Severe Acute Infection Research Articles

Integrating SARS-CoV-2-specific interferon-γ release assay testing in the evaluation of patients hospitalized with COVID-19.

T cell-mediated immunity is crucial for protection against severe COVID-19. The performance of SARS-CoV-2-specific IFN-γ release assays (IGRAs) to measure T cell responses during severe acute infection is unknown. We conducted a prospective, longitudinal analysis of patients hospitalized for confirmed COVID-19. A standardized SARS-CoV-2-specific quantitative IGRA was measured on admission. Follow-up lasted 90 days. Two hundred forty-eight patients were included; 181 (73%) were vaccinated, 142 (57.3%) were infected with the Omicron variant, and 106 (42.7%) were infected with the Delta variant. The SARS-CoV-2-IGRA result was positive (>200 mIU/mL) in 125 (50.5%) patients, with 44 (35.2%) showing concomitant mitogen-induced IFN-γ response. Compared with patients with negative and borderline results, those with positive SARS-CoV-2 IGRA were younger and showed lower frequency of co-existing comorbidities, lower median Charlson comorbidity index, lower frequency of World Health Organization (WHO) severity score > 4, higher peripheral arterial oxygen saturation to inspired fraction of oxygen (SpO2/FiO2) ratio on admission, higher S-IgG and N-IgG antibody responses, and lower mortality at 28/60/90 days. These findings were consistent for both the Omicron and Delta variants. Similar patterns to those described above were observed in the subset of patients with positive SARS-CoV-2-IGRA and indeterminate mitogen-induced responses, as well as in those exhibiting both positive SARS-CoV-2-specific and mitogen responses. Twenty-eight (11.3%) patients had borderline (100-200 mIU/mL) SARS-CoV-2-IGRA results and shared several similarities with patients with negative SARS-CoV-2 IGRA. In an adjusted Cox model, a negative SARS-CoV-2-IGRA result was found to be an independent predictor of mortality. Using a receiver operating characteristics curve analysis, we found that an IFN-γ value of 150 mIU/mL was identified as the optimal cut-off point for predicting mortality, with 79% [95% confidence interval (CI) 61-93] sensitivity, 61% (95% CI 55-68) specificity, 18% (95% CI 15-22) positive predictive value, 96% (95% CI 93-98) negative predictive value, and an area under the curve (AUC) of 70%. The assay's performance remained consistent regardless of mitogen results or the presence of the Delta or Omicron variants. IMPORTANCE The cellular immune response is essential in the protection against severe disease in patients with established SARS-CoV-2 infection. The novelty of this study lies in the evaluation of the overall performance of a standardized assay to measure cellular immune response, the SARS-CoV-2-specific interferon-γ release assay (IGRA), in hospitalized patients with severe COVID-19. The SARS-CoV-2 IGRA was shown to accurately classify patients based on disease severity and prognosis, and the study revealed that test performance was not affected by the SARS-CoV-2 variant or control tube results. We identified an assay cut-off point with a high negative predictive value against mortality. The SARS-CoV-2 IGRA in patients hospitalized for COVID-19 may be a useful tool to assess cellular immunity and adopt targeted therapeutic and preventive measures.

Successful results of early nucleos(t)ide analogue treatment for liver transplantation candidates with severe acute hepatitis B infection.

Early treatment of severe acute hepatitis B virus (HBV) infection with nucleos(t)ide analogues may prevent progression to acute liver failure (ALF). The charts of 24 patients who were treated for severe acute HBV infection (either INR ≥ 1.5 or INR≥ 1.4 and total bilirubin ≥ 20 mg/dL at the referring institution or after admission) between April 2021 and May 2023 (inclusive) were evaluated retrospectively. Twelve patients were women; median [range] age: 48 [35-68]. Entecavir (0.5 mg/day) (n = 16) or tenofovir disoproxil fumarate (245 mg/day) (n =8) were used depending on availability. Two patients required liver transplant which was performed successfully in one (no suitable donor for the other). Deterioration to ALF was prevented in 22 of the 24 cases (92%); these patients could be discharged after median (range) 12 (5-24) days following initiation of the antiviral drug. There was no significant difference in efficacy between the two antiviral agents. The anti-HBsAg antibody became positive in 16 patients (73%); one other patient became HBsAg negative at 1 month after discharge but was lost to follow up. Five patients (23%) are still HBsAg positive but all except one have started treatment in the last 6 months. One of the recently treated 4 patients stopped taking the antiviral drug at his own will and one has become anti-HIV antibody positive during follow up. Early treatment of severe acute HBV infection with entecavir or tenofovir disoproxil fumarate prevents the need for liver transplant and consideration of living donors.

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5-5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4-10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32-4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23-11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. UK Research and Innovation and National Institute for Health Research.

An integrated multi-omics analysis of identifies distinct molecular characteristics in pulmonary infections of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.

Three to Six-Months Follow-Up Chest CT Findings after COVID-19 Pneumonitis, Incidence of Complications and Correlation to Different Risk Factors

Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, has become a global pandemic. As of November 19, 2020, World Health Organization stated that this disease has been found in more than 200 countries. Pathology studies have shown that COVID-19 causes injuries in multiple organs and tissues, with extensive pulmonary involvement similar to that found in other coronavirus infections (ie, severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus infection). Aim of the Work to evaluate pulmonary changes on 3-6 months follow-up chest CT scans and to explore the risk factors for fibrotic-like changes in the lung in patients who recovered from COVID-19 pneumonia. Patients and Methods This was a retrospective and prospective study that included 50 patients who had Symptoms of variable degree of fever, cough, and dyspnea with RT-PCR confirmed COVID- 19 infection at Ain Shams University Hospitals referred to the Radiodiagnosis Department for HRCT chest examination. All patients were evaluated for: (I): Incidence of complications (residual fibrotic like changes in their follow up CT chest scans). (Il): Correlation to different risk factors such as (smoking, diabetes mellitus, hypertension, pre-existing pulmonary disease, pre-existing renal disease and steroid therapy). Results 56% of cases showed residual fibrotic like changes in their follow up chest CT scans while 44% of cases showed total resolution of the disease process. Smoking and old age were significant risk factors while steroid therapy decreased risk of fibrotic like change. Conclusion Twenty eight cases (56%) showed residual fibrotic like changes in their 3-6 months follow-up chest CT scan (CO-RADS III to V). Patients with older age and smokers have higher incidence of residual fibrotic like changes in their follow up chest CT scans, while patients on steroid therapy have less liability to develop fibrotic changes.

Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis: A meta summary of case reports.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are commonly prescribed to manage patients with diabetes mellitus. These agents may rarely lead to the development of euglycemic diabetic ketoacidosis (EDKA), which may complicate the disease course of these patients. To analyze the demographic profile, predisposing factors, symptomology, clinical interventions and outcomes of patients presenting with EDKA secondary to SGLT2i use by reviewing the published case reports and series. We performed a systematic search of PubMed, Science Direct, Google Scholar and Reference Citation Analysis databases using the terms "canagliflozin" OR "empagliflozin" OR "dapagliflozin" OR "SGLT2 inhibitors" OR "Sodium-glucose cotransporter-2" AND "euglycemia" OR "euglycemic diabetic ketoacidosis" OR "metabolic acidosis". The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported EDKA secondary to SGLT2i. Furthermore, the data were filtered from the literature published in the English language and on adults (> 18 years). We excluded: (1) Conference abstracts; and (2) Case reports or series which did not have individual biochemical data. All the case reports and case series were evaluated. The data extracted included patient demographics, clinical symptomatology, clinical interventions, intensive care unit course, need for organ support and outcomes. Overall, 108 case reports and 17 cases series with 169 unique patients that met all the inclusion criteria were included. The majority of patients were females (54.4%, n = 92), and the commonly reported symptoms were gastrointestinal (nausea/vomiting 65.1%, abdominal pain 37.3%) and respiratory (breathlessness 30.8%). One hundred and forty-nine (88.2%) patients had underlying type II diabetes, and the most commonly involved SGLT-2 inhibitor reported was empagliflozin (46.8%). A triggering factor was reported in most patients (78.7%), the commonest being acute severe infection (37.9%), which included patients with sepsis, coronavirus disease 2019, other viral illnesses, and acute pancreatitis. 61.5% were reported to require intensive unit care, but only a minority of patients required organ support in the form of invasive mechanical ventilation (13%), vasopressors (6.5%) or renal replacement therapy (5.9%). The overall mortality rate was only 2.4%. Patients on SGLT2i may rarely develop EDKA, especially in the presence of certain predisposing factors, including severe acute infections and following major surgery. The signs and symptoms of EDKA may be similar to that of DKA but with normal blood sugar levels, which may make the diagnosis challenging. Outcomes of EDKA are good if recognized early and corrective actions are taken. Hence, physicians managing such patients must be aware of this potential complication and must educate their patients accordingly to ensure early diagnosis and management.

Severe Acute Bacterial Infections in Children With Sickle Cell Disease in Togo.

Bacterial infections are considered a major cause of morbidity and mortality in patients, especially children, with sickle cell disease. This study aims at determining, a year after the introduction of the 13-valent pneumococcal conjugate vaccine the distribution of severe acute bacterial infections and germs in children with sickle cell disease. Records of children 0 to 15 years of age and admitted from January 1, 2015 to December 31, 2019 (5 y), were examined retrospectively in the four sickle cell monitoring units in Lomé. The main infections found were pleuropulmonary (46.1%), urinary tract (32.8%), and osteoarticular (9.3%). A germ was isolated in 139 of the 265 cases (52.4%). 65.5% of the microorganisms isolated were Gram-negative organisms, with mostly Escherichia coli (31.6%) , and Klebsiella pneumoniae (18%) being the main germs. They were mainly responsible of urinary tract and osteoarticular infections. The majority of these Enterobacteriaceae was Extended-Spectrum Beta-Lactamase-Producing (41.1%, n = 37). Gram-positive cocci were represented by Staphylococcus sp (25.9%), Streptococcus sp (4.3%), Streptococcus pneumoniae (2.9%), and Enterococcus (1.4%). Staphylococcus aureus was the most common germ in pleuropulmonary (40%), osteoarticular (47.3%), and sepsis (28.6%) infections. Even if the infections found remained classic, there is a redistribution of germs with a decline in Salmonella and increase of Escherichia coli , Klebsiella pneumoniae , and Staphylococcus aureus .

Clinicopathologic Features of Severe Acute Hepatitis Associated With Adenovirus Infection in Children.

A recent increase in reports of severe acute hepatitis of unknown etiology in children is under investigation. Although adenovirus has been frequently detected, its role remains unclear, and systematic histopathologic analysis is lacking. We conducted a retrospective study of 11 children hospitalized between October 2021 and May 2022 with unexplained acute hepatitis and concurrent adenovirus infection. Liver biopsies collected shortly after admission demonstrated moderately to severely active hepatitis in 8/11 (73%) cases, characterized by marked portal mixed inflammation, moderate-to-severe interface activity, and milder lobular inflammation. Clusters of plasma cells were present in 6/11 (55%) cases, mimicking autoimmune hepatitis. Semiquantitative scoring of 17 discrete histologic features found that greater degrees of portal inflammation, interface activity, bile duct injury, bile ductular reaction, lobular inflammation, Kupffer cell activation, and hepatocyte focal necrosis were significantly more common in these cases in comparison to the control group of unexplained acute severe hepatitis without adenovirus infection. Liver biopsy immunohistochemistry was negative for adenovirus in all cases. Polymerase chain reaction testing of liver tissue was positive for the enteric adenovirus serotypes 41 (species F) in 10/11 (91%) cases. An immunoprofile study of hepatic infiltrating lymphocytes in 1 patient revealed the presence of large numbers of CD3 + and CD4 + lymphocytes. Nine patients received supportive treatment without steroids and recovered without the need for liver transplantation. In summary, liver injury in children with severe acute hepatitis and adenovirus infection is characterized by a hepatitic pattern that resembles severe autoimmune hepatitis and may represent an immune-mediated process associated with viral infection.

Passive Transfer of Animal-Derived Polyclonal Hyperimmune Antibodies Provides Protection of Mice from Lethal Lassa Virus Infection.

Lassa virus (LASV) can cause severe acute systemic infection in humans. No approved antiviral drugs or vaccines are currently available. Antibody-based therapeutics are considered a promising treatment strategy in the management of LASV disease. We used chimeric Ifnar-/- C57BL/6 (Ifnar-/- Bl6) mice, a lethal LASV mouse model, to evaluate the protective efficacy of polyclonal antibodies purified from sera of rabbits hyperimmunized with virus-like particles displaying native-like LASV glycoprotein GP spikes. Polyclonal anti-LASV GP antibodies provided 100% protection against lethal LASV infection in a pre- and post-exposure treatment setting and prevented LASV disease. Treatment also significantly lowered viremia level and virus load in organs. When treatment was initiated at the onset of symptoms, the hyperimmune antibodies provided partial protection and increased the survival rate by 80%. Our findings support the consideration of animal-derived hyperimmune antibodies targeting GP as an effective treatment option for highly pathogenic LASV.

Long COVID in children and adolescents: prevalence, clinical manifestations, and management strategies.

Long COVID, also known as Post-Acute Sequelae of SARS-CoV-2 infection (PASC), has been defined as signs and symptoms which persist for 4 weeks or even lasting for 6 months after the initial infection. Although the prevalence of long COVID in children is currently unknown, epidemiological investigations have reported cases in pediatric populations. Clinical manifestations of long COVID in children include respiratory symptoms, such as cough and dyspnea, as well as neuropsychiatric and general conditions, including fatigue, headache, and muscle weakness. The pathophysiology of long COVID in children is still being investigated, but potential mechanisms include viral persistence, autoimmunity, and neuroinflammation. Risk factors for long COVID in children are not yet well understood, but studies have suggested that children with a history of severe acute COVID-19 infection or comorbidities may be at increased risk. Evaluation for respiratory symptoms of long COVID in children is essential, including spirometry and imaging studies to assess lung function and any potential damage. Furthermore, long COVID in children has been associated with a higher prevalence of mental health problems than in adults, emphasizing the importance of monitoring and addressing these aspects in pediatric patients Although our understanding of long COVID in children and adolescents is still evolving, it is clear that the condition can have significant impacts on their health and well-being. The aim of this review is to synthesize the current knowledge on the prevalence, risk factors, and pathophysiology of long COVID in children and adolescents, and to discuss potential management strategies based on existing evidence.

Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19

A growing number of patients with SARS-CoV-2 infections experience long-lasting symptoms. Even patients who suffered from a mild acute infection show a variety of persisting and debilitating neurocognitive, respiratory, or cardiac symptoms (Long-Covid syndrome), consequently leading to limitations in everyday life. Because data on health-related quality of life (HRQoL) is scarce, we aimed to characterize the impact of Long-Covid symptoms after a mild or moderate acute infection on HRQoL. In this observational study, outpatients seeking counseling in the interdisciplinary Post-Covid consultation of the University Hospital Zurich with symptoms persisting for more than 4 weeks were included. Patients who received an alternative diagnosis or suffered from a severe acute Covid-19 infection were excluded. St. George’s Respiratory Questionnaire (SGRQ), Euroquol-5D-5L (EQ-5D-5L), and the Short form 36 (SF-36) were distributed to assess HRQoL. 112 patients were included, 86 (76.8%) were female, median (IQR) age was 43 (32.0, 52.5) years with 126 (91, 180) days of symptoms. Patients suffered frequently from fatigue (81%), concentration difficulties (60%), and dyspnea (60%). Patients mostly stated impairment in performing usual activities and having pain/discomfort or anxiety out of the EQ-5D-5L. EQ index value and SGRQ activity score component were significantly lower in females. SF-36 scores showed remarkably lower scores in the physical health domain compared to the Swiss general population before and during the COVID-19 pandemic. Long-Covid syndrome has a substantial impact on HRQoL. Long-term surveillance of patients must provide clarity on the duration of impairments in physical and mental health.Trial registration: The study is registered on www.ClinicalTrials.gov, NCT04793269.

Clinical efficacy and safety of prolonged versus intermittent administration of antipseudomonal beta-lactam antibiotics in adults with severe acute infections: A meta-analysis of randomized controlled trials

IntroductionIn order to compare the clinical efficacy and safety of prolonged versus intermittent antipseudomonal beta-lactam antibiotic infusion for the treatment of severe acute infections in adult patients, a meta-analysis of randomized controlled trials (RCTs) was performed. MethodsWe systematically searched MEDLINE and Cochrane Library databases until December 2022. The outcomes were all-cause mortality, clinical success, microbiological eradication and adverse events. The pooled risk ratios (RR) were estimated by the fixed or random effect methods according to heterogeneity statistics. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the certainty of evidence for each outcome. ResultsTwenty eligible RCTs with 2081 participants were included in the meta-analysis. The risk of all-cause mortality was significantly lower in the prolonged infusion group than in the intermittent infusion group (RR 0.77, 95% confidence interval [CI] 0.63–0.95, p = 0.01, I2 = 0%; moderate certainty). Treatment with prolonged infusion showed significant benefit in clinical success (RR 1.09, 95% CI 1.02–1.17, p = 0.008, I2 = 19%; moderate certainty). There were no significant differences in microbiological eradication (RR 1.12, 95% CI 0.99–1.28, p = 0.07, I2 = 49%; low certainty), any adverse events (RR 0.96, 95% CI 0.86–1.08, p = 0.50, I2 = 27%; moderate certainty) and serious adverse events (RR 0.99, 95%CI 0.70–1.39 p = 0.95, I2 = 0%; low certainty). ConclusionsProlonged antipseudomonal beta-lactam infusion probably decreases all-cause mortality. Additionally, it probably increases clinical success in adults with severe acute infections. This infusion strategy may result in little to no difference in microbiological eradication and is probably not associated with a rise in any adverse events.The evidence suggests that prolonged infusion may not increase serious adverse events.

Immune system perturbations in patients with severe long COVID

Abstract SARS-CoV-2 infections have different outcomes ranging from mild to severe acute infection as well as post-infectious multi-system inflammatory syndromes (MIS-C/A). Post-acute sequelae of COVID-19 (PASC) or long COVID is another outcome, which is poorly understood and range from mild to very severe persistent organ dysfunction and damages. To maximize our chances of identifying underlying mechanisms of long COVID we focus on the most severe cases with objective measures of disease such as lung damages, microvascular and autonomic nerve dysfunction. We are testing the following hypotheses that I) long COVID is a super-antigen mediated disease, II) an autoimmune condition driven by pathogenic autoantibodies, and/or III) a disease caused by viral persistence. A cohort of over 100 long COVID patients, 24 recovered long COVID patients as well as 9 COVID convalescent controls have been recruited thus far and blood samples analyzed for plasma proteome (Olink assays), immune cell composition and phenotypes (mass cytometry), T-cell repertoire (scTCR-seq), innate cell activation (circulating nucleosomes), and auto-antibody analyses (Luminex arrays) in order to understand immune perturbations in severe long COVID patients. Unlike children with hyperinflammatory MIS-C, we have not found any evidence of superantigen-mediated T-cell activation in long COVID, but instead substantial clonal expansion of memory T cell clones with effector memory states and shared clonality across patients. Additionally, cytokine perturbations such as elevated levels of IL8 and elevated levels of circulating nucleosomes indicate persistent activation of neutrophils in severe long COVID.

Abstract 263: Prothrombotic State Exists In Long-COVID Even After Mild Acute Infection

Long-term consequences of COVID-19 (long-COVID) are becoming a significant burden to health care. Many people remain symptomatic for months or years after recovery from COVID-19, including some who had only mild symptoms during acute infection. Sustained increases in pro-thrombotic markers have been reported in patients who were initially hospitalized with acute COVID-19. However, whether patients with less severe acute infection develop a prothrombotic-state during long-COVID is unclear. Our objective was to measure prothrombotic factors in long-COVID patients with mild disease (non-hospitalization) during acute infection. We recruited 47 consecutive adult patients with long-COVID symptoms seen in the Post-COVID clinic. All patients had a confirmed COVID-19 diagnosis by RT-PCR or antibody test during acute infection and had at least one of the symptoms of long-COVID per WHO criteria. Twenty asymptomatic healthy subjects not previously diagnosed with COVID-19 were recruited as controls. Markers of platelet activation and platelet-neutrophil aggregates (PNA) were quantified using whole blood flow cytometry. Serum levels of cell-free DNA (cfDNA) and citrullinated histones (H3Cit) and thrombin generation potential in plasma was measured. At the time of recruitment (6 weeks to 2 years after acute infection), the most common post-COVID symptoms included fatigue, chest pain, shortness of breath, headache, and dizziness. In whole blood, activation with TRAP caused increased surface expression of P-selectin without inducing activation of integrin αII b β 3 on platelets (P&lt;0.001 and P=0.5 respectively vs control). Concurrently, there was increased PNA in the long-COVID cohort (P&lt;0.01 vs. control). H3Cit and cfDNA were elevated in long-COVID (P&lt;0.01 and P&lt;0.05 respectively vs. control) and thrombin generation potential was increased, reflected by shorter lag-time, higher peak thrombin and increased velocity index (P&lt;0.01, P&lt;0.05 and P&lt;0.0001 respectively vs control). Within the long-COVID cohort, these markers were not different for age, sex, BMI or time since infection. We conclude that a prothrombotic state persists for months to years in long-COVID patients who exhibited mild disease at the time of initial infection.

Predictors of length of hospital stay in patients with acute COVID-19

The aim of the study was to identify the predictors of length of hospital stay in patients with acute COVID-19, based on the pathophysiological particularities of SARS. Materials and methods: The study was conducted from December 2020 to May 2021 on 103 randomized patients (59 men, mean age 62±13 years, body mass index 30.3±5.5 kg/m2 ) with moderate to severe acute COVID-19 infection who were hospitalized for emergency non-invasive oxygen therapy. Log-regression models were used to assess the suitability of some functional spirometric variables and/or SpO2/FiO2 surrogate oxygenation index to predict the duration of inpatient treatment from the day of the examination (≤ 7 vs. &gt; 7 days). Results: The analysis of the receiver operating characteristic curves showed that the relative indicator of the “ventilatory reserve” (the ratio of maximum voluntary ventilation to minute ventilation at rest, VR= MVV / MV) has sufficient sensitivity (82%), specificity (69%) and the area under the curve (AUC=0.7), although the SpO2/FiO2 ratio has a better predictive capacity (78%, 84% and 0.8 accordingly). The model combining these two integral indicators of gas exchange and the respiratory muscles reserve showed the best sensitivity (89%), specificity (84%) and area under the curve (0.9). Conclusion: The proposed model for determining of the hypoxia vector by assessing the severity of ventilation-perfusion dissociation with indicators of oxygenation and ventilation showed that the MVV/MV ratio and SpO2/FiO2 ratio can be used alone and especially in combination, as effective outcome predictors of the acute phase of the infectious process caused by SARS-CoV-2.

Macrophage migration inhibitory factor (MIF) and severe acute COVID-19 infection.

Macrophage migration inhibitory factor (MIF) and severe acute COVID-19 infection.

European Working Group on SARS-CoV-2: Current Understanding, Unknowns, and Recommendations on the Neurological Complications of COVID-19.

Background: The emergence of COVID-19 was rapidly followed by infection and the deaths of millions of people across the globe. With much of the research and scientific advancement rightly focused on reducing the burden of severe and critical acute COVID-19 infection, the long-term effects endured by those who survived the acute infection has been previously overlooked. Now, an appreciation for the post-COVID-19 condition, including its neurological manifestations, is growing, although there remain many unknowns regarding the etiology and risk factors of the condition, as well as how to effectively diagnose and treat it. Methods: Here, drawing upon the experiences and expertise of the clinicians and academics of the European working group on COVID-19, we have reviewed the current literature to provide a comprehensive overview of the neurological sequalae of the post-COVID-19 condition. Results: In this review, we provide a summary of the neurological symptoms associated with the post-COVID-19 condition, before discussing the possible mechanisms which may underly and manifest these symptoms. Following this, we explore the risk factors for developing neurological symptoms as a result of COVID-19 and the post-COVID-19 condition, as well as how COVID-19 infection may itself be a risk factor for the development of neurological disease in the future. Lastly, we evaluate how the post-COVID condition could be accurately diagnosed and effectively treated, including examples of the current guidelines, clinical outcomes, and tools that have been developed to aid in this process, as well as addressing the protection provided by COVID-19 vaccines against the post-COVID-19 condition. Conclusions: Overall, this review provides a comprehensive overview of the neurological sequalae of the post-COVID-19 condition. Impact statement With our understanding of the neurological complications of the post-COVID-19 condition currently lacking sufficient depth, this review aimed at highlighting the current knowns and unknowns of the post-COVID-19 condition. In this review, we draw upon the experiences and expertise of the clinicians and academics of the European working group on COVID-19, as well as explore the current published literature, to evaluate a range of topics associated with the neurological complications of the post-COVID-19 condition. As a result, we have provided a comprehensive review of the topic. The European Working Group on SARS-CoV-2 Many essential questions surrounding COVID-19 remain unanswered, including its neurological complications and associated sequalae. In this review, we aim at identifying the current gaps in our understanding of post-COVID-19 neurological sequalae and suggest how future studies should be undertaken to fill these gaps. This review will draw upon the current biological and mechanistic understanding of COVID-19 and post-COVID-19 complications to discuss the clinically relevant aspects associated with the neurological manifestations of post-COVID-19 syndrome. From our discussions, the following questions were considered highly relevant for contemplation.

Sclerotherapy of lower limb veins: Indications, contraindications and treatment strategies to prevent complications - A consensus document of the International Union of Phlebology-2023.

Sclerotherapy is a non-invasive procedure commonly used to treat superficial venous disease, vascular malformations and other ectatic vascular lesions. While extremely rare, sclerotherapy may be complicated by serious adverse events. To categorise contraindications to sclerotherapy based on the available scientific evidence. An international, multi-disciplinary panel of phlebologists reviewed the available scientific evidence and developed consensus where evidence was lacking or limited. Absolute Contraindications to sclerotherapy where the risk of harm would outweigh any benefits include known hypersensitivity to sclerosing agents; acute venous thromboembolism (VTE); severe neurological or cardiac adverse events complicating a previous sclerotherapy treatment; severe acute systemic illness or infection; and critical limb ischaemia. Relative Contraindications to sclerotherapy where the potential benefits of the proposed treatment would outweigh the risk of harm or the risks may be mitigated by other measures include pregnancy, postpartum and breastfeeding; hypercoagulable states with risk of VTE; risk of neurological adverse events; risk of cardiac adverse events and poorly controlled chronic systemic illness. Conditions and circumstances where Warnings and Precautions should be considered before proceeding with sclerotherapy include risk of cutaneous necrosis or cosmetic complications such as pigmentation and telangiectatic matting; intake of medications such as the oral contraceptive and other exogenous oestrogens, disulfiram and minocycline; and psychosocial factors and psychiatric comorbidities that may increase the risk of adverse events or compromise optimal treatment outcomes. Sclerotherapy can achieve safe clinical outcomes provided that (1) patient-related risk factors and in particular all material risks are (1a) adequately identified and the risk benefit ratio is clearly and openly discussed with treatment candidates within a reasonable timeframe prior to the actual procedure; (1b) when an individual is not a suitable candidate for the proposed intervention, conservative treatment options including the option of 'no intervention as a treatment option' are discussed; (1c) complex cases are referred for treatment in controlled and standardised settings and by practitioners with more expertise in the field; (1d) only suitable individuals with no absolute contraindications or those with relative contraindications where the benefits outweigh the risks are offered intervention; (1e) if proceeding with intervention, appropriate prophylactic measures and other risk-mitigating strategies are adopted and appropriate follow-up is organised; and (2) procedure-related risk factors are minimised by ensuring the treating physicians (2a) have adequate training in general phlebology with additional training in duplex ultrasound, procedural phlebology and in particular sclerotherapy; (2b) maintain their knowledge and competency over time and (2c) review and optimise their treatment strategies and techniques on a regular basis to keep up with the ongoing progress in medical technology and contemporary scientific evidence.

Cell division factor ZapE regulates Pseudomonas aeruginosa biofilm formation by impacting the pqs quorum sensing system.

Pseudomonas aeruginosa is one of the leading nosocomial pathogens that causes both severe acute and chronic infections. The strong capacity of P. aeruginosa to form biofilms can dramatically increase its antibiotic resistance and lead to treatment failure. The biofilm resident bacterial cells display distinct gene expression profiles and phenotypes compared to their free-living counterparts. Elucidating the genetic determinants of biofilm formation is crucial for the development of antibiofilm drugs. In this study, a high-throughput transposon-insertion site sequencing (Tn-seq) approach was employed to identify novel P. aeruginosa biofilm genetic determinants. When analyzing the novel biofilm regulatory genes, we found that the cell division factor ZapE (PA4438) controls the P. aeruginosa pqs quorum sensing system. The ∆zapE mutant lost fitness against the wild-type PAO1 strain in biofilms and its production of 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) had been reduced. Further biochemical analysis showed that ZapE interacts with PqsH, which encodes the synthase that converts 2-heptyl-4-quinolone (HHQ) to PQS. In addition, site-directed mutagenesis of the ATPase active site of ZapE (K72A) abolished the positive regulation of ZapE on PQS signaling. As ZapE is highly conserved among the Pseudomonas group, our study suggests that it is a potential drug target for the control of Pseudomonas infections.

Correlations between disease severity and rehabilitation outcomes in patients recovering from covid-19 infection.

Based on long-term follow-up of patients with COVID-19, to evaluate whether the severity of acute COVID-19 infection affects rehabilitation outcomes. Observational cohort study. A total of 61 post-acute COVID-19 patients underwent inpatient and outpatient customized rehabilitation treatment. The severity of acute COVID-19 infection was measured with the World Health Organization Clinical Progression Scale (WHO-CPS). Motor, cognitive, and functional variables were measured using standard and specified scales 6 months or more after acute illness. Of the 61 subjects, 65.6% had severe disease according to WHO-CPS. Significant improvement was found in activities of daily living functions (Functional Independence Measure (FIM) at admission 103.7 ± 18.9 vs FIM at discharge 118.7 ± 6.8) (p < 0.00). Of participants, 88% were able to wean off oxygen completely. A significant correlation was found between higher WHO-CPS, prolonged acute hospitalization, and days of ventilation on the one hand, and lower total and motor FIM at admission, but not with cognitive FIM or Montreal Cognitive Assessment (MoCA). No correlation was found between these parameters and functional level at discharge. The severity of acute COVID-19 infection affects the functional status of survivors at admission to rehabilitation, but, contrary to expectations, not the functional outcomes at discharge. These findings emphasize the importance of customized multidisciplinary rehabilitation programmes for improving the daily functioning and wellbeing of patients with severe COVID-19.