ABSTRACT
Besides parenchymal changes that have been described extensively in COVID-19, bronchiectasis is also reported but detailed characterization of airway changes is lacking. Hence, we aimed to quantify the number of visible airways and their diameters in end-stage COVID-19 lungs. Explanted right lungs, obtained after lung transplantation (n=2) or autopsy (n=1) (65.3+/-26.7 days after symptom onset), were inflated to total lung capacity, frozen and scanned with whole lung microCT (155 mum). Airways were segmented using Mimics Innovation Suite (Materialise, Belgium) and airway count and diameter were assessed using Neuronstudio. Three discarded donor lungs were used as controls. Number of visible airways increased in COVID-19 lungs compared to controls (fig.1a) potentially caused by airway remodeling and bronchiectasis (fig.1b, red arrows) due to fibrotic rearrangement (fig. 1b). Small airway count (diameter 0-2 mm) in generation (G) 1-11 was lower in COVID-19 patients compared to controls, with a shift of small airways from lower generations (G1-11) to higher generations (G12-27) in COVID-19 patients. Simultaneously, airways with a diameter > 2 mm were increased in all generations in COVID-19 (present until G21 compared to G13 in controls). This study shows that COVID-19 causes a remodeling of the (small) airways, leading to an increase of visible airways and diameter of large and small airways, similar to that seen in idiopathic pulmonary fibrosis due to traction bronchiectasis. (Figure Presented).
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an ongoing global pandemic. Phase III trials have demonstrated excellent efficacies of mRNA vaccines against SARS-CoV-2 in large population studies (Baden LR, NEJM, 2021;Polack FP, NEJM, 2020). Immunosuppressed individuals such as chronic lymphocytic leukemia (CLL) patients are at risk for a suboptimal response to 2 vaccine doses (Herishanu Y, Blood, 2021). The French National Authority for Health recommends the use of a third dose in immunosuppressed patients. However, seroconversion rate after the triple-dose vaccine is not yet known. The objective of our study was to evaluate SARS-CoV-2 antibody responses after the first, second and third doses of the BNT162b2 and mRNA-1273 vaccines. Data were collected from 17 French Innovative Leukemia Organization (FILO) investigating centers and the French CLL patients' association (SILLC). SARS-CoV-2 IgG anti-Spike levels were measured at 4-6 weeks after each vaccine dose. A total of 530 patients and 14 controls were included in the study. Vaccine response was evaluated post-dose 1 for 158 CLL patients, post-dose 2, for 506 patients and post-dose 3 for 66 patients. Peripheral blood lymphocyte subsets were studied post-dose 2 by flow cytometry in 80 CLL patients and 14 controls. The median age of the patients was 71 years (range 37-93), 218 (40%) were treatment-naïve (TN), 136 (26%) had a prior CLL treatment and 176 (34%) were on therapy. Post-dose 1, the global response rate was 27% (43/158). TN patients had a response rate of 34% (23/67), similar to those who had a prior CLL treatment (33%,12/36), and higher compared to on-therapy patients (15%, 8/55, P=0.02). Post-dose 2, the global response rate was 52% (265/506). TN patients had the highest response rate of 72% (151/210) compared to previously treated patients, mostly by immunochemotherapy (60%, 78/130, P=0.02) and on-therapy patients (22%, 36/166, P<0.001) (Figure 1A). Among the 166 on-therapy patients, mostly receiving targeted agents, those receiving venetoclax monotherapy achieved a significantly higher response rate (52%, 12/23) than those treated with BTK inhibitors (BTKi) ibrutinib or acalabrutinib (22%, 23/104, P<0.001). Patients treated with venetoclax+anti-CD20 monoclonal antibodies (n=19) or venetoclax+BTKi (n=6) were all seronegative after the second dose of vaccine (Figure 1B). In multivariate analysis, the variables found to be significantly associated with seroconversion were age >65 years (OR 0.55, 95% CI 0.33-0.92, P=0.02), ongoing CLL treatment (OR 0.13, 95% CI 0.07-0.23, P<0.001) and gamma-globulins ≤6g/L (OR 0.41, 95% CI 0.19-0.88, P=0.03). Flow cytometry results suggest a differential balance of the T CD4+ cell subpopulations in Binet stage A and in patients on targeted therapy compared to healthy controls. Post-dose 2 seronegative patients were proposed a third dose and to date, 66 have been tested for the antibody response 4-6 weeks post-dose 3. The post-dose 3 response rate was 42% (28/66). TN patients and previously treated patients had a significantly higher response rate (57%, 16/28) compared to on-therapy patients (32%, 12/38, P=0.03). We further analyzed patients tested post-dose 2 with the Abbott Architect SARS-CoV-2 IgG anti-Spike assay (n=24). Those who achieved seroconversion after the third dose (n=10) had significantly higher titers post-dose 2 (median 12, IQR 3.0-40.8) compared to those who remained seronegative (n=14) (median 2.2, IQR 0.5-5.1, p<0.01), although both median values are considered below the threshold by the manufacturer. An additional cohort of 40 CLL patients who presented a SARS-CoV-2 infection prior to vaccination participated to the study and was analyzed independently. All patients achieved seroconversion after infection and a single dose of vaccine, even though 30% (n=12) had an ongoing CLL treatment. In conclusion, double-dose mRNA vaccination generated a humoral response in 52% of our CLL cohort and a third dose induced seroconversion in 42% of the patients who remained seronegat ve after the second dose. The major independent predictor of negative antibody response was ongoing treatment with BTKi. The strongest boost to immune response against the virus seems to be SARS CoV-2 infection, as a substantial increase in anti-Spike antibodies was observed in all CLL patients with prior infection, after a single dose vaccination.
ABSTRACT
Chronic lymphocytic leukemia (CLL) patients experience both humoral and cellular immune deficiency, with a reduced number of normal B lymphocytes, and hypogammaglobulinemia. Previous large studies on vaccination efficacy are scarce but it is well-established that CLL patients have a poorer response than normal subjects to vaccination and are at increased risk of infection. Efficacy of anti-SARS-Cov-2 vaccination in CLL has been recently published by the Israeli group (Herishanu, 2021) showing that among hematological malignancies, patients who presented CLL disease are the least responsive to vaccination. We have collected the results of a large cohort of 502 French patients after vaccination by either BNT162b2 or mRNA-1273 mRNA vaccine. Patients received 2 doses at a 4-week interval. For those who received the 3rd dose, the interval was usually longer (between 6 and 8 weeks after 2nd dose). The median time to sample collection for serology was 4 weeks, and IgG anti-SARS-CoV-2 Spike antibody levels were measured by commercially available tests. We evaluated patients after the 1st and 2nd doses and collected matched samples whenever possible. Patients who had a previous COVID-19 infection were analyzed separately. We evaluated 176 patients after the 1st dose and the global seroconversion rate was only 31% (55/176). We evaluated 455 patients after the 2nd dose, and the global rate of seroconversion was 54% (246/455). Matched samples after both first and second doses were available for 118 patients. In this cohort, among the 87 patients who were seronegative after the first dose, 42 patients (48%) became positive after the second dose. Most patients who remained seronegative after two doses, received the third dose. The administration of the third dose program started recently, therefore, to date, we have the results for 31 patients only. Among these patients, 18 remained negative after this 3rd dose, while 13 (42%) seroconverted. Therefore, if we extrapolate these data, it is expected that approximately only 70-75% of CLL patients will be protected by vaccination (either by two or three doses) at the end of the vaccination program. On the other hand, 40 patients who received at least one dose of vaccine had presented a COVID-19 infection before vaccination. In this group of patients, the humoral response was evaluated in 29 patients. All of them except one, presented very high anti-Spike antibodies titer, even after one dose, and the only patient who remained seronegative after vaccination was on prolonged anti-CD20 therapy for autoimmune thrombocytopenia. We also collected cases of COVID-19 infection post-vaccination. Nineteen patients presented a COVID-19 infection after vaccination, 11/19 presented the infection after the first dose, and 8/19 after the second dose. Among those eight patients, five presented the first symptoms within the first 2 weeks after the second dose and had a more severe COVID-19 infection while the three patients with a later onset of symptoms (4-6 weeks after vaccination) had very mild symptoms. All patients tested had no antibody response before COVID infection but had highly positive anti-Spike titers after infection. Currently, the COVID- 19 pandemic has settled down and it is difficult to know if the absence of post-vaccination COVID-19 infection is related to the slowing of the pandemic or if CLL patients are protected by cell-mediated immunity, even in the absence of antibody response. In conclusion, double-dose mRNA vaccination generated a humoral response in 54% of our CLL cohort, and a third dose induced seroconversion in 40% of the patients who were seronegative after the second dose. However, the strongest boost to the immune response against the virus seems to be the COVID-19 infection, as a substantial increase in anti-Spike antibodies was observed in all CLL patients after infection, even if they were negative post-vaccination.
ABSTRACT
Background: Endothelial damage caused by COVID-19 may imperil the cardiovascular health of millions. More than a year since WHO declared the COVID-19 pandemic, information on the lasting effects of this infection on the cardiovascular system beyond the acute phase is still lacking. Purpose: To study macrovascular endothelial dysfunction and activation, coagulation and inflammation, 3 months after resolution of acute COVID- 19 symptoms. Methods: A cross-sectional observational cohort study was conducted including 203 patients with PCR confirmed COVID-19 disease, 6-20 weeks after acute COVID-19. The primary endpoint was macrovascular endothelial function, assessed by the carotid artery reactivity (CAR) test. The CAR measures the carotid artery diameter in response to hand in icewater immersion. A historic cohort of 313 subjects served as controls. Propensity score matching was used to correct for baseline differences. Plasma endothelin-1 (ET-1), interleukin (IL)-1ra, IL-6, IL-18 were measured by ELISA. ET-1 levels were also measured in a partially overlapping COVID-19 cohort of which plasma samples were available during the acute phase. Coagulation enzyme:inhibitor complexes for thrombin:antithrombin (TAT), factor (F) IXa:AT, FVIIa:AT, FXIa:AT, FXIa:alpha 1 antitrypsin (a1AT), FXIa:C1 esterase inhibitor (C1inh), kallikrein(PKa):C1inh and von Willebrand Factor:antigen (vWF:Ag), were assessed by in house developed ELISA. Results: After propensity score matching, the prevalence of macrovascular dysfunction did not differ between the COVID-19 (22.5%) versus the historical control cohort (18.6%, RD -3.92%, 95%-CI -15 to 7.19, p=0.49). Plasma concentrations of markers for endothelial activation were elevated (>1 SD above normal);ET-1 (64.9%), and vWF:Ag (80.8%). In controls, ET- 1 levels were significantly lower as compared to COVID-19 patients during the acute phase and after 3 months. ET-1 levels were significantly higher 3 months after COVID-19 as compared to the acute phase. Cytokines were high in a majority of patients: IL-18 (73.9%), IL-6 (51.2%), and IL- 1ra (48.9%). TAT and FIXa:AT, reflecting a prothrombotic state, were high in 48.3% and 29.6% of the patients, respectively. FVIIa:AT, as marker of the extrinsic pathway, was elevated (35%). Markers of contact activation were also increased: PKa:C1inh (16.3%), FXIa:AT (16.3%), FXIa:a1AT (20.7%), and FXIa:C1inh (17.7%) (picture 1). Conclusions: At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction as compared to matched historic controls;there was evidence, however, of sustained thrombo-inflammation, indicated by high circulating concentrations of ET-1, vWF:Ag, proinflammatory cytokines, and markers of coagulation (picture 2). Elevated IL-18 levels could potentially induce arterial inflammation and subsequent atherogenesis. Our data highlight the importance of further studies on SARS-CoV-2 related thrombo-inflammation, as well as longer follow-ups in recovered patients. (Figure Presented).
ABSTRACT
INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.