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BACKGROUND: Defining patterns of symptoms in long COVID is necessary to advance therapies for this heterogeneous condition. Here we aimed to describe clusters of symptoms in individuals with long COVID and explore the impact of the emergence of variants of concern (VOCs) and vaccination on these clusters. METHODS: In a prospective, multi centre cohort study, individuals with symptoms persisting > 4 weeks from acute COVID-19 were divided into two groups based on timing of acute infection; pre-Alpha VOC, denoted wild type (WT) group and post-Alpha VOC (incorporating alpha and delta dominant periods) denoted VOC group. We used multiple correspondence analysis (MCA) and hierarchical clustering in the WT and VOC groups to identify symptom clusters. We then used logistic regression to explore factors associated with individual symptoms. RESULTS: A total of 417 individuals were included in the analysis, 268 in WT and 149 in VOC groups respectively. In both groups MCA identified three similar clusters; a musculoskeletal (MSK) cluster characterised by joint pain and myalgia, a cardiorespiratory cluster and a less symptomatic cluster. Differences in characteristic symptoms were only seen in the cardiorespiratory cluster where a decrease in the frequency of palpitations (10% vs 34% p = 0.008) and an increase in cough (63% vs 17% p < 0.001) in the VOC compared to WT groups was observed. Analysis of the frequency of individual symptoms showed significantly lower frequency of both chest pain (25% vs 39% p = 0.004) and palpitations (12% vs 32% p < 0.001) in the VOC group compared to the WT group. In adjusted analysis being in the VOC group was significantly associated with a lower odds of both chest pain and palpitations, but vaccination was not associated with these symptoms. CONCLUSION: This study suggests changes in long COVID phenotype in individuals infected later in the pandemic, with less palpitations and chest pain reported. Adjusted analyses suggest that these effects are mediated through introduction of variants rather than an effect from vaccination.
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COVID-19 , Síndrome de COVID-19 Pós-Aguda , Humanos , COVID-19/prevenção & controle , Estudos de Coortes , Estudos Prospectivos , Vacinação , Dor no Peito , FenótipoRESUMO
We describe the expansion and adaptation of a frailty response team to assess older people in their usual place of residence. The team had commenced a weekend service to a limited area in February 2020. As a consequence of demand related to the COVID-19 pandemic, we expanded it and adapted the model of care to provide a 7-day service to our entire catchment area. Five hundred and ninety two patient reviews have been completed in the first 105 days of operation with 43 patients transferred to hospital for further investigation or management following assessment.
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Infecções por Coronavirus/epidemiologia , Serviços Médicos de Emergência/organização & administração , Idoso Fragilizado , Avaliação Geriátrica , Serviços de Saúde para Idosos/organização & administração , Serviços Hospitalares de Assistência Domiciliar/organização & administração , Pneumonia Viral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Feminino , Humanos , Irlanda/epidemiologia , Masculino , Pandemias , SARS-CoV-2RESUMO
Background: Coinfection with human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV)-related liver fibrosis. Macrophages are triggered during both viral infections and are critical in liver inflammation/fibrogenesis. Liver fibrosis strongly associates with serum soluble CD163 (sCD163, a macrophage activation marker); comprehensive evaluation in HIV/HCV coinfection is lacking. Methods: We retrospectively analyzed sCD163 (enzyme-linked immunosorbent assay) and hepatic CD163 (immunofluorescent CD163/CD68 costaining) in patients infected with HIV/HCV, HCV, or HIV, pre- and post-antiviral therapy. Results: sCD163 was significantly higher in HIV/HCV compared to either monoinfection, and decreased following successful antiviral therapy, although did not fully normalize. In HIV/HCV, sCD163 was associated with necroinflammation, Ishak fibrosis scores, and noninvasive fibrosis scores. We observed a novel trend whereby sCD163 levels progressively increase with increasing Ishak fibrosis score, peaking at stage 4, above which levels plateaued. Periportal CD163+ macrophage frequency was also higher with increasing fibrosis score. When stratified by fibrosis stage, sCD163 levels were higher in HIV/HCV than HCV but only in individuals with mild to moderate fibrosis. Conclusions: In HIV/HCV, increasing sCD163 levels accompanied periportal CD163+ macrophage enrichment in mild to moderate fibrosis, but not in established cirrhosis, suggesting that sCD163 is a dynamic biomarker of fibrogenesis rather than accumulated fibrosis. Our findings implicate HIV-related macrophage activation in accelerated fibrosis progression in HIV/HCV coinfection.
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Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Coinfecção/metabolismo , Infecções por HIV/metabolismo , Hepatite C Crônica/metabolismo , Cirrose Hepática/metabolismo , Ativação de Macrófagos/fisiologia , Receptores de Superfície Celular/metabolismo , Adulto , Idoso , Coinfecção/virologia , Feminino , HIV/patogenicidade , Infecções por HIV/virologia , Hepacivirus/patogenicidade , Hepatite C Crônica/virologia , Humanos , Fígado/metabolismo , Fígado/virologia , Cirrose Hepática/virologia , Macrófagos/metabolismo , Macrófagos/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
We report a patient with psoriasis who developed Mycobacterium marinum (M. marinum) infection after seven years of treatment with adalimumab, a human anti-TNF (tumor necrosis factor) monoclonal antibody. TNF is a pro-inflammatory cytokine that plays a central role in the pathogenesis of psoriasis and a number of other immune-mediated inflammatory diseases. TNF plays an important role in granuloma formation and host defense against mycobacterial infections. Several cases of atypical mycobacterial infections in patients on TNF inhibitors have been reported. To our knowledge, this is the second reported case of M. marinum infection in a patient on adalimumab for the treatment of psoriasis.
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Adalimumab/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Infecções por Mycobacterium não Tuberculosas/induzido quimicamente , Psoríase/tratamento farmacológico , Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Humanos , Lacerações/complicações , Masculino , Pessoa de Meia-Idade , Alga MarinhaRESUMO
OBJECTIVES: Use of ART containing HIV PIs has previously been associated with toxicity in subcutaneous adipose tissue (SAT), potentially contributing to the development of lipodystrophy and insulin resistance. However, the effect of PIs on SAT function in ART-naive patients independent of other ART classes is unknown. This study aimed to elucidate the effect of initiating PI-only ART on SAT function in ART-naive subjects. METHODS: In the HIVNAT-019 study, 48 HIV-infected, ART-naive Thai adults commencing PI-only ART comprising lopinavir/ritonavir/saquinavir for 24 weeks underwent assessments of fasting metabolic parameters and body composition. In a molecular substudy, 20 subjects underwent SAT biopsies at weeks 0, 2 and 24 for transcriptional, protein, mitochondrial DNA (mtDNA) and histological analyses. ClinicalTrials.gov registration number: NCT00400738. RESULTS: Over 24 weeks, limb fat increased (+416.4 g, Pâ=â0.023), coinciding with larger adipocytes as indicated by decreased adipocyte density in biopsies (-32.3 cells/mm2, Pâ=â0.047) and increased mRNA expression of adipogenesis regulator PPARG at week 2 (+58.1%, Pâ=â0.003). Increases in mtDNA over 24 weeks (+600 copies/cell, Pâ=â0.041), decreased NRF1 mRNA expression at week 2 (-33.7%, Pâ<â0.001) and increased COX2/COX4 protein ratio at week 24 (+288%, Pâ=â0.038) indicated improved mitochondrial function. Despite decreased AKT2 mRNA at week 2 (-28.6%, Pâ=â0.002) and increased PTPN1 mRNA at week 24 (+50.3%, Pâ=â0.016) suggesting insulin resistance, clinical insulin sensitivity [by homeostasis model assessment (HOMA-IR)] was unchanged. CONCLUSIONS: Initiation of PI-only ART showed little evidence of SAT toxicity, the changes observed being consistent with a return to health rather than contributing to lipodystrophy.
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Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/fisiologia , Adulto , Biópsia , DNA Mitocondrial/análise , Feminino , Perfilação da Expressão Gênica , Histocitoquímica , Humanos , Masculino , Proteoma/análise , TailândiaAssuntos
Asma/epidemiologia , Infecções por Coronavirus , Pacientes Internados , Pandemias , Pneumonia Viral , Adulto , Betacoronavirus , COVID-19 , Comorbidade , Humanos , Prevalência , Fatores de Risco , SARS-CoV-2Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Idoso , COVID-19 , Humanos , Oxigênio , SARS-CoV-2RESUMO
OBJECTIVES: Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid. METHODS: Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab. RESULTS: The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R(2)=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition. CONCLUSIONS: The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.
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Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Imunidade Celular , Imunoglobulina G/imunologia , Miofibroblastos/imunologia , Adulto , Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Biópsia , Progressão da Doença , Feminino , Fibrose , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Miofibroblastos/patologiaRESUMO
BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with increased cardiovascular risk and reduced high-density lipoprotein cholesterol (HDL-c). In vitro, HIV impairs monocyte-macrophage cholesterol efflux, a major determinant of circulating HDL-c, by increasing ABCA1 degradation, with compensatory upregulation of ABCA1 messenger RNA (mRNA). METHODS: We examined expression of genes involved in cholesterol uptake, metabolism, and efflux in monocytes from 22 HIV-positive subjects on antiretroviral therapy (ART-Treated), 30 untreated HIV-positive subjects (ART-Naive), and 22 HIV-negative controls (HIV-Neg). RESULTS: HDL-c was lower and expression of ABCA1 mRNA was higher in ART-Naive subjects than in both ART-Treated and HIV-Neg subjects (both P < .01), with HDL-c inversely correlated with HIV RNA (ρ = -0.52; P < .01). Expression of genes involved in cholesterol uptake (LDLR, CD36), synthesis (HMGCR), and regulation (SREBP2, LXRA) was significantly lower in both ART-Treated and ART-Naive subjects than in HIV-Neg controls. CONCLUSIONS: In vivo, increased monocyte ABCA1 expression in untreated HIV-infected patients and normalization of ABCA1 expression with virological suppression by ART supports direct HIV-induced impairment of cholesterol efflux previously demonstrated in vitro. However, decreased expression of cholesterol sensing, uptake, and synthesis genes in both untreated and treated HIV infection suggests that both HIV and ART affect monocyte cholesterol metabolism in a pattern consistent with accumulation of intramonocyte cholesterol.
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Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Regulação da Expressão Gênica , Infecções por HIV/metabolismo , Monócitos/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Adulto , Fármacos Anti-HIV/uso terapêutico , Transporte Biológico , Doenças Cardiovasculares/metabolismo , HDL-Colesterol/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Obesity is increasingly described in people living with HIV (PLWH), but its impact on immune activation and inflammation in HIV is still poorly characterised. We aimed to analyse the difference in circulating cytokines involved in pathways associated with co-morbidities in PLWH according to the presence or absence of obesity. METHODS: Age and sex matched PLWH with and without obesity (BMI ≥30 kg/m2) from a multicentre, prospective cohort were recruited with a 1:2 ratio. Twenty-three biomarkers covering pathways associated with systemic inflammation (hsCRP, IL-2, IL-6, TNFR1, TNFR2, TNF-α, IFN-γ, IL-18), coagulation (vWF, D-dimer, sCD40L), endothelial function (E-selectin, P-selectin, sICAM-1, sVCAM-1), atherosclerosis (MPO, Lp-PLA2), immune regulation (IL-1RA), innate immune activation (MIP-1, MCP-1, sCD163, sCD14) and microbial translocation (LBP) were measured in the two groups. Between-group difference in biomarkers were assessed using Mann-Whitney test. Associations between obesity and biomarkers were assessed using logistic regression adjusted for age, gender, ethnicity, smoking status, and antiretroviral therapy (ART). RESULTS: Ninety-nine ART-treated PLWH were included in the analysis (33 with obesity, 66 without obesity). PLWH with obesity had higher levels of hsCRP, IL-6, vWF, D-dimer, E-selectin, MPO, IL-1RA, and LBP. Six markers (hsCRP, IL-6, vWF, E-selectin, MPO, IL-1RA), reflecting systemic inflammation, coagulation and atherosclerosis pathways were associated with increased odds of obesity in the adjusted logistic regression model: hsCRP (aOR 2.7, 95% CI [1.7, 4.29]), IL-6 (3.77 [1.43, 9.93]), vWF (5.33 [1.51, 18.75]), E-selectin (6.28 [1.36, 29.04]), MPO (6.85 [1.87, 25.04]), IL-1RA (6.45 [2.28, 18.2]). No association was observed between obesity and markers of innate immune activation and gut microbial translocation. CONCLUSIONS: Obesity in PLWH was associated with activation of systemic inflammatory, endothelial, atherosclerosis and coagulation pathways, rather than those associated with innate immune activation and gut microbial translocation. These pathways point towards an unfavourable cardiovascular profile in PLWH with obesity, which will have to be further explored in future studies on long-term outcomes.
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Systemic inflammation and innate immune activation are associated with COVID-19 disease severity. Knowledge gaps remain in the relationships between microbiome, inflammation and COVID-19 disease severity. To better characterise these associations, we performed 16SrDNA analysis of stool samples in COVID-19 subjects to explore diversity and taxanomic composition. We correlated these to host inflammatory profiles, derived from soluble plasma biomarkers measured by bead-based fluorescence and electrochemiluminescence immunoassays. Associations of microbial diversity and inflammatory biomarkers on maximal COVID-19 severity (mild, moderate v severe/critical) was explored using logistic regression and weighted gene correlation network analysis (WGCNA). Of 79 subjects, 58% were male and 88% were Caucasian with 36% experiencing mild disease, 22% moderate disease and 40% critical/severe COVID-19. Hierarchical clustering and principal component analysis (PCo) revealed distinct inflammatory clusters that were found to correlate with 4 modules of microbiome profiles. Modules 3 and 4 were associated with both older age and severe/critical disease outcomes. These modules were enriched in pathogenic and inflammatory bacteria that mapped to a pro-inflammatory biomarker cluster. In contrast, module 1 exhibited enrichment of anti-inflammatory bacteria, was associated with younger age and mild/moderate disease outcomes and mapped to a less-inflamed biomarker cluster. This study provides further insights into links between host microbiome, inflammatory responses to SARS-CoV-2 infection and clinical COVID-19 disease severity, suggesting a role for the microbiome in shaping distinct host inflammatory responses to infection.
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COVID-19 , Microbiota , Humanos , Masculino , Feminino , SARS-CoV-2 , Inflamação , Gravidade do Paciente , BiomarcadoresRESUMO
Background: The inflammatory changes that underlie the heterogeneous presentations of COVID-19 remain incompletely understood. In this study we aimed to identify inflammatory profiles that precede the development of severe COVID-19, that could serve as targets for optimised delivery of immunomodulatory therapies and provide insights for the development of new therapies. Methods: We included individuals sampled <10 days from COVID-19 symptom onset, recruited from both inpatient and outpatient settings. We measured 61 biomarkers in plasma, including markers of innate immune and T cell activation, coagulation, tissue repair and lung injury. We used principal component analysis and hierarchical clustering to derive biomarker clusters, and ordinal logistic regression to explore associations between cluster membership and maximal disease severity, adjusting for known risk factors for severe COVID-19. Results: In 312 individuals, median (IQR) 7 (4-9) days from symptom onset, we found four clusters. Cluster 1 was characterised by low overall inflammation, cluster 2 was characterised by higher levels of growth factors and markers of endothelial activation (EGF, VEGF, PDGF, TGFα, PAI-1 and p-selectin). Cluster 3 and 4 both had higher overall inflammation. Cluster 4 had the highest levels of most markers including markers of innate immune activation (IL6, procalcitonin, CRP, TNFα), and coagulation (D-dimer, TPO), in contrast cluster 3 had the highest levels of alveolar epithelial injury markers (RAGE, ST2), but relative downregulation of growth factors and endothelial activation markers, suggesting a dysfunctional inflammatory pattern. In unadjusted and adjusted analysis, compared to cluster 1, cluster 3 had the highest odds of progressing to more severe disease (unadjusted OR (95%CI) 9.02 (4.53-17.96), adjusted OR (95%CI) 6.02 (2.70-13.39)). Conclusion: Early inflammatory profiles predicted subsequent maximal disease severity independent of risk factors for severe COVID-19. A cluster with downregulation of growth factors and endothelial activation markers, and early evidence of alveolar epithelial injury, had the highest risk of severe COVID-19.
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BACKGROUND: Diabetic foot ulceration (DFU) has become an increasingly common emergency presentation. These patients are presenting at a younger age and with increasingly complex co-morbidities. They require frequent hospitalisation for management of DFU which has significant consequences for management of health resources but also for quality of life in the diabetic patient population. AIM: The aim of this study was to evaluate the impact of the development of a coordinated, streamlined acute diabetic foot pathway for management of in-patients presenting as emergencies with DFU on length of stay, re-admission to hospital and minor and major amputations. METHODS: A dedicated acute diabetic foot pathway was introduced to St. Vincent's University Hospital (SVUH) in April 2016. Management of patients admitted urgently to the emergency department or out-patient clinics of St. Vincent's University Hospital during the 3-year period before April 2016 was compared to that of patients admitted in the 3 years after April 2016 following introduction of the acute diabetic foot pathway. Demographic data hospital length of stay, need for re-admission, major and minor amputations performed and cost of hospital stay were compared before and after introduction of the pathway. RESULTS: There were 931 admissions with acute diabetic foot ulceration or infection between January 2012 and December 2019; 419 were admitted between January 2012 and March 2016 and 512 between April 2016 and December 2019. There was no difference in demographic data between the two time periods. Length of stay decreased from 13 +/- 4.24 to 3 +/- 1.41 days between the two time periods (p < 0.001). Re-admission rates within 30 days decreased from 21.7 to 10.1% (p < 0.05). The number of major lower limb amputations decreased over the two time periods from 8.8 to 7.2% with a concomitant increase in minor amputations from 16.7 to 25.3%. Risk of major lower limb amputation was significantly higher in those patients living more than 20 km from the hospital. Costs associated with in-patient stay for management of DFU decreased from 9,247,700 to 8,988,100 despite an 18% increase in the number of patients treated and a 9.9% increase in hospital admissions. CONCLUSION: Introduction of a dedicated, streamlined pathway involving multi-disciplinary input resulted in a significant improvement in patient management as assessed by length of hospital stay and need for re-admission. While the number of major lower limb amputations has decreased there has been a significant increase in the number of minor amputations.
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Diabetes Mellitus , Pé Diabético , Humanos , Pé Diabético/cirurgia , Qualidade de Vida , Amputação Cirúrgica , Comorbidade , Tempo de Internação , Estudos Retrospectivos , Diabetes Mellitus/epidemiologiaRESUMO
Objectives: Prosthetic joint infection (PJI) is a serious complication following arthroplasties. This study assessed the clinical outcomes, readmission rates and financial impact of PJIs treated with outpatient parenteral antimicrobial therapy (OPAT). Methods: The study used prospectively collected data from the OPAT patient database at a tertiary care Irish hospital for PJI cases managed between 2015 and 2020. Data was analyzed using IBM-SPSS. Results: Forty-one patients with PJIs were managed via OPAT over five years, with median age of 71.6 years. Median duration of OPAT was 32 days. Hospital readmission occurred in 34% of cases. Reasons for readmission included progression of infection in 64.3%, unplanned reoperation in 21.4% and planned admission for joint revision in 14.3%. Type 2 Diabetes Mellitus (T2DM) was found to have a statistically significant association with unplanned readmission (OR 8.5, CI 95% 1.1-67.6; p < 0.01). OPAT saved a mean of 27.49 hospital-bed days per patient. 1,127 bed days were saved in total, estimating a total savings of 963,585 euros and median savings of 26,505 euros. Conclusions: The readmission rate observed was comparable to international data. Most readmissions were related to primary infections rather than due to OPAT-specific complications. Our main findings were that patients with PJIs can be safely managed via OPAT, and the finding of association between T2DM and increased risk of readmission.
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Background: Liver stiffness measurements can be used to assess liver fibrosis and can be acquired by transient elastography using FibroScan® and with Acoustic Radiation Force Impulse imaging. The study aimed to establish liver stiffness measurement scores using FibroScan® and Acoustic Radiation Force Impulse in a chronic hepatitis C cohort and to explore the correlation and agreement between the scores and the factors influencing agreement. Methods: Patients had liver stiffness measurements acquired with FibroScan® (right lobe of liver) and Acoustic Radiation Force Impulse (right and left lobe of liver). We used Spearman's correlation to explore the relationship between FibroScan® and Acoustic Radiation Force Impulse scores. A Bland-Altman plot was used to evaluate bias between the mean percentage differences of FibroScan® and Acoustic Radiation Force Impulse scores. Univariable and multivariable analyses were used to assess how factors such as body mass index, age and gender influenced the agreement between liver stiffness measurements. Results: Bland-Altman showed the average (95% CI) percentage difference between FibroScan® and Acoustic Radiation Force Impulse scores was 27.5% (17.8, 37.2), p < 0.001. There was a negative correlation between the average and percentage difference of the FibroScan® and Acoustic Radiation Force Impulse scores ( r (95% CI) = -0.41 (-0.57, -0.21), p < 0.001), thus showing that percentage difference gets smaller for greater FibroScan® and Acoustic Radiation Force Impulse scores. Body mass index was the biggest influencing factor on differences between FibroScan® and Acoustic Radiation Force Impulse (r = 0.12 (0.01, 0.23), p = 0.05). Acoustic Radiation Force Impulse scores at segment 5/8 and the left lobe showed good correlation (r (95% CI) = 0.83 (0.75, 0.89), p < 0.001). Conclusion: FibroScan® and Acoustic Radiation Force Impulse had similar predictive values for the assessment of liver stiffness in patients with chronic hepatitis C infection; however, the level of agreement varied across lower and higher scores.
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Background: Dysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are thought to underlie the progression of coronavirus disease 2019 (COVID-19) to severe disease. We sought to determine whether early host immune-related gene expression could predict clinical progression to severe disease. Methods: We analysed the expression of 579 immunological genes in peripheral blood mononuclear cells taken early after symptom onset using the NanoString nCounter and compared SARS-CoV-2 negative controls with SARS-CoV-2 positive subjects with mild (SARS+ Mild) and Moderate/Severe disease to evaluate disease outcomes. Biobanked plasma samples were also assessed for type I (IFN-α2a and IFN-ß), type II (IFN-γ) and type III (IFN-λ1) interferons (IFNs) as well as 10 additional cytokines using multiplex immunoassays. Results: We identified 19 significantly deregulated genes in 62 SARS-CoV-2 positive subject samples within 5 days of symptom onset and 58 SARS-CoV-2 negative controls and found that type I interferon (IFN) signalling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1) and genes encoding proinflammatory cytokines (TNF, TNFSF4, PTGS2 and IL1B) were upregulated in both SARS+ groups. Moreover, we found that FCER1, involved in mast cell activation, was upregulated in the SARS+ Mild group but significantly downregulated in the SARS+ Moderate/Severe group. In both SARS+ groups we discovered elevated interferon type I IFN-α2a, type II IFN and type III IFN λ1 plasma levels together with higher IL-10 and IL-6. These results indicate that those with moderate or severe disease are characterised by deficiencies in a mast cell response together with IFN hyper-responsiveness, suggesting that early host antiviral immune responses could be a cause and not a consequence of severe COVID-19. Conclusions: This study suggests that early host immune responses linking defects in mast cell activation with host interferon responses correlates with more severe outcomes in COVID-19. Further characterisation of this pathway could help inform better treatment for vulnerable individuals.
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COVID-19 , Interferon Tipo I , Humanos , SARS-CoV-2 , Leucócitos Mononucleares , Mastócitos , Linhagem Celular , Citocinas , Ligante OX40RESUMO
BACKGROUND: Monitoring systems have been developed during the COVID-19 pandemic enabling clinicians to remotely monitor physiological measures including pulse oxygen saturation (SpO2), heart rate (HR), and breathlessness in patients after discharge from hospital. These data may be leveraged to understand how symptoms vary over time in COVID-19 patients. There is also potential to use remote monitoring systems to predict clinical deterioration allowing early identification of patients in need of intervention. METHODS: A remote monitoring system was used to monitor 209 patients diagnosed with COVID-19 in the period following hospital discharge. This system consisted of a patient-facing app paired with a Bluetooth-enabled pulse oximeter (measuring SpO2 and HR) linked to a secure portal where data were available for clinical review. Breathlessness score was entered manually to the app. Clinical teams were alerted automatically when SpO2 < 94 %. In this study, data recorded during the initial ten days of monitoring were retrospectively examined, and a random forest model was developed to predict SpO2 < 94 % on a given day using SpO2 and HR data from the two previous days and day of discharge. RESULTS: Over the 10-day monitoring period, mean SpO2 and HR increased significantly, while breathlessness decreased. The coefficient of variation in SpO2, HR and breathlessness also decreased over the monitoring period. The model predicted SpO2 alerts (SpO2 < 94 %) with a mean cross-validated. sensitivity of 66 ± 18.57 %, specificity of 88.31 ± 10.97 % and area under the receiver operating characteristic of 0.80 ± 0.11. Patient age and sex were not significantly associated with the occurrence of asymptomatic SpO2 alerts. CONCLUSION: Results indicate that SpO2 alerts (SpO2 < 94 %) on a given day can be predicted using SpO2 and heart rate data captured on the two preceding days via remote monitoring. The methods presented may help early identification of patients with COVID-19 at risk of clinical deterioration using remote monitoring.
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COVID-19 , Deterioração Clínica , Humanos , Frequência Cardíaca , Saturação de Oxigênio , Pandemias , Estudos Retrospectivos , COVID-19/diagnóstico , HospitaisRESUMO
Quantifying neutralising capacity of circulating SARS-COV-2 antibodies is critical in evaluating protective humoral immune responses generated post-infection/post-vaccination. Here we describe a novel medium-throughput flow cytometry-based micro-neutralisation test to evaluate Neutralising Antibody (NAb) responses against live SARS-CoV-2 Wild Type and Variants of Concern (VOC) in convalescent/vaccinated populations. Flow Cytometry-Based Micro-Neutralisation Test (Micro-NT) was performed in 96-well plates using clinical isolates WT-B, WT-B.1.177.18 and/or VOCs Beta and Omicron. Plasma samples (All Ireland Infectious Diseases (AIID) Cohort) were serially diluted (8 points, half-log) from 1:20 and pre-incubated with SARS-CoV-2 (1h, 37°C). Virus-plasma mixture were added onto Vero E6 or Vero E6/TMPRSS2 cells for 18h. Percentage infected cells was analysed by automated flow cytometry following trypsinisation, fixation and SARS-CoV-2 Nucleoprotein intracellular staining. Half-maximal Neutralisation Titres (NT50) were determined using non-linear regression. Our assay was compared to Plaque Reduction Neutralisation Test (PRNT) and validated against the First WHO International Standard for anti-SARS-CoV-2 immunoglobulin. Both Micro-NT and PRNT achieved comparable NT50 values. Further validation showed adequate correlation with PRNT using a panel of secondary standards of clinical convalescent and vaccinated plasma samples. We found the assay to be reproducible through measuring both repeatability and intermediate precision. Screening 190 convalescent samples and 11 COVID-19 naive controls (AIID cohort) we demonstrated that Micro-NT has broad dynamic range differentiating NT50s <1/20 to >1/5000. We could also characterise immune-escape VOC Beta and Omicron BA.5, achieving fold-reductions in neutralising capacity similar to those published. Our flow cytometry-based Micro-NT is a robust and reliable assay to quantify NAb titres, and has been selected as an endpoint in clinical trials.
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COVID-19 , Vacinas , Humanos , Citometria de Fluxo , SARS-CoV-2 , Testes de Neutralização , Anticorpos Neutralizantes , Anticorpos AntiviraisRESUMO
SARS-CoV-2 neutralising antibodies provide protection against COVID-19. Evidence from early vaccine trials suggested binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether these thresholds predict sufficient neutralising capacity against variants of concern (VOCs), and whether this is impacted by vaccine or infection history remains unclear. Here we analyse individuals recovered from, vaccinated or with hybrid immunity against SARS-CoV-2. An NT50 ≥ 100 IU confers protection in vaccine trials, however, as VOC induce a reduction in NT50, we use NT50 ≥ 1000 IU as a cut off for WT NT50 that would retain neutralisation against VOC. In unvaccinated convalescent participants, a receptor binding domain (RBD) IgG of 456 BAU/mL predicts an NT50 against WT of 1000 IU with an accuracy of 80% (95%CI 73-86%). This threshold maintains accuracy in determining loss of protective immunity against VOC in two vaccinated cohorts. It predicts an NT50 < 100 IU against Beta with an accuracy of 80% (95%CI 67-89%) in 2 vaccine dose recipients. In booster vaccine recipients with a history of COVID-19 (hybrid immunity), accuracy is 87% (95%CI 77-94%) in determining an NT50 of <100 IU against BA.5. This analysis provides a discrete threshold that could be used in future clinical studies.