daniele focosi md phd msc

TTV viral load as a predictor of antibody response to SARS COV-2 vaccination

Daniele focosi.

a North-Western Tuscany Blood Bank, Pisa University Hospital, Pisa, Italy

Andreina Baj

b Department of Medicine and Surgery, University of Insubria

Lorenzo Azzi

Federica novazzi, fabrizio maggi.

c National Institute for Infectious Diseases “L. Spallanzani”, Roma, Italy

The measure of torquetenovirus (TTV) viremia is widely recognized as an optimal biomarker of an individual immune status. In the context of COVID-19, the predictive role of TTV load with regard to vaccine response has also been demonstrated, suggesting other intriguing applications for this widespread anellovirus.

Torquetenovirus (TTV), a widespread anellovirus recognized as the main component of the healthy human virome, displays viremia that is highly susceptible to variations in immune competence. In general, higher viremias are associated with poor immune competence (e.g., causing opportunistic infections), while lower viremias are associated with hyperactive immune system (e.g., causing allograft rejection). In COVID-19, the applications of TTV monitoring is dual.

The first aspect is the correlation between the TTV loads and prognosis, which is rather controversial. Querido et al reported a kidney transplant recipient who had a TTV load of 5.6 log 10 copies/ml, which increased to 7.9 log 10 copies/ml on day 43 after the diagnosis of SARS-CoV-2 infection, when the patient seroreverted. 1 Froque’ et al reported that COVID-19 patients with detectable TTV DNA had an increased risk of subsequently developing infectious events (HR 9.28) and a trend ( p  = 0.05) toward higher TTV DNA area under a curve between days 7 and 17 after intensive care unit (ICU) admission in patients who died, as compared to survivors. 2 In line with the fact that the most severe presentations of COVID-19 are due to an exaggerated immune response, Solis et al reported that the rate of severe cases was higher in patients with low TTV DNA load in plasma, considering a threshold of 700 copies/ml. In severe patients, SARS-CoV-2 viremia positivity rates were higher than those in mild-moderate cases at any time point. When combined, TTV DNA load and SARS-CoV-2 viremia allowed to predict the outcome of COVID-19 infection, with a higher risk (HR = 12.4) of ICU admission in patients with low TTV DNA load and positive SARS-CoV-2 viremia. 3 Stincarelli et al reported that serum TTV DNA seems unrelated to COVID-19 severity, while TTV miRNA tth8 seems related. 4 At the other end of the spectrum, Emmel et al found that the 100-day survival rate in cancer patients who died from COVID-19 was significantly lower in the TTV-positive group than in the TTV-negative group ( p  = 0.0475), and that in the cancer TTV-positive group, those who died also had a higher load of TTV than those who did not die ( p  = 0.0097). 5

Saliva is an alternative (more easily accessible than blood) biological sample for PCR methods: Mendes-Correa et al reported that the saliva TTV and nasal-oropharyngeal SARS-CoV-2 loads were correlated ( p  = 0.008), and the TTV level decreased as symptoms resolved in the SARS-CoV-2 infected group ( p  = 0.028), but remained unchanged in the SARS-CoV-2 negative controls. 6

A second, more relevant, aspect is the predictive role of TTV load with regard to vaccine responses. Healthy individuals with a median baseline TTV load of 3.8 log 10 copies/ml have an efficient immune response to the influenza vaccine 30 days after vaccination; more than 80% of healthy individuals with a median baseline TTV load of 4.1 log 10 copies/ml have a response to hepatitis B vaccine when measured at day 90 after vaccination. 7 In lung transplantation, Hoek et al showed an odds ratio (OR) of 0.54 ( p < 0.0001) for response to the first mRNA-1273 vaccine dose, 8 while Gallais et al showed an adjusted OR of 17.8 ( p  = 0.001) for pre-vaccine TTV viral load ≥6.2 log 10 copies/ml and response to third BNT162b2 vaccine dose among 173 SARS-CoV-2- naïve recipients. 9 In kidney transplantation, Reindl-Schwaighofer et al showed OR = 0.92 for homologous (ChAdOx1) or heterologous third dose in 2-dose mRNA vaccine nonresponders. 10 No studies have been reported so far investigating TTV loads and COVID-19 vaccine responses in liver or hematopoietic stem cell transplantations. We have found that healthcare workers with a baseline TTV load equal to or below 3.4 log 10 copies/ml of serum showed higher anti-Spike antibody levels when measured on day 30 after the first BNT162b2 vaccine dose ( p < 0.001; data not shown).

Compared to other solid organ transplant recipients, lung transplant recipients receive higher levels of immunosuppression and accordingly have reduced COVID-19 vaccine responses. 11 These findings suggest a continuum where the higher the immunosuppression, the better the correlation between the basal TTV loads and vaccine-elicited antibody responses. Rezahosseini et al suggested that TTV load can be used to identify the optimal moment for vaccination in patients under maintenance immunosuppression, 12 and evidences published so far are strenghtening this intuition. Despite at this stage further and larger observational clinical trials are required to consolidate this hypothesis, TTV-driven vaccine boosts represent an intriguing opportunity to increase the response rate of immunocomprimised patients. In this regard, integration of a pilot trial within the Horizon2020-funded “TTV Guide Tx” project ( https://www.ttv-guide.eu/ ) should be warranted, to assess utility in association with futher correlates of vaccine response. So far only advanced age, 8 mycophenolate use, 9 , 13 triple immunosuppression, 10 and more advanced stage of organ failure 13 are reliable predictors of vaccine responses, while there are discordant results for time since transplantation. 8 , 10

Author contributions

D.F. searched the literature and wrote the first draft. A.B., L.A., and F.N. provided raw data for the HCW cohort. F.M. revised the manuscript.

Disclosure statement

The authors declare no conflict of interest related to this manuscript.

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Time From Hospital Arrival Until Endovascular Thrombectomy and Patient-Reported Outcomes in Acute Ischemic Stroke

• 1 Division of Neurology, Department of Medicine, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
• 2 Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
• 3 Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary and Foothills Medical Centre, Calgary, Alberta, Canada
• 4 Department of Community Health Sciences, Cumming School of Medicine, University of Calgary and Foothills Medical Centre, Calgary, Alberta, Canada
• 5 Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• 6 Department of Neurology, UPMC Stroke Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
• 7 Department of Interventional Radiology, Warren Alpert Medical School of Brown University, Providence, Rhode Island
• 8 Department of Radiology, Cumming School of Medicine, University of Calgary and Foothills Medical Centre, Calgary, Alberta, Canada
• 9 Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada
• 10 Department of Radiology, University of Alberta Hospital, Edmonton, Canada
• 11 Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
• 12 Department of Neurology, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
• 13 Division of Neurology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
• 14 Department of Neurology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
• 15 Department of Neurology, Erlanger Hospital, Chattanooga, Tennessee
• 16 Lyerly Neurosurgery, Baptist Hospital, Jacksonville, Florida
• 17 Department of Neurology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
• 18 Dresden Neurovascular Center, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
• 19 University Health Network, Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada
• 20 Department of Medicine and Neurology, The Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
• 21 Department of Neuroradiology, Alfred Krupp Krankenhaus Essen, Essen, Germany
• 22 NoNO Inc, Toronto, Ontario, Canada
• 23 Department of Medicine, Cumming School of Medicine, University of Calgary and Foothills Medical Centre, Calgary, Alberta, Canada
• Original Investigation IVT + Thrombectomy vs Thrombectomy Alone in Acute Ischemic Stroke Johannes Kaesmacher, MD, PhD; Fabiano Cavalcante, MD; Manon Kappelhof, MD, PhD; Kilian M. Treurniet, MD, PhD; Leon Rinkel, MD; Jianmin Liu, MD; Bernard Yan, DMedSci; Wenjie Zi, MD; Kazumi Kimura, MD, PhD; Omer F. Eker, MD, PhD; Yongwei Zhang, MD; Eike I. Piechowiak, MD; Wim van Zwam, MD, PhD; Sheng Liu, MD; Daniel Strbian, MD, MSc, PhD; Maarten Uyttenboogaart, MD, PhD; Tomas Dobrocky, MD; Zhongrong Miao, MD; Kentaro Suzuki, MD, PhD; Lei Zhang, MD; Robert van Oostenbrugge, MD, PhD; Thomas R. Meinel, MD, PhD; Changwei Guo, MD; David Seiffge, MD; Congguo Yin, MD; Lukas Bütikofer, PhD; Hester Lingsma, PhD; Daan Nieboer, PhD; Pengfei Yang, MD; Peter Mitchell, MMed; Charles Majoie, MD, PhD; Urs Fischer, MD, MSc; Yvo Roos, MD, PhD; Jan Gralla, MD, MSc; IRIS Collaborators; Raul Nogueira; Qingwu Yang; Yuji  Matsumaru; Steven Bush; Fengli Li; Jiacheng Huang; Jiaxing Song; Bo Hong; Wenhuo Chen; Ya Peng; Hongxing Han; Liyong Zhang; Shouchun Wang; Qi Fang; Chenghua Xu; Yongxin Zhang; Zifu Li; Pengfei Xing; Hongjian Shen; Ping Zhang; Xiaoxi Zhang; Stephen Davis; Huy-Thang Nguyen; Geoffrey Donnan; Xiaochuan Huo; Guangxian Nan; Andrew  Bivard; Henry Ma; Vu Dang Luu; Bruce  Campbell; Bart J  Emmer; Jonathan M  Coutinho; Natalie E  LeCouffe; Diederik W J  Dippel; Aad van der  Lugt; Vincent  Costalat; Geert  Lycklama; Jeannette  Hofmeijer; Anouk van  Norden; Toshiaki Otsuka; Masataka Takeuchi; Masafumi Morimoto; Ryuzaburo Kanazawa; Yohei Takayama; Yuki Kamiya; Keigo Shigeta; Seiji Okubo; Mikito Hayakawa; Christophe Cognard; Simon  Jung; Marnat Gaultier; Igor Sibon; Romain Bourcier; Solene de  Gaalon; Chrysanthi Papagiannaki; Margaux Lefebvre; David S  Liebeskind JAMA

Question   Is faster treatment with endovascular thrombectomy in large vessel occlusion stroke associated with improved patient-reported quality of life?

Findings   In this secondary analysis of 1043 patients from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, faster time from hospital arrival to endovascular thrombectomy was associated with improved self-reported mobility, usual activities, self-care, pain or discomfort, anxiety or depression, and overall quality of life.

Meaning   Results of this cohort study suggest that faster treatment with endovascular thrombectomy was associated with a substantial improvement in outcomes from the perspective of the patient.

Importance   The time-benefit association of endovascular thrombectomy (EVT) in ischemic stroke with patient-reported outcomes is unknown.

Objective   To assess the time-dependent association of EVT with self-reported quality of life in patients with acute ischemic stroke.

Design, Setting, and Participants   Data were used from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, which tested the effect of nerinetide on functional outcomes in patients with large vessel occlusion undergoing EVT and enrolled patients from March 1, 2017, to August 12, 2019. The ESCAPE-NA1 trial was an international randomized clinical trial that recruited patients from 7 countries. Patients with EuroQol 5-dimension 5-level (EQ-5D-5L) index values at 90 days and survivors with complete domain scores were included in the current study. Data were analyzed from July to September 2023.

Exposure   Hospital arrival to arterial puncture time and other time metrics.

Main Outcomes and Measures   EQ-5D-5L index scores were calculated at 90 days using country-specific value sets. The association between time from hospital arrival to EVT arterial-access (door-to-puncture) and EQ-5D-5L index score, quality-adjusted life years, and visual analog scale (EQ-VAS) were evaluated using quantile regression, adjusting for age, sex, stroke severity, stroke imaging, wake-up stroke, alteplase, and nerinetide treatment and accounting for clustering by site. Using logistic regression, the association between door-to-puncture time and reporting no or slight symptoms (compared with moderate, severe, or extreme problems) was determined in each domain (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) or across all domains. Time from stroke onset was also evaluated, and missing data were imputed in sensitivity analyses.

Results   Among 1105 patients in the ESCAPE-NA1 trial, there were 1043 patients with EQ-5D-5L index values at 90 days, among whom 147 had died and were given a score of 0, and 1039 patients (mean [SD] age, 69.0 [13.7] years; 527 male [50.7%]) in the final analysis as 4 did not receive EVT. There were 896 survivors with complete domain scores at 90 days. There was a strong association between door-to-puncture time and EQ-5D-5L index score (increase of 0.03; 95% CI, 0.02-0.04 per 15 minutes of earlier treatment), quality-adjusted life years (increase of 0.29; 95% CI, 0.08-0.49 per 15 minutes of earlier treatment), and EQ-VAS (increase of 1.65; 95% CI, 0.56-2.72 per 15 minutes of earlier treatment). Each 15 minutes of faster door-to-puncture time was associated with higher probability of no or slight problems in each of 5 domains and all domains concurrently (range from 1.86%; 95% CI, 1.14-2.58 for pain or discomfort to 3.55%; 95% CI, 2.06-5.04 for all domains concurrently). Door-to-puncture time less than 60 minutes was associated higher odds of no or slight problems in each domain, ranging from odds ratios of 1.49 (95% CI, 1.13-1.95) for pain or discomfort to 2.59 (95% CI, 1.83-3.68) for mobility, with numbers needed to treat ranging from 7 to 17. Results were similar after multiple imputation of missing data and attenuated when evaluating time from stroke onset.

Conclusions and Relevance   Results suggest that faster door-to-puncture EVT time was strongly associated with better health-related quality of life across all domains. These results support the beneficial impact of door-to-treatment speed on patient-reported outcomes and should encourage efforts to improve patient-centered care in acute stroke by optimizing in-hospital processes and workflows.

Read More About

Joundi RA , Smith EE , Ganesh A, et al. Time From Hospital Arrival Until Endovascular Thrombectomy and Patient-Reported Outcomes in Acute Ischemic Stroke. JAMA Neurol. Published online June 03, 2024. doi:10.1001/jamaneurol.2024.1562

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Yale Cancer Center Researchers and Trainees Present at ASCO

55 presentations from yale were made at the annual society of clinical oncology annual meeting, asco annual meeting 2024.

Yale Cancer Center scientists and trainees attended the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago May 31-June 4 to present research advances from Yale Cancer Center and Smilow Cancer Hospital. The ASCO meeting is the most significant gathering of oncology professionals worldwide, initiating connections and forging collaborations that will change the landscape of cancer care.

This year's program featured over 200 sessions complementing the meeting theme The Art and Science of Cancer Care: From Comfort to Cure. Yale Cancer Center presented 55 oral, educational, and poster presentations during the meeting highlighting advances in cancer care and treatment from clinical trials and laboratory research at Yale and Smilow Cancer Hospital.

"Our emphasis moving forward has to be on new and better science, identifying who really benefits and who doesn't, and then figuring out how to deliver the care," Eric Winer, MD, Director of Yale Cancer Center and President and Physician-in-Chief, Smilow Cancer Hospital said of the meeting.

“Each year the faculty and trainees at Yale Cancer Center surpass expectations at ASCO with podium and poster presentations and this year was no exception. I was honored to join my colleagues in sharing the excellent advances from our laboratories and clinics on an international platform,” Roy S. Herbst, MD, PhD, Deputy Director of Yale Cancer Center said.

During the meeting, seven trainees were honored by the Conquer Cancer Foundation with awards, including Young Investigator Award recipients Talal El Zarif, MD; Rebecca Forman, MD; Yiduo Hu, MD, PhD; Ritu Jayakrishnan, MD; Tendai Kwaramba, MD, MSc; and Alejandro Rios-Hoyo, MD, and ASCO Education Scholar Thejal Srikumar, MD.

To unwind with colleagues, Yale Cancer Center hosted a cocktail and dessert reception on Sunday evening for current and former Yale oncology faculty and trainees. Hosted by Eric Winer, MD, and Roy Herbst, MD, PhD, the evening featured a jazz band and welcomed over 100 people to an intimate space to catch up away from the busy atmosphere of the meeting.

ASCO 2025 will take place May 30 - June 3, 2025 in Chicago.

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• Yale Cancer Center participation at ASCO 2024