Treatment with Remdesivir of Children with SARS-CoV-2 Infection: Experience from a Clinical Hospital in Romania.

BACKGROUND: The COVID-19 pandemic was characterized by mild-to-moderate disease in children and adolescents, with low incidences of severe cases and mortality. Most of the information on drug therapy in COVID-19-positive children was derived from research in adult patients. Remdesivir, an inhibitor of viral RNA polymerase, was shown to be effective in COVID-19 patients with moderate-to-severe disease. In this study, we present our experience of the use of remdesivir in pediatric patients hospitalized with COVID-19. MATERIALS AND METHODS: This retrospective study was based on the early use of remdesivir in 14 children with mild, moderate, and severe clinical forms of COVID-19, who were hospitalized between 1 January 2022, and 30 September 2023. RESULTS: The patients included eight infants and six children older than 1 day (the age range was 2 months to 17 years). Most of them (92.85%) had documented pneumonia. Four patients had associated acute laryngitis, and another had bronchiolitis. Coinfections with Streptococcus pneumoniae were diagnosed in two patients. The clinical course was favorable in 12/14 (85.71%) children. Two patients were transferred to the pediatric intensive care unit because of aggravation of associated acute diseases (acute laryngitis and bronchiolitis, respectively). Mild increases in alanine aminotransferase levels occurred in two patients, with no increase in serum creatinine, during treatment with remdesivir. CONCLUSION: The appropriate use of remdesivir proved safe and efficient in our group of patients. However, further studies are required to support the efficiency, tolerability, and safety of remdesivir in children.

The knowns and unknowns of long COVID-19: from mechanisms to therapeutical approaches.

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has been defined as the greatest global health and socioeconomic crisis of modern times. While most people recover after being infected with the virus, a significant proportion of them continue to experience health issues weeks, months and even years after acute infection with SARS-CoV-2. This persistence of clinical symptoms in infected individuals for at least three months after the onset of the disease or the emergence of new symptoms lasting more than two months, without any other explanation and alternative diagnosis have been named long COVID, long-haul COVID, post-COVID-19 conditions, chronic COVID, or post-acute sequelae of SARS-CoV-2 (PASC). Long COVID has been characterized as a constellation of symptoms and disorders that vary widely in their manifestations. Further, the mechanisms underlying long COVID are not fully understood, which hamper efficient treatment options. This review describes predictors and the most common symptoms related to long COVID's effects on the central and peripheral nervous system and other organs and tissues. Furthermore, the transcriptional markers, molecular signaling pathways and risk factors for long COVID, such as sex, age, pre-existing condition, hospitalization during acute phase of COVID-19, vaccination, and lifestyle are presented. Finally, recommendations for patient rehabilitation and disease management, as well as alternative therapeutical approaches to long COVID sequelae are discussed. Understanding the complexity of this disease, its symptoms across multiple organ systems and overlapping pathologies and its possible mechanisms are paramount in developing diagnostic tools and treatments.

Long COVID: Molecular Mechanisms and Detection Techniques.

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), has emerged as a significant health concern following the COVID-19 pandemic. Molecular mechanisms underlying the occurrence and progression of long COVID include viral persistence, immune dysregulation, endothelial dysfunction, and neurological involvement, and highlight the need for further research to develop targeted therapies for this condition. While a clearer picture of the clinical symptomatology is shaping, many molecular mechanisms are yet to be unraveled, given their complexity and high level of interaction with other metabolic pathways. This review summarizes some of the most important symptoms and associated molecular mechanisms that occur in long COVID, as well as the most relevant molecular techniques that can be used in understanding the viral pathogen, its affinity towards the host, and the possible outcomes of host-pathogen interaction.

Spontaneous Pneumomediastinum in a 16-Year-Old Patient with SARS-CoV-2 Infection: A North-East Romanian Case.

Spontaneous pneumomediastinum (SPM) associated with SARS-CoV-2 infection is a rare condition but can represent a medical emergency. It is probably related to alveolar damage secondary to SARS-CoV-2 infection, which allows air to escape in the surrounding lung tissue. Cough and airways' barotrauma are also mentioned as contributing mechanisms. Treatment is generally conservative, but surgery may be required in severe cases. This paper presents the case of a 16-year-old girl with COVID-19-associated SPM who was treated conservatively in our department. The clinical course was favorable with resolution of respiratory symptoms and radiological (chest CT scan) image of pneumomediastinum. The patient was discharged 7 days after the confirmation of the initial SP diagnosis with appropriate treatment and recommendations for isolation. The sudden occurrence of chest pain and dyspnea should raise the suspicion of SPM in COVID-19 patients. Close surveillance and proper radiological monitoring are required in such cases. Treatment should be strictly individualized based on clinical course and radiological appearance.

A Randomized Clinical Trial of Regdanvimab in High-Risk Patients With Mild-to-Moderate Coronavirus Disease 2019.

Background: We evaluated clinical effectiveness of regdanvimab (CT-P59), a severe acute respiratory syndrome coronavirus 2 neutralizing monoclonal antibody, in reducing disease progression and clinical recovery time in patients with mild-to-moderate coronavirus disease 2019 (COVID-19), primarily Alpha variant. Methods: This was phase 3 of a phase 2/3 parallel-group, double-blind, randomized clinical trial. Outpatients with mild-to-moderate COVID-19 were randomized to single-dose regdanvimab 40 mg/kg (n = 656) or placebo (n = 659), alongside standard of care. The primary endpoint was COVID-19 disease progression up to day 28 among "high-risk" patients. Key secondary endpoints were disease progression (all randomized patients) and time to recovery (high-risk and all randomized patients). Results: Of 1315 randomized patients, 880 were high risk; the majority were infected with Alpha variant. The proportion with disease progression was lower (14/446, 3.1% [95% confidence interval {CI}, 1.9%-5.2%] vs 48/434, 11.1% [95% CI, 8.4%-14.4%]; P < .001) and time to recovery was shorter (median, 9.27 days [95% CI, 8.27-11.05 days] vs not reached [95% CI, 12.35-not calculable]; P < .001) with regdanvimab than placebo. Consistent improvements were seen in all randomized and non-high-risk patients who received regdanvimab. Viral load reductions were more rapid with regdanvimab. Infusion-related reactions occurred in 11 patients (4/652 [0.6%] regdanvimab, 7/650 [1.1%] placebo). Treatment-emergent serious adverse events were reported in 5 of (4/652 [0.6%] regdanvimab and 1/650 [0.2%] placebo). Conclusions: Regdanvimab was an effective treatment for patients with mild-to-moderate COVID-19, significantly reducing disease progression and clinical recovery time without notable safety concerns prior to the emergence of the Omicron variant. Clinical Trials Registration: NCT04602000; 2020-003369-20 (EudraCT).

A Conservative Replacement in the Transmembrane Domain of SARS-CoV-2 ORF7a as a Putative Risk Factor in COVID-19.

The ongoing COVID-19 pandemic follows an unpredictable evolution, driven by both host-related factors such as mobility, vaccination status, and comorbidities and by pathogen-related ones. The pathogenicity of its causative agent, SARS-CoV-2 virus, relates to the functions of the proteins synthesized intracellularly, as guided by viral RNA. These functions are constantly altered through mutations resulting in increased virulence, infectivity, and antibody-evasion abilities. Well-characterized mutations in the spike protein, such as D614G, N439K, Δ69-70, E484K, or N501Y, are currently defining specific variants; however, some less studied mutations outside the spike region, such as p. 3691 in NSP6, p. 9659 in ORF-10, 8782C > T in ORF-1ab, or 28144T > C in ORF-8, have been proposed for altering SARS-CoV-2 virulence and pathogenicity. Therefore, in this study, we focused on A105V mutation of SARS-CoV-2 ORF7a accessory protein, which has been associated with severe COVID-19 clinical manifestation. Molecular dynamics and computational structural analyses revealed that this mutation differentially alters ORF7a dynamics, suggesting a gain-of-function role that may explain its role in the severe form of COVID-19 disease.

Emergence of the First Strains of SARS-CoV-2 Lineage B.1.1.7 in Romania: Genomic Analysis.

BACKGROUND: The United Kingdom reported the emergence of a new and highly transmissible SARS-CoV-2 variant (B.1.1.7) that rapidly spread to other countries. The impact of this new mutation-which occurs in the S protein-on infectivity, virulence, and current vaccine effectiveness is still under evaluation. OBJECTIVE: The aim of this study is to sequence SARS-CoV-2 samples of cases in Romania to detect the B.1.1.7 variant and compare these samples with sequences submitted to GISAID. METHODS: SARS-CoV-2 samples were sequenced and amino acid substitution analysis was performed using the CoV-GLUE platform. RESULTS: We have identified the first cases of the B.1.1.7 variant in samples collected from Romanian patients, of which one was traced to the region of the United Kingdom where the new variant was originally sequenced. Mutations in nonstructural protein 3 (Nsp3; N844S and D455N) and ORF3a (L15F) were also detected, indicating common ancestry with UK strains as well as remote connections with strains from Nagasaki, Japan. CONCLUSIONS: These results indicate, for the first time, the presence and characteristics of the new variant B.1.1.7 in Romania and underscore the need for increased genomic sequencing in patients with confirmed COVID-19.

Introduction and Characteristics of SARS-CoV-2 in North-East of Romania During the First COVID-19 Outbreak.

Romania officially declared its first Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) case on February 26, 2020. The first and largest coronavirus disease 2019 (COVID-19) outbreak in Romania was recorded in Suceava, North-East region of the country, and originated at the Suceava regional county hospital. Following sheltering-in-place measures, infection rates decreased, only to rise again after relaxation of measures. This study describes the spread of SARS-CoV-2 in Suceava and other parts of Romania and analyses the mutations and their association with clinical manifestation of the disease during the period of COVID-19 outbreak. Sixty-two samples were sequenced via high-throughput platform and screened for variants. For selected mutations, putative biological significance was assessed, and their effects on disease severity. Phylogenetic analysis was conducted on Romanian genomes (n = 112) and on sequences originating from Europe, United Kingdom, Africa, Asia, South, and North America (n = 876). The results indicated multiple introduction events for SARS-CoV-2 in Suceava, mainly from Italy, Spain, United Kingdom, and Russia although some sequences were also related to those from the Czechia, Belgium, and France. Most Suceava genomes contained mutations common to European lineages, such as A20268G, however, approximately 10% of samples were missing such mutations, indicating a possible different arrival route. While overall genome regions ORF1ab, S, and ORF7 were subject to most mutations, several recurring mutations such as A105V were identified, and these were mainly present in severe forms of the disease. Non-synonymous mutations, such as T987N (Thr987Asn in NSP3a domain), associated with changes in a protein responsible for decreasing viral tethering in human host were also present. Patients with diabetes and hypertension exhibited higher risk ratios (RR) of acquiring severe forms of the disease and these were mainly related to A105V mutation. This study identified the arrival routes of SARS-CoV-2 in Romania and revealed potential associations between the SARS-CoV-2 genomic organization circulating in the country and the clinical manifestation of COVID-19 disease.

[Clinical aspects of tuberculous meningitis in children]. / Aspecte clinico-evolutive ale meningitei tuberculoase la copil.

UNLABELLED: The aim of the study was to investigate the particularities of the clinical manifestation and evolution of tuberculous meningitis at children. MATERIAL AND METHOD: The study was made between January 2000 and December 2008 in Clinic of Infectious Diseases IaSi and Emergency County Hospital ,,Sf. Ioan cel Nou" Suceava on a group of 169 children with tuberculous meningitis. RESULTS: The majority (78.1%) of patients had poor socio-economic conditions and 22.4$ had a family TB contact. The onset of the symptoms was atypical in infants and small children with fever associated with digestive, neurological or pulmonary manifestations. The admission in hospital was delayed in 56.8% of patients and 39.05% had a severe general status with coma. The positive diagnosis was based on cytological and biochemical features of CSF, results of QuantilFERON. TB Gold, pulmonary images, family TB contact and evolution under anti-tuberculous therapy. We observed a high rate of complications represented by hydrocephaly (28.9%). 18 patients died (4 infants), the cause of dead being meningeal coma or complications. CONCLUSION: The diagnosis of tuberculous meningitis at children remains a problem because of the atypical clinical manifestation, the delay of initiating the therapy causing high mortality and frequent complications.

[The utility of QuantiFERON TB Gold for diagnosing tuberculous meningitis in children]. / Utilitatea testului quantiFERON TB gold in diagnosticul meningitei tuberculoase la copil.

MATERIAL AND METHODS: We performed QuantiFERON-TB Gold in Tube (QFT-G) in blood and CSF at 40 children diagnosed with TB meningitis and at 39 children with non TB meningitis, admitted between October 2006 and December 2009. RESULTS: The CSF analyses were suggestive for TB at 27 patients and only 14 had positive culture. The sensitivity of QFT-G in CSF was 72.72% and 69.44% in blood; specificity 96.96% in CSF and 89.18% in blood; the positive predictive value was 96% in CSF and 86.2% in blood; negative predictive value was 78.04% in CSF and 75% in blood. The sensitivity of TST was 61.76% and specificity 82.05%. The sensitivity of the culture from CSF was only 35%. The sensitivity and specificity of QFT-G was higher than TST and culture and better in CSF than in blood. CONCLUSIONS: The determination of alpha-interferon in serum and CSF is useful diagnostic marker of tuberculosis who could improve the management of TB meningitis.