle-Villagrán, María A Navarro-Puerto, Jorge Sánchez-Villegas, Rocío Gómez-Herreros, Isabel Manoja-Bustos, Daniel León-Martí, Lucía Serrano-Rodríguez, Alejandra de Miguel-Albarreal, María J Velasco-Romero, Francisco Mula-Falcón, Pilar Fernández-Pérez, Isabel Melguizo-Moya, María J Pérez-Quintana, Guillermo Romero-Molina, Salvador Vergara-López, José L Marenco-de la Fuente, Jorge Marín-Martín and José A Mira-Escartiadd Show full author list remove Hide full author list
J. Clin. Med. 2021, 10(17), 4019; https://doi.org/10.3390/jcm10174019 - 06 Sep 2021
Cited by 12 | Viewed by 2626
Abstract
Background: Immunomodulatory drugs have been used in patients with severe COVID-19. The objective of this study was to evaluate the effects of two different strategies, based either on an interleukin-1 inhibitor, anakinra, or on a JAK inhibitor, such as baricitinib, on the survival [...] Read more.
Background: Immunomodulatory drugs have been used in patients with severe COVID-19. The objective of this study was to evaluate the effects of two different strategies, based either on an interleukin-1 inhibitor, anakinra, or on a JAK inhibitor, such as baricitinib, on the survival of patients hospitalized with COVID-19 pneumonia. Methods: Individuals admitted to two hospitals because of COVID-19 were included if they fulfilled the clinical, radiological, and laboratory criteria for moderate-to-severe disease. Patients were classified according to the first immunomodulatory drug prescribed: anakinra or baricitinib. All subjects were concomitantly treated with corticosteroids, in addition to standard care. The main outcomes were the need for invasive mechanical ventilation (IMV) and in-hospital death. Statistical analysis included propensity score matching and Cox regression model. Results: The study subjects included 125 and 217 individuals in the anakinra and baricitinib groups, respectively. IMV was required in 13 (10.4%) and 10 (4.6%) patients, respectively (p = 0.039). During this period, 22 (17.6%) and 36 (16.6%) individuals died in both groups (p = 0.811). Older age, low functional status, high comorbidity, need for IMV, elevated lactate dehydrogenase, and use of a high flow of oxygen at initially were found to be associated with worse clinical outcomes. No differences according to the immunomodulatory therapy used were observed. For most of the deceased individuals, early interruption of anakinra or baricitinib had occurred at the time of their admission to the intensive care unit. Conclusions: Similar mortality is observed in patients treated with anakinra or baricitinib plus corticosteroids. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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8 pages, 1006 KiB  
Article
An Immunogenicity Report for the Comparison between Heterologous and Homologous Prime-Boost Schedules with ChAdOx1-S and BNT162b2 Vaccines
by Alexandre Vallée, Marc Vasse, Laurence Mazaux, Brigitte Bonan, Carline Amiel, Sara Zia-Chahabi, Aurélie Chan-Hew-Wai, Eric Farfour, Eve Camps, Pauline Touche, Flavie Barret, François Parquin, David Zucman and Erwan Fourn
J. Clin. Med. 2021, 10(17), 3817; https://doi.org/10.3390/jcm10173817 - 25 Aug 2021
Cited by 15 | Viewed by 3679
Abstract
Background: There is a small amount of immunological data on COVID-19 heterologous vaccination schedules in humans. We assessed the immunogenicity of BNT162b2 (Pfizer/BioNTech) administered as a second dose in healthcare workers primed with ChAdOx1-S (Vaxzevria, AstraZeneca). Methods: 197 healthcare workers were included in [...] Read more.
Background: There is a small amount of immunological data on COVID-19 heterologous vaccination schedules in humans. We assessed the immunogenicity of BNT162b2 (Pfizer/BioNTech) administered as a second dose in healthcare workers primed with ChAdOx1-S (Vaxzevria, AstraZeneca). Methods: 197 healthcare workers were included in a monocentric observational study in Foch hospital, France, between June and July 2021. The main outcome was the immunogenicity measured by serum SARS-CoV-2 IgG antibodies. Results: 130 participants received the ChAdOx1-S/BNT vaccine and 67 received the BNT/BNT vaccine. The geometric mean of IgG antibodies was significantly higher in the BNT/BNT vaccine group compared to the ChAdOx1-S/BNT vaccine group, namely 10,734.9, 95% CI (9141.1–12,589.3) vs. 7268.6, 95% CI (6501.3–8128.3), respectively (p < 0.001). However, after adjustment for time duration between the prime and second vaccinations, no significant difference was observed (p = 0.181). A negative correlation between antibody levels and time duration between second dose and serology test was observed for the BNT/BNT vaccine (p < 0.001), which remained significant after adjustment for all covariates (p < 0.001), but not for the ChAdOx1-S/BNT vaccine (p = 0.467). Conclusions: Heterologous and homologous schedules of ChAdOx1-S and BNT vaccines present robust immune responses after the second vaccination. The results observed were equivalent after adjustment for covariates and emphasize the importance of flexibility in deploying mRNA and viral vectored vaccines. Nevertheless, applying the ChAdOx1-S schedule vaccination for the heterologous second dose of BNT was associated with decreased IgG antibody levels compared to the homologous BNT/BNT vaccination. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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9 pages, 550 KiB  
Article
Efficacy of Remdesivir-Containing Therapy in Hospitalized COVID-19 Patients: A Prospective Clinical Experience
by Alessandro Russo, Erica Binetti, Cristian Borrazzo, Elio Gentilini Cacciola, Luigi Battistini, Giancarlo Ceccarelli, Claudio Maria Mastroianni and Gabriella d’Ettorre
J. Clin. Med. 2021, 10(17), 3784; https://doi.org/10.3390/jcm10173784 - 24 Aug 2021
Cited by 13 | Viewed by 2062
Abstract
Objectives: Remdesivir is currently approved for the treatment of COVID-19. The recommendation for using remdesivir in patients with COVID-19 was based on the in vitro and in vivo activity of this drug against SARS-CoV-2. Methods: This was a prospective observational study conducted on [...] Read more.
Objectives: Remdesivir is currently approved for the treatment of COVID-19. The recommendation for using remdesivir in patients with COVID-19 was based on the in vitro and in vivo activity of this drug against SARS-CoV-2. Methods: This was a prospective observational study conducted on a population of patients hospitalized for COVID-19. The primary endpoint of this study was the impact of remdesivir-containing therapy on 30-day mortality; the secondary endpoint was the impact of remdesivir-containing therapy on the need for high-flow oxygen therapy (HFNC), non-invasive ventilation (NIV), or mechanical ventilation. The data were analyzed after propensity score matching. Results: A total of 407 patients with SARS-CoV-2 pneumonia were consecutively enrolled. Out of these, 294 (72.2%) were treated with remdesivir and 113 (27.8%) were not. Overall, 61 patients (14.9%) were treated during hospitalization with HFNC, NIV, or mechanical ventilation, while 30-day mortality was observed in 21 patients (5.2%). Univariate analysis of patients treated with remdesivir or not showed no differences in 30-day mortality (4% vs. 6%, p = 0.411) in the two study groups. Cox regression analysis, after propensity score matching, showed that therapies, including remdesivir-containing therapy, were not statistically associated with 30-day survival or mortality. The Kaplan–Meier curves of 30-day survival in patients treated with remdesivir or not before (p = 0.24) and after (p = 0.88) propensity score matching showed no differences between the two study groups. Finally, patients treated with remdesivir or not showed the same need for HFNC/NIV or mechanical ventilation. Conclusions: This real-life experience of remdesivir use in hospitalized patients with COVID-19 was not associated with significant increases in rates of survival or reduced use of HFNC/NIV or mechanical ventilation compared with patients treated with other therapies not including remdesivir. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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9 pages, 964 KiB  
Article
Ciclesonide Inhaler Treatment for Mild-to-Moderate COVID-19: A Randomized, Open-Label, Phase 2 Trial
by Joon-Young Song, Jin-Gu Yoon, Yu-Bin Seo, Jacob Lee, Joong-Sik Eom, Jin-Soo Lee, Won-Suk Choi, Eun-Young Lee, Young-Ah Choi, Hak-Jun Hyun, Hye Seong, Ji-Yun Noh, Hee-Jin Cheong and Woo-Joo Kim
J. Clin. Med. 2021, 10(16), 3545; https://doi.org/10.3390/jcm10163545 - 12 Aug 2021
Cited by 26 | Viewed by 5425
Abstract
Although some intravenous drugs have been used to treat coronavirus disease 2019 (COVID-19), no effective antiviral agents are currently available in the outpatient setting. We aimed to evaluate the efficacy and adverse events of 14-day ciclesonide treatment vs. standard care for patients with [...] Read more.
Although some intravenous drugs have been used to treat coronavirus disease 2019 (COVID-19), no effective antiviral agents are currently available in the outpatient setting. We aimed to evaluate the efficacy and adverse events of 14-day ciclesonide treatment vs. standard care for patients with mild-to-moderate COVID-19. A randomized, open-label, multicenter clinical trial of ciclesonide inhalers was conducted in patients with mild-to-moderate COVID-19. Patients were enrolled within 3 days of diagnosis or within 7 days from symptom onset and randomly assigned to receive either ciclesonide (320 µg inhalation twice per day for 14 days) or standard care. The primary endpoint was the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) eradication rate on day 14 from study enrollment. Clinical status was assessed once daily, and serial nasopharyngeal viral load was evaluated by quantitative reverse transcription polymerase chain reaction. There were 35 and 26 patients in the ciclesonide and standard care groups, respectively. The SARS-CoV-2 eradication rate at day 14 was significantly higher in the ciclesonide group (p = 0.021). In multivariate analysis, SARS-CoV-2 negative conversion within 14 days was 12 times more likely in the ciclesonide group (95% confidence interval, 1.187–125.240). Additionally, the clinical failure rate (high-flow nasal oxygen therapy or mechanical ventilation) was significantly lower in the ciclesonide group (p = 0.034). In conclusion, ciclesonide inhalation shortened SARS-CoV-2 viral shedding duration, and it may inhibit the progression to acute respiratory failure in patients with mild-to-moderate COVID-19. Clinical Trial Registration NCT04330586. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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Review

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18 pages, 329 KiB  
Review
Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials
by Konstantinos G. Kyriakoulis, Evangelos Dimakakos, Ioannis G. Kyriakoulis, Mariella Catalano, Alex C. Spyropoulos, Sam Schulman, James Douketis, Anna Falanga, Anthony Maraveyas, Dan-Mircea Olinic, Jill Belch, Grigorios Gerotziafas, Konstantinos Syrigos, Anastasios Kollias and COVID-19 Thrombosis Collaborative Group, Endorsed by VAS-European Independent Foundation in Angiology/Vascular Medicine, UEMS Division of Angiology/Vascular Medicine/and ESVM-European Society of Vascular Medicine and Supported by the Balkan Working Group
J. Clin. Med. 2022, 11(20), 5997; https://doi.org/10.3390/jcm11205997 - 11 Oct 2022
Cited by 17 | Viewed by 3357
Abstract
Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not [...] Read more.
Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
15 pages, 1049 KiB  
Review
Current Effective Therapeutics in Management of COVID-19
by Kavya Atluri, Iris Aimlin and Shitij Arora
J. Clin. Med. 2022, 11(13), 3838; https://doi.org/10.3390/jcm11133838 - 01 Jul 2022
Cited by 22 | Viewed by 4086
Abstract
The current pandemic due to the SARS-CoV-2 virus has caused irreparable damage globally. High importance is placed on defining current therapeutics for Coronavirus Disease 2019 (COVID-19). In this review, we discuss the evidence from pivotal trials that led to the approval of effective [...] Read more.
The current pandemic due to the SARS-CoV-2 virus has caused irreparable damage globally. High importance is placed on defining current therapeutics for Coronavirus Disease 2019 (COVID-19). In this review, we discuss the evidence from pivotal trials that led to the approval of effective therapeutics in the treatment and prevention of COVID-19. We categorize them as effective outpatient and inpatient management strategies The review also attempts to contextualize the efficacy of therapeutics to the emerging variants. Vaccines, which remain the most effective prevention against hospitalization and deaths is not included in this review. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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31 pages, 1116 KiB  
Review
Current Treatment Options for COVID-19 Associated Mucormycosis: Present Status and Future Perspectives
by Yasasve Madhavan, Kadambari Vijay Sai, Dilip Kumar Shanmugam, Aashabharathi Manimaran, Karthigadevi Guruviah, Yugal Kishore Mohanta, Divyambika Catakapatri Venugopal, Tapan Kumar Mohanta, Nanaocha Sharma and Saravanan Muthupandian
J. Clin. Med. 2022, 11(13), 3620; https://doi.org/10.3390/jcm11133620 - 23 Jun 2022
Cited by 12 | Viewed by 2835
Abstract
Mucormycosis has become increasingly associated with COVID-19, leading to the use of the term “COVID-19 associated mucormycosis (CAM)”. Treatment of CAM is challenging due to factors such as resistance to many antifungals and underlying co-morbidities. India is particularly at risk for this disease [...] Read more.
Mucormycosis has become increasingly associated with COVID-19, leading to the use of the term “COVID-19 associated mucormycosis (CAM)”. Treatment of CAM is challenging due to factors such as resistance to many antifungals and underlying co-morbidities. India is particularly at risk for this disease due to the large number of patients with COVID-19 carrying comorbidities that predispose them to the development of mucormycosis. Additionally, mucormycosis treatment is complicated due to the atypical symptoms and delayed presentation after the resolution of COVID-19. Since this disease is associated with increased morbidity and mortality, early identification and diagnosis are desirable to initiate a suitable combination of therapies and control the disease. At present, the first-line treatment involves Amphotericin B and surgical debridement. To overcome limitations associated with surgery (invasive, multiple procedures required) and amphotericin B (toxicity, extended duration and limited clinical success), additional therapies can be utilized as adjuncts or alternatives to reduce treatment duration and improve prognosis. This review discusses the challenges associated with treating CAM and the critical aspects for controlling this invasive fungal infection—early diagnosis and initiation of therapy, reversal of risk factors, and adoption of a multipronged treatment strategy. It also details the various therapeutic options (in vitro, in vivo and human case reports) that have been used for the treatment of CAM. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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11 pages, 1036 KiB  
Review
High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis
by Anastasios Kollias, Konstantinos G. Kyriakoulis, Ioannis P. Trontzas, Vassiliki Rapti, Ioannis G. Kyriakoulis, Christina A. Theochari, Evangelos Dimakakos, Garyphallia Poulakou and Konstantinos Syrigos
J. Clin. Med. 2021, 10(23), 5549; https://doi.org/10.3390/jcm10235549 - 26 Nov 2021
Cited by 14 | Viewed by 2544
Abstract
Thromboprophylaxis in hospitalized patients with COVID-19 has been associated with a survival benefit and is strongly recommended. However, the optimal dose of thromboprophylaxis remains unclear. A systematic review and meta-analysis (PubMed/EMBASE) of studies comparing high (intermediate or therapeutic dose) versus standard (prophylactic dose) [...] Read more.
Thromboprophylaxis in hospitalized patients with COVID-19 has been associated with a survival benefit and is strongly recommended. However, the optimal dose of thromboprophylaxis remains unclear. A systematic review and meta-analysis (PubMed/EMBASE) of studies comparing high (intermediate or therapeutic dose) versus standard (prophylactic dose) intensity of thrombo-prophylaxis with regard to outcome of hospitalized patients with COVID-19 was performed. Randomized and non-randomized studies that provided adjusted effect size estimates were included. Meta-analysis of 7 studies comparing intermediate versus prophylactic dose of thromboprophylaxis (2 randomized and 5 observational, n = 2009, weighted age 61 years, males 61%, ICU 53%) revealed a pooled adjusted relative risk (RR) for death at 0.56 (95% confidence intervals (CI) 0.34, 0.92) in favor of the intermediate dose. For the same comparison arms, the pooled RR for venous thromboembolism was 0.84 (95% CI 0.54, 1.31), and for major bleeding events was 1.63 (95% CI 0.79, 3.37). Meta-analysis of 17 studies comparing therapeutic versus prophylactic dose of thromboprophylaxis (2 randomized and 15 observational, n = 7776, weighted age 64 years, males 54%, ICU 21%) revealed a pooled adjusted RR for death at 0.73 (95% CI 0.47, 1.14) for the therapeutic dose. An opposite trend was observed in the unadjusted analysis of 15 observational studies (RR 1.24 (95% CI 0.88, 1.74)). For the same comparison arms, the pooled RR for venous thromboembolism was 1.13 (95% CI 0.52, 2.48), and for major bleeding events 3.32 (95% CI 2.51, 4.40). In conclusion, intermediate compared with standard prophylactic dose of thromboprophylaxis appears to be rather safe and is associated with additional survival benefit, although most data are derived from observational retrospective analyses. Randomized studies are needed to define the optimal thromboprophylaxis in hospitalized patients with COVID-19. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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15 pages, 1695 KiB  
Review
Immunomodulation and Reduction of Thromboembolic Risk in Hospitalized COVID-19 Patients: Systematic Review and Meta-Analysis of Randomized Trials
by Dimitrios Sagris, Matilda Florentin, Panagiotis Tasoudis, Eleni Korompoki, Nikolaos Gatselis, Evangelos J. Giamarellos-Bourboulis, Haralampos Milionis, James Douketis, Alex C. Spyropoulos, George Dalekos and George Ntaios
J. Clin. Med. 2021, 10(22), 5366; https://doi.org/10.3390/jcm10225366 - 18 Nov 2021
Cited by 8 | Viewed by 2312
Abstract
Background: We aimed to investigate the potential beneficial effect of immunomodulation therapy on the thromboembolic risk in hospitalized COVID-19 patients. Methods: We searched PubMed and Scopus for randomized trials reporting the outcomes of venous thromboembolism (VTE), ischemic stroke or systemic embolism, myocardial infarction, [...] Read more.
Background: We aimed to investigate the potential beneficial effect of immunomodulation therapy on the thromboembolic risk in hospitalized COVID-19 patients. Methods: We searched PubMed and Scopus for randomized trials reporting the outcomes of venous thromboembolism (VTE), ischemic stroke or systemic embolism, myocardial infarction, any thromboembolic event, and all-cause mortality in COVID-19 patients treated with immunomodulatory agents. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the Mantel–Haenszel random effects method. Results: Among 8499 patients hospitalized with COVID-19, 4638 were treated with an immunomodulatory agent, 3861—with usual care only. Among the patients prescribed immunomodulatory agents, there were 1.77 VTEs per 100 patient-months compared to 2.30 among those treated with usual care (OR: 0.84, 95% CI: 0.61–1.16; I2: 0%). Among the patients who received an interleukin 6 (IL-6) antagonist, VTEs were reported in 12 among the 1075 patients compared to 20 among the 848 receiving the usual care (OR: 0.52, 95% CI: 0.22–1.20; I2: 6%). Immunomodulators as an add-on to usual care did not reduce the risk of stroke or systemic embolism (OR: 1.10, 95% CI: 0.50–2.40; I2: 0%) or of myocardial infarction (OR: 1.06, 95% CI: 0.47–2.39; I2: 0%) and there was a nonsignificant reduction in any thromboembolic event (OR: 0.86, 95% CI: 0.65–1.14; I2: 0%). Conclusions: We did not identify a statistically significant effect of immunomodulation on prevention of thromboembolic events in COVID-19. However, given the large effect estimate for VTE prevention, especially in the patients treated with IL-6 antagonists, we cannot exclude a potential effect of immunomodulation. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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8 pages, 424 KiB  
Review
The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis
by Konstantinos G. Kyriakoulis, Anastasios Kollias, Garyphallia Poulakou, Ioannis G. Kyriakoulis, Ioannis P. Trontzas, Andriani Charpidou and Konstantinos Syrigos
J. Clin. Med. 2021, 10(19), 4462; https://doi.org/10.3390/jcm10194462 - 28 Sep 2021
Cited by 15 | Viewed by 2949
Abstract
The role of immunomodulatory agents in the treatment of hospitalized patients with COVID-19 has been of increasing interest. Anakinra, an interleukin-1 inhibitor, has been shown to offer significant clinical benefits in patients with COVID-19 and hyperinflammation. An updated systematic review and meta-analysis regarding [...] Read more.
The role of immunomodulatory agents in the treatment of hospitalized patients with COVID-19 has been of increasing interest. Anakinra, an interleukin-1 inhibitor, has been shown to offer significant clinical benefits in patients with COVID-19 and hyperinflammation. An updated systematic review and meta-analysis regarding the impact of anakinra on the outcomes of hospitalized patients with COVID-19 was conducted. Studies, randomized or non-randomized with adjustment for confounders, reporting on the adjusted risk of death in patients treated with anakinra versus those not treated with anakinra were deemed eligible. A search was performed in PubMed/EMBASE databases, as well as in relevant websites, until 1 August 2021. The meta-analysis of six studies that fulfilled the inclusion criteria (n = 1553 patients with moderate to severe pneumonia, weighted age 64 years, men 66%, treated with anakinra 50%, intubated 3%) showed a pooled hazard ratio for death in patients treated with anakinra at 0.47 (95% confidence intervals 0.34, 0.65). A meta-regression analysis did not reveal any significant associations between the mean age, percentage of males, mean baseline C-reactive protein levels, mean time of administration since symptoms onset among the included studies and the hazard ratios for death. All studies were considered as low risk of bias. The current evidence, although derived mainly from observational studies, supports a beneficial role of anakinra in the treatment of selected patients with COVID-19. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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4 pages, 213 KiB  
Brief Report
Humoral and T-Cell Response before and after a Fourth BNT162b2 Vaccine Dose in Adults ≥60 Years
by Erez Bar-Haim, Noa Eliakim-Raz, Amos Stemmer, Hila Cohen, Uri Elia, Asaf Ness, Muhammad Awwad, Nassem Ghantous, Neta Moskovits, Shahar Rotem and Salomon M. Stemmer
J. Clin. Med. 2022, 11(9), 2649; https://doi.org/10.3390/jcm11092649 - 08 May 2022
Cited by 6 | Viewed by 3390
Abstract
Both humoral and cellular anamnestic responses are significant for protective immunity against SARS-CoV-2. In the current study, the responses in elderly people before and after a fourth vaccine dose of BNT162b2 were compared to those of individuals immunized with three vaccine doses. Although [...] Read more.
Both humoral and cellular anamnestic responses are significant for protective immunity against SARS-CoV-2. In the current study, the responses in elderly people before and after a fourth vaccine dose of BNT162b2 were compared to those of individuals immunized with three vaccine doses. Although a boost effect was observed, the high response following the third administration questions the necessity of an early fourth boost. Full article
(This article belongs to the Special Issue COVID-19: Clinical Advances and Challenges)
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