ABSTRACT
Cancer patients display immunomodulation related to malignancy and anti-cancer therapies, but how these factors impact COVID-19 remains unknown. To investigate immune responses in cancer patients with COVID-19, we undertook a prospective case-control study, enrolling hospitalized solid tumor patients with acute COVID-19, as well as age-, gender-, and comorbidity-matched COVID-19 patients without cancer as controls. Using biospecimens collected during hospitalization, we performed virologic measurements as well as in-depth immunophenotyping of cellular, antibody and cytokine responses. We enrolled 17 cancer patients (cases) admitted to Yale-New Haven Hospital between March 15 and June 30, 2020 with COVID-19, as well as 17 matched non-cancer patients (controls) admitted with COVID-19. No significant differences were observed between cases and controls based on patient characteristics (age, gender, race, co-morbidities, smoking history, days from symptom onset to COVID-19 diagnosis) or outcomes (COVID-19 severity, length of hospital stay, rate of intubation or mortality). The most common primary tumor sites were lung (4/17) and gastrointestinal (4/17);all cases had received cancer-directed therapy within 6 months of COVID-19 diagnosis, with 13/17 receiving treatment less than 1 month prior to hospitalization. Three of 17 cases had received immune checkpoint inhibitor therapies. Despite having similar SARS-CoV-2 viral RNA loads at the time of COVID-19 diagnosis when compared with controls, cancer cases had increased viral RNA abundance during hospitalization, suggesting slower clearance. Antibody responses against SARS-CoV-2 were preserved in cancer cases, with cases displaying similar levels of IgM and IgG antibodies directed against SARS-CoV-2 epitopes compared to controls. Cytokine profiling revealed higher plasma levels of CCL3, IL1A and CXCL12 in cancer cases compared to controls. Using flow cytometric immunophenotyping, we found that innate immune and non-T cell adaptive immune parameters were similar between cases and controls hospitalized with COVID-19. However, among cancer cases on conventional therapies, T cell lymphopenia was more profound, and these cases demonstrated higher levels of CD8+ exhausted (CD8+CD45RA-PD1+TIM3+ ), CD8+GranzymeB+ and CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ activated T cells when compared with controls;interestingly, these differences were not observed in patients who had received immune checkpoint inhibition. Thus, we found reduced viral RNA clearance and specific alterations in T cell and cytokine responses in cancer patients hospitalized with COVID-19 compared with matched controls with COVID-19. This dysregulated T cell response in cancer patients, which may reflect immune modulation due to chronic antigen stimulation as well as cancer therapies, may lead to altered virologic and clinical outcomes in this population.
ABSTRACT
Purpose or Objective To share the lessons learned from 2 years monitoring and analysis of near misses in a RO department. Emphasis will be put on the changes in the quality and safety culture amongst the different professional groups in the department. Materials and Methods Ten years ago a general-purpose voluntary Incident Learning System (ILS) was implemente, however few incidents (5 per year) were reported by the RO staff. Two years ago, a structured RO voluntary ILS based on RedCap and linked to a QR code was implemented to facilitate near misses and incident reporting. A multidisciplinary committee, meeting twice a month, to monitor the ILS was created. Bimonthly feedback to the staff was given. An ILS database temporal analysis focusing on the different staff members reporting and number of events reported on each treatment process station was performed. On January 2021, a survey to all staff to assess their adherence to the ILS and their perception its relevance on safety culture was sent. Results 3,315 events were reported;92.5% near misses and 7.5% incidents. Lack of evaluating patient specific QA (40% of all incidents) followed by delays in the treatment initiation (23%) and misadministration of the treatment (8.5%) were the most frequent incidents. The temporal trends on number of reported events, incidents andnumber of events per station are shown on fig. 1 and 2. We detected that while the number of events reported at the treatment unit was constant the number of events reported on plan and treatment chart evaluation has decreased considerably over the last 6 months. This could be caused as a result of an in-depth study, by requirement of the dosimetrists, on the most frequent events during treatment planning resulting on a reduction of events. On the last 3 months a relaxation of MP in reporting has also been detected with an increase of events reaching the treatment unit. The number of personnel reporting was around 30 (SD 9) on the studied time period. A reduction on reported events during the first COVID wave, attributed to a reduction of on-site staff and disruption of feedback was observed. 50/63 staff members answered the survey. 90% agreed that ILS is an important tool for the treatments safety , 60% that contributed improve safety culture, 82% agreed on the importance of regular feedback. Only 10 respondents had never reported an adverse event (0 administrative staff, 1/3 of RO and 1/2 of nurses). The most frequent causes for non-reporting were;forget to report (32%), lack of time (20%), not sure if reportable (15%), fear to consequences (5%). 26/50 had detected an adverse event but only 15 had reported it.
ABSTRACT
BACKGROUND AND AIMS: Angiotensin converting enzyme 2 (ACE2) is one of the components of the renin-angiotensin system (RAS) that mainly degrades angiotensin II to angiotensin-(1-7). ACE2 is predominantly expressed in the kidney and the heart, but it has been evidenced in type 2 alveolar lung cells, where it acts as a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this context, a controversy arose as to whether the use of RAS blockers could increase ACE2 lung expression and the risk infection by COVID-19. This study aimed to investigate the effect of an ACE inhibitor (Ramipril) on ACE2 expression in experimental diabetes. METHOD: 12 weeks old diabetic db/db mice (n=7) were given ramipril (8 mg/Kg/day) during 8 weeks or the respective vehicle. db/m (n=7) vehicle-treated non-diabetic mice were included as controls. ACE2 mRNA expression and enzymatic activity were studied in kidney, heart and lung samples of these animals to identify if the diabetic condition or treatment with ramipril modulated ACE2 expression. RESULTS: In vehicle-treated diabetic db/db animals, ACE2 mRNA expression was significantly increased in the kidney (p<0.001) and ramipril treatment reversed this effect (p=0.026). In the heart, ACE2 expression decreased in db/db when compared to db/m littermates (p=0.035) and ramipril had no effect. We found no differences in ACE2 gene expression in the lung. Besides, ACE2 enzymatic activity was increased in the kidney (29%) and also in the lung (16%) of db/db mice when compared to controls. Ramipril treatment decreased ACE2 activity a 19% in the lung and had no effect in the kidney when compared to untreated db/db (see figure). In the heart, ACE2 activity tended to decrease in db/db mice (29%) when compared to db/m and ramipril increased ACE2 activity (18%) but did not exceed the cardiac ACE2 activity of the db/ m. CONCLUSION: ACE2 is increased in the kidney and the lung, and decreased in the heart of diabetic mice. Ramipril treatment restores ACE2 levels. The results suggest that ACE inhibitors do not increase ACE2 expression and the activity decrease exerted in the lung may be protective against COVID-19 infection.