scholarly journals Antibody therapy reverses biological signatures of COVID-19 progression

Author(s):  
M. Cyrus Maher ◽  
Leah B. Soriaga ◽  
Anil Gupta ◽  
Julia di Iulio ◽  
Sarah Ledoux ◽  
...  

Understanding who is at risk of progression to severe COVID-19 is key to effective treatment. We studied correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of SARS-CoV-2 infection. Several laboratory parameters identified study participants at greater risk of severe disease, including a high neutrophil-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test and whole blood transcriptome profiles. Sotrovimab treatment in these groups was associated with normalization of NLR and the transcriptomic profile, and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provided the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identified a 10-gene signature with similar predictive accuracy. In summary, we identified markers of risk for disease progression and demonstrated that normalization of these parameters occurs with antibody treatment of established infection.

2021 ◽  
Vol 14 (8) ◽  
pp. e243469
Author(s):  
Carlos X Rabascall ◽  
Becky X Lou ◽  
Brianne Navetta-Modrov ◽  
Stella S Hahn

As we are over a year into the COVID-19 pandemic, we have made many forward strides in therapeutics. These treatments, such as monoclonal antibodies, have help mitigate the detrimental and often fatal consequences of COVID-19. The current indication for the use of monoclonal antibodies is mild to moderate COVID-19 infection within 10 days of symptom onset in those who are at high risk of progression to severe disease. However, their role in patients with prolonged symptoms is not clear. We present a unique case of monoclonal antibodies use after 54 days of symptom onset in an immunosuppressed patient with persistent COVID-19 infection despite standard treatment. This case illustrates the potential use of monoclonal antibodies outside of the current recommended therapeutic window in immunosuppressed patients, who may have difficulty with viral clearance.


Infection ◽  
2021 ◽  
Author(s):  
Johanna Koehler ◽  
Barbara Ritzer ◽  
Simon Weidlich ◽  
Friedemann Gebhardt ◽  
Chlodwig Kirchhoff ◽  
...  

AbstractAdditional treatment options for coronavirus disease (COVID-19) are urgently needed, particularly for populations at high risk of severe disease. This cross-sectional, retrospective study characterized the outcomes of 43 patients with nosocomial severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection with and without treatment using monoclonal SARS-CoV-2 spike antibodies (bamlanivimab or casirivimab/imdevimab). Our results indicate that treatment with monoclonal antibodies results in a significant decrease in disease progression and mortality when used for asymptomatic patients with early SARS-CoV-2 infection.


mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Arturo Casadevall ◽  
Liise-anne Pirofski ◽  
Michael J. Joyner

ABSTRACT Antibody therapies such as convalescent plasma and monoclonal antibodies have emerged as major potential therapeutics for coronavirus disease 2019 (COVID-19). Immunoglobulins differ from conventional antimicrobial agents in that they mediate direct and indirect antimicrobial effects that work in concert with other components of the immune system. The field of infectious diseases pioneered antibody therapies in the first half of the 20th century but largely abandoned them with the arrival of conventional antimicrobial therapy. Consequently, much of the knowledge gained from the historical development and use of immunoglobulins such as serum and convalescent antibody therapies was forgotten; principles and practice governing their use were not taught to new generations of medical practitioners, and further development of this modality stalled. This became apparent during the COVID-19 pandemic in the spring of 2020 when convalescent plasma was initially deployed as salvage therapy in patients with severe disease. In retrospect, this was a stage of disease when it was less likely to be effective. Lessons of the past tell us that antibody therapy is most likely to be effective when used early in respiratory diseases. This article puts forth three principles of antibody therapy, namely, specificity, temporal, and quantitative principles, connoting that antibody efficacy requires the administration of specific antibody, given early in course of disease in sufficient amount. These principles are traced to the history of serum therapy for infectious diseases. The application of the specificity, temporal, and quantitative principles to COVID-19 is discussed in the context of current use of antibody therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Author(s):  
Elisabetta Schiaroli ◽  
Anna Gidari ◽  
Giovanni Brachelente ◽  
Sabrina Bastianelli ◽  
Alfredo Villa ◽  
...  

IntroductionCOVID-19 is characterized by a wide range of clinical expression and by possible progression to critical illness and death. Therefore it is essential to identify risk factors predicting progression towards serious and fatal diseases. The aim of our study was to identify laboratory predictive markers of clinical progression in patients with moderate/severe disease and in those with acute respiratory distress syndrome (ARDS).Material and methodsUsing electronic medical records for all demographic, clinical and laboratory data, a retrospective study on all consecutive patients with COVID-19 admitted to the Infectious Disease Clinic of Perugia was performed. The PaO2/FiO2 ratio (P/F) assessment cut‑off of 200 mm Hg was used at baseline to categorize the patients into two clinical groups. The progression towards invasive ventilation and/or death was used to identify critical outcome. Statistical analysis was performed. Multivariate logistic regression analysis was adopted to identify risk factors of critical illness and mortality.ResultsIn multivariate logistic regression analysis neutrophil/lymphocyte ratio (NLR) was the only significant predictive factor of progression to a critical outcome (p = 0.03) and of in-hospital mortality (p = 0.03). In ARDS patients no factors were associated with critical progression. Serum ferritin > 1006 ng/ml was the only predictive value of critical outcome in COVID-19 subjects with moderate/severe disease (p = 0.02).ConclusionsNeutrophil/lymphocyte ratio and serum ferritin are the only biomarkers that can help to stratify the risk of severity and mortality in patients with COVID-19.


2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Izumi Yamaguchi ◽  
Kohei Nakajima ◽  
Kenji Shono ◽  
Yoshifumi Mizobuchi ◽  
Toshitaka Fujihara ◽  
...  

Abstract Background Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. Methods Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. Results Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). Conclusions Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.


2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A54.2-A54
Author(s):  
Francis Mhimbira ◽  
Jerry Hella ◽  
Hellen Hiza ◽  
Emmanuel Mbuba ◽  
Magreth Chiryamkubi ◽  
...  

BackgroundThe study aim is to describe the prevalence of respiratory pathogens in tuberculosis (TB) patients and in their household contact controls, and to determine the clinical significance of respiratory pathogens in TB patients.MethodsWe studied 489 smear-positive adult TB patients and 305 household contact controls without TB with nasopharyngeal swab samples within an ongoing prospective cohort study in Dar es Salaam, Tanzania, between 2013 and 2015. We used multiplex real-time PCR to detect 16 respiratory viruses and seven bacterial pathogens from nasopharyngeal swabs.ResultsThe median age of the study participants was 33 years; 61% (484/794) were men, and 21% (168/794) were HIV-positive. TB patients had a higher prevalence of HIV (28.6%; 140/489) than controls (9.2%; 28/305). Overall prevalence of respiratory viral pathogens was 20.4% (160/794; 95% CI 17.7%–23.3%) and of bacterial pathogens 38.2% (303/794; 95% CI 34.9%–41.6%). TB patients and controls did not differ in the prevalence of respiratory viruses (Odds Ratio [OR] 1.00, 95% CI 0.71–1.44), but respiratory bacteria were less frequently detected in TB patients (OR 0.70, 95% CI 0.53–0.94). TB patients with both respiratory viruses and respiratory bacteria were likely to have more severe disease (adjusted OR [aOR] 1.6, 95% CI 1.1–2.4; p 0.011). TB patients with respiratory viruses tended to have more frequent lung cavitations (aOR 1.6, 95% CI 0.93–2.7; p 0.089).ConclusionRespiratory viruses are common for both TB patients and household controls. TB patients may present with more severe TB disease, particularly when they are co-infected with both bacteria and viruses.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Funaki ◽  
T Adachi ◽  
M Kameshima ◽  
H Fujiyama ◽  
N Iritani ◽  
...  

Abstract Background Long-term prognosis after percutaneous coronary intervention (PCI), particularly non-target region stenosis, has not been well improved. Therefore, lifestyle modification should be considered along with medication to prevent the progression of coronary atherosclerosis. Particularly, the promotion of physical activity (PA) is recommended as a core intervention for secondary prevention because of its direct effects on coronary risk factors. However, the factors related to PA after PCI have not been fully investigated. Purpose To explore predictors of PA after discharge in patients underwent PCI. Methods We conducted a multicenter prospective cohort study. Participants were patients aged <75 years who underwent PCI. The main outcome was PA {step counts (SC) and a time of moderate-to-vigorous physical activity (MVPA)} measured for 7 consecutive days using an accelerometer at 3-month post discharge. We collected demographic data, comorbidities, medical history, laboratory data, and medications from medical record. In addition, severity of chest pain at the onset, physician's explanation regarding long-term prognosis, exercise environments, social support, work, lifestyle except exercise, self-efficacy for walking, difficulty in daily activities and depression were evaluated using questionnaires at discharge and 1-month post-discharge. The study participants were divided into two groups based on the median SC and MVPA at 3-month, and clinical characteristics were compared between the groups using χ2test or Mann Whitney U test. Then, multiple logistic regression analysis adjusted for age, gender, and diagnosis {stable angina or acute coronary syndrome (ACS)} was conducted with 3-month PA as dependent variable. Independent variables were those with a p<0.2 in the univariate analysis. In addition, the area under the curve (AUC) was calculated by receiver operating characteristic analysis to assess predictive accuracy of the regression model. Results We enrolled 313 patients [median age: 63 {inter-quartile range (IQR):56–67} years, women: 13.1%, ACS: 16.4%]. The median of SC and MVPA at 3-month were 6902 steps (IQR:5078–9095) and 16.2 min (IQR: 8.6–28.9), respectively. Predictors of SC at 3-month ≥the median were SC at 1-month (odds ratio 1.78, per 1000 steps/day; 95% confidence interval 1.51–2.09), hemoglobin (1.43, per 1g/dl; 1.10–1.86), body mass index (BMI) (0.87, per 1kg/m2; 0.82–0.99), use of β-blocker (0.49, 0.25–0.95), and self-efficacy for walking (1.06, per 1 point; 1.00–1.11). Predictors of MVPA ≥the median were MVPA at 1-month (5.66, per 10 minutes/day; 3.63–8.84), hemoglobin (1.57, per 1g/dl; 1.19–2.06), and BMI (0.85, per 1kg/m2; 0.76–0.94). The AUC of the regression model for SC and MVPA were 0.87 and 0.89, respectively. Conclusion PA after PCI could be predicted by modifiable factors with good predictive accuracy. The findings of this study suggest the possibility to develop tailored PA promotion program. Funding Acknowledgement Type of funding source: None


2015 ◽  
Vol 47 (1) ◽  
pp. 212-222 ◽  
Author(s):  
T. Ronan Leahy ◽  
Ross McManus ◽  
Derek G. Doherty ◽  
Robert Grealy ◽  
Tanya Coulter ◽  
...  

Disease severity in viral bronchiolitis in infancy is difficult to predict and has been linked to host innate immunity. The study aimed to investigate the innate cytokine interleukin-15 (IL-15) as a marker of disease severity.A prospective single-centre observational study was conducted in a university-affiliated paediatric teaching hospital, comparing children (0–18 months) hospitalised for viral bronchiolitis, those admitted to the paediatric intensive care unit with severe disease and healthy age-matched controls. IL-15-related parameters were compared between groups. PCR and microRNA (miRNA) sequencing was undertaken on natural killer (NK) cells collected from study participants.Samples from 88 children with viral bronchiolitis and 43 controls enrolled between 2009 and 2012 were analysed. Peripheral blood mononuclear cell (PBMC) IL-15 mRNA expression was significantly higher in those with moderate severity bronchiolitis compared with controls and those with severe disease. Serum IL-15 levels correlated with disease severity. The relative frequency of NK cells in peripheral blood was significantly reduced in participants with bronchiolitis. The NK cell miRNA transcriptome in bronchiolitis was distinct. Targets of de-regulated miRNA were differentially expressed in bronchiolitis, including JAK3, STAT5A and NFKB1 on the IL-15 signalling pathway.IL-15 is associated with disease severity in children hospitalised with viral bronchiolitis.


2020 ◽  
Author(s):  
Xu Lengnan ◽  
Liu Xin ◽  
Zhou Yangwei ◽  
Liu Aihua ◽  
Xu Xiaomao ◽  
...  

Abstract Background Older adults are more susceptible to the novel coronavirus disease 2019 (hereafter, COVID-19) and more likely to develop severe illness. Cytokine release syndrome (CRS) may be an important factor in the development of severe disease in patients with COVID-19. Interleukin-6 (IL-6) is an important cytokine in CRS, and tocilizumab can block the IL-6 receptor. In this study, we analyzed the therapeutic effects and safety of tocilizumab on CRS in older patients with severe COVID-19. Methods Between February 10 and March 21, 2020, a total of 19 patients with severe or critical COVID-19 aged ≥ 60 years met the study inclusion criteria at Tongji hospital in Wuhan city, Hubei Province, China. Patients were divided into two groups: 1. The tocilizumab group, whose IL-6 levels exceeded the upper limit of normal by > 10-fold; and 2. The no tocilizumab group, with 1L-6 levels < 10-fold the upper normal limit. Results Patients in the tocilizumab group were older (73.20 ± 4.44 vs. 66.21 ± 5.06 years, P = 0.014); had lower lymphocyte counts (0.71 ± 0.18 vs. 1.18 ± 0.59 × 109/L, P = 0.016); and higher high-sensitivity C-reactive protein (hsCRP) levels (94.04 ± 57.24 vs. 51.65 ± 45.37 mg/L, P = 0.035). The increases in ferritin (FER) and hsCRP levels in patients in the tocilizumab group were marked. Except in one patient who died, IL-6, FER, and hsCRP levels, and the neutrophil/lymphocyte ratio, in the remaining four patients decreased following treatment with tocilizumab. Further, patient computerized tomography scan results improved after 3–8 days of tocilizumab treatment. Tocilizumab did not cause any serious adverse reactions. There were no differences in mortality or days until lung computerized tomography improvement between the two groups. The total mortality rate was 10.53%. Conclusions Our results support the therapeutic efficacy and safety of tocilizumab on older patients with severe COVID-19.


2021 ◽  
Author(s):  
Noha Asem ◽  
Mohamed Hassany ◽  
Khaled Taema ◽  
Hossam Masoud ◽  
Gehan Elassal ◽  
...  

Introduction: Since the worldwide emergence of the COVID-19, several protocols were used by different healthcare organisations. We evaluated in this study the demographic and clinical characteristics of COVID-19 disease in Egyptian population with special consideration for its mortality predictors. Methodology: 8162 participants (mean age 48.7 years,54.5% males) with RT-PCR positive COVID-19 were included. The electronic medical records were reviewed for demographic, clinical, laboratory, and radiologic features. The primary outcome was the in-hospital mortality rate. Results: The in-hospital mortality was 11.2%. There was a statistically significant strong association of in-hospital mortality with age >60 years old (OR:4.7; 95% CI 4.1-5.4;p<0.001), diabetes mellitus (OR:4.6; 95% CI 3.99-5.32;p<0.001), hypertension (OR:3.9; 95% CI 3.4-4.5;p<0.001), coronary artery disease (OR:2.7; 95% CI 2.2-3.2;p<0.001), chronic obstructive pulmonary disease (OR:2.1; 95% CI 1.7-2.5;p<0.001), chronic kidney disease (OR:4.8; 95% CI 3.9-5.9;p<0.001), malignancy (OR:3.7; 95% CI 2.3-5.75;p<0.001), neutrophil-lymphocyte ratio >3.1 (OR:6.4; 95% CI 4.4-9.5;P< 0.001), and ground glass opacities (GGOs) in CT chest (OR:3.5; 95% CI 2.84-4.4;P<0.001), respectively. There was a statistically significant moderate association of in-hospital mortality with male gender (OR:1.6; 95% CI 1.38-1.83;p<0.001) and smoking (OR:1.6; 95% CI 1.3-1.9;p<0.001). GGOs was reported as the most common CT finding (occurred in 73.1% of the study participants). Conclusions: This multicenter, retrospective study ascertained the higher in-hospital mortality rate in Egyptian COVID-19 patients with different comorbidities.


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