ABSTRACT
We sought to determine parameters of the acute phase response, a feature of innate immunity activated by infectious noxae and cancer, deranged by Covid-19 and establish oncological indices' prognostic potential for patients with concomitant cancer and Covid-19. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive referrals of patients with cancer and Covid-19 aged 18 from the U.K., Spain, Italy, Belgium, and Germany. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values and the pre-established risk categorizations from literature utilized for the mGPS and PI. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of 1 comorbidity (52.1% TS, 49.8% VS), development of 1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P<0.0001) with a return to pre-Covid-19 diagnosis NLR, PNI, and mGPS categorizations following recovery (P<0.01). In the TS, higher mortality rates were associated with NLR>6 (44.6% vs 28%, P<0.0001), PNI<40 (46.6% vs 20.9%, P<0.0001), mGPS (50.6% for mGPS2 vs 30.4% and 11.4% for mGPS1 and 0, P<0.0001), and PI (50% for PI2 vs 40% for PI1 and 9.1% for PI0, P<0.0001). Findings were confirmed in the VS (P<0.001 for all comparisons). Patients in poor risk categories had shorter median overall survival [OS], (NLR>6 30 days 95%CI 1-63, PNI<40 23 days 95%CI 10-35, mGPS2 20 days 95%CI 8-32, PI2 23 days 95%CI 1-56) compared to patients in good risk categories, for whom median OS was not reached (P<0.001 for all comparisons). The PLR was not associated with survival. Analyses of survival in the VS confirmed the NLR (P<0.0001), PNI (P<0.0001), PI (P<0.01), and mGPS (P<0.001) as predictors of survival. In a multivariable Cox regression model including all inflammatory indices and pre-established prognostic factors for severe Covid-19 including sex, age, comorbid burden, malignancy status, and receipt of anti-cancer therapy at Covid-19 diagnosis, the PNI was the only factor to emerge with a significant hazard ratio [HR] in both TS and VS analysis (TS HR 1.97, 95%CI 1.19-3.26, P=0.008;VS HR 2.48, 95%CI 1.47- 4.20, P=0.001). We conclude that systemic inflammation drives mortality from Covid-19 through hypoalbuminemia and lymphocytopenia as measured by the PNI and propose the PNI as the OnCovid Inflammatory Score (OIS) in this context.
ABSTRACT
Background: Data from the first wave of COVID-19 infection demonstrated that a history of cancer and SACT was associated with poorer outcomes. Our study compares outcomes for cancer patients matched to non-cancer patients between the two waves in order to explore further how cancer and its treatment may impact COVID-19 mortality. Methods: Data was collected for patients with positive PCR and history of cancer between 1 Mar to 20 May 2020 and 1 Dec to 8 Feb 2021 for wave 1 and 2, respectively. A contemporaneous cohort of patients without cancer were age- and sex-matched for comparison. Results: The total number of patients presenting with COVID-19 was higher in wave two (1135 vs 626). 207 of these patients had cancer, and were matched to 452 patients without cancer from both waves. There was a significantly improved chance of mortality in wave 2 (HR 0.41, p < 0.0001). When adjusting for age, sex and co-morbidities, cancer was an independent risk factor for mortality amongst patients hospitalised with COVID-19 in wave 1 (HR 1.62, p = 0.02), but not in wave 2. There was a trend towards improved survival for hospitalised patients in wave 2 receiving COVID-19 specific treatment including dexamethasone, remdesivir, tocilizumab (HR 0.75, p = 0.086). For the combined cancer cohort, SACT was an independent predictor of mortality, as was metastatic disease. [Formula presented] Conclusions: The mortality for both cancer and non-cancer patients improved between waves of the pandemic. Advances in detection, prevention and treatment may account for this. Cancer was no longer a risk factor for mortality in the second wave, however SACT and metastatic cancer remained risk factors for mortality within the cancer cohort. This emphasises the need for ongoing protection of patients with advanced cancer and those on SACT, including through their prioritisation for COVID-19 vaccination globally. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: H. Shaw: Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: Novartis;Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: BMS;Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: MSD;Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: Immunocore;Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: Idera;Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: Iovance;Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: Sanofi Genzyme/Regeneron;Financial Interests, Personal, Invited Speaker, Advisory/Consultancy: Macrogenics;Financi Interests, Personal, Invited Speaker, Advisory/Consultancy: Roche. R. Roylance: Financial Interests, Personal, Other, Personal Fees: Novartis;Financial Interests, Personal, Other, Personal Fees & None-financial support: Daiichi Sankyo;Financial Interests, Personal, Other, Personal Fees: Eli-Lilly;Financial Interests, Personal, Other, Personal Fees: Pfizer;Financial Interests, Personal, Other, Personal Fees & None-financial support: G1 Therapeutics;Non-Financial Interests, Personal, Other, None-financial support: Roche;Non-Financial Interests, Personal, Other, None-financial support: AstraZeneca. All other authors have declared no conflicts of interest.
ABSTRACT
Objective: NA Background: There has been increasing recognition of neurologic symptoms in coronavirus disease 19 (COVID-19) patients. Pathophysiology underlying the encephalopathy induced by SARS-CoV-2 is yet to be elucidated, but immune system seems involved. Design/Methods: We analysed well characterised human Neurocovid samples (CSF and serum) for the presence of neurologically relevant auto-antibodies and pro-inflammatory cytokines. In addition, we investigated the molecular mechanisms underlying Covid19-related neurophysiological dysfunctions in disease-relevant neuronal models, such as rodent primary neuronal cultures and human neurons derived from induced pluripotent stem cells. Results: We gathered cerebrospinal fluid (CSF) from 13 COVID-19 patients showing central and peripheral neurological involvement. We collected CSF also from two patients affected by normal pressure hydrocephalus as controls. All CSF samples resulted negative for the presence of SARS-CoV-2 virus. We stained with CSF samples a human immortalized cell line, HEK293, over-expressing cleaved SARS-CoV-2 spike protein in not permeabilizing condition. We detected a strong immunoreactivity in specimens. We monitored the reactivity against spike along the time. To this aim, we collected CSF from one patient two months after the acute phase. We still observed a strong immuno-reactivity towards Spike-expressing HEK293 cells Having observed such an immunoreactivity profile, we aimed to identify the potential target(s) recognized by IgG present in the Neurocovid CSFs. We immobilized 50 ul of 2 CSF on agarose beads. Then we incubated the beads with different protein samples, lysate obtained from murine adult brain tissue, mouse cortical culture, membrane fraction prepared from cortical culture, and HEK293 cells. We eluted bound proteins and we analysed the samples by SDS-PAGE followed by silver staining. We excised and measured by MS/MS the protein bands appearing only in Neurocovid samples. Conclusions: Based on our findings we demonstrated that upon SARS-CoV-2 infection, the immune system generates anti-spike antibodies. These antibodies may recognize and attack neurological autoantigens due to molecular mimicry.
ABSTRACT
Background: Despite high contagiousness and rapid spread, SARS-Cov-2 has led to heterogeneous outcomes across affected nations. Within Europe, the United Kingdom is the most severely affected country, with a death toll in excess of 100.000 as of February 2021. We aimed to compare the national impact of Covid19 on the risk of death in UK cancer patients versus those in continental Europe (EU). Methods: We performed a retrospective analysis of the OnCovid study database, a European registry of cancer patients consecutively diagnosed with Covid-19 in 27 centres from February 27 to September 10, 2020. We analysed case fatality rates and risk of death at 30 days and 6 months stratified by region of origin (UK versus EU). We compared patient characteristics at baseline, oncological and Covid-19 specific therapy across cohorts and tested these in multivariable Cox regression models to identify predictors of adverse outcome in UK versus EU patients. Results: Compared to EU patients (n = 924), UK patients (n = 468) were characterised by higher case fatality rates (40.38% versus 26.5%, p < 0.0001), higher risk of death at 30 days (hazard ratio, HR 1.64 [95%CI 1.36-1.99]) and 6 months after Covid-19 diagnosis (47.64% versus 33.33%, p < 0.0001, HR 1.59 [95%CI 1.33-1.88]). UK patients were more often males, of older age and more co-morbid than EU counterparts (p < 0.01). Receipt of anti-cancer therapy was lower in UK versus EU patients (p < 0.001). Despite equal proportions of complicated Covid-19, rates of intensive care admission and use of mechanical ventilation, UK cancer patients were less likely to receive anti-Covid-19 therapies including corticosteroids, anti-virals and interleukin-6 antagonists (p < 0.0001). Multivariable analyses adjusted for imbalanced prognostic factors confirmed the UK cohort to be characterised by worse risk of death at 30 days and 6 months, independent of patient's age, gender, tumour stage and status, number of co-morbidities, Covid-19 severity, receipt of anti-cancer and anti-Covid-19 therapy. Rates of permanent cessation of anti-cancer therapy post Covid-19 were similar in UK versus EU. Conclusions: UK cancer patients have been more severely impacted by the unfolding of the Covid-19 pandemic despite societal risk mitigation factors and rapid deferral of anti-cancer therapy. The increased frailty of UK cancer patients highlights high-risk groups that should be prioritised for anti-SARS-Cov-2 vaccination. Continued evaluation of long-term outcomes is warranted.
ABSTRACT
Background: The COVID-19 (C19) pandemic has prompted alterations to systemic anti-cancer therapy (SACT) due to concerns of immunosuppression and healthcare exposure. However, the effects of SACT on mortality in patients who acquire C19 are not well understood. As a national cancer centre within a major C19 hotspot, we seek to address these risks at scale. Method(s): Patients with a history of solid cancers and laboratory confirmed C19 (1 Mar to 31 May 2020) were included. Haematological malignancies were excluded. The primary outcome was time from C19 diagnosis to death. The last follow-up date was 22 Jun 2020. Result(s): We identified 94 cancer patients;62 males (median age 73, BMI 24.9), and 32 females (median age 68.5, BMI 25.7). Genitourinary (n = 24) cancers were the most common, followed by gastrointestinal (n = 23), thoracic (n = 15), and gynaecological (n = 9) cancers. 25 patients received SACT: chemotherapy (n = 15), endocrine therapy (n = 8), immunotherapy (n = 4), and targeted anti-cancer therapy (n = 2). 16 patients received SACT with palliative intent. Patients on SACT had a greater incidence of metastatic disease (48.0% vs 10.6%, p 0.001) and were younger (median age 62.5 vs 73.0, p = 0.01). They were also more likely to have renal impairment (p = 0.02), lymphopaenia (p = 0.01) and anaemia (p = 0.04) compared to those not on SACT. The univariate analysis showed age and co-morbidities were associated with mortality (Table). Adjusting for age, ethnicity, co-morbidities and the presence of metastatic cancer, SACT was an independent risk factor for C19 mortality (HR 2.46, 1.09 - 5.5, p = 0.03). Age, South Asian ethnicity, hypertension and cerebrovascular disease were also independent risk factors for C19 mortality. [Formula presented] Conclusion(s): C19 infection poses a substantial risk to cancer patients and our data suggests that SACT is an independent risk factor for mortality in C19 infection. These findings call for a nuanced approach to C19 risk, focusing on established risk factors such as age and co-morbidities to guide treatment decisions. Legal entity responsible for the study: University College London Hospital. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest. Copyright © 2020
ABSTRACT
Background: The COVID-19 pandemic remains of pressing concern for patients with cancer. Mortality from COVID-19 is predicted by age and co-morbidities, but the relative contribution of cancer is poorly understood. As a tertiary academic hospital serving a large general and cancer population in a COVID-19 epicentre, we are uniquely placed to investigate this. We report data from our study, comparing cancer patients to an age- and sex-matched non-cancer cohort. Methods: Patients with laboratory confirmed COVID-19 from 1 March to 31 May 2020 were included. Patients with a history of solid cancer were compared to an age- and sex-matched non-cancer cohort. Patients with haematological malignancies were excluded. Results: We identified 94 patients with cancer and 226 patients without cancer. In univariate analysis, age, South Asian ethnicity and co-morbidities predicted mortality (see table). More in the cancer cohort had died compared to the non-cancer cohort (43.6% vs 34.1%). The higher mortality among cancer patients was statistically significant among those aged 70 years and above (OR 2.28, 1.14-4.50, p = 0.02). After adjusting for age, ethnicity and co-morbidities, a history of cancer was an independent predictor of mortality following COVID-19 (HR 1.57, 95% CI:1.04-2.4, p = 0.03). Patients with active malignancy also had similarly increased adjusted mortality (HR 1.64, 95% CI: 1.03 – 2.6, p = 0.04). Increasing age (HR 1.49 every 10 years, 95% CI:1.25-1.8, p <0.001), South Asian ethnicity (HR 2.92, 95% CI:1.73-4.9, p <0.001) and cerebrovascular disease (HR 1.93, 95% CI:1.18-3.2, p = 0.008) were also confirmed as independent predictors of mortality. [Formula presented] Conclusions: Along with known risk factors, cancer confers an independent risk for mortality in COVID-19. Taken together, our findings support the need to continue ‘shielding’ patients with cancer from exposure to COVID-19 infection. Increasing age and co-morbidity should take precedence when weighing up risk factors for severe COVID-19 infection in cancer patients. Legal entity responsible for the study: University College London Hospitals NHS Foundation Trust. Funding: Has not received any funding. Disclosure: H.M. Shaw: Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis, BMS, MSD;Advisory/Consultancy: Immunocore, Idera, Iovance, Genmab, Sanofi Genzyme/Regeneron, Macrogenics, Roche;Speaker Bureau/Expert testimony: Sanofi Genzyme. All other authors have declared no conflicts of interest.