Covid-19 Vaccination Impacts Functional Immune Responses and Plasma Proteome in Plwh

Background: The impact of COVID-19 infection or COVID-19 vaccination on the immune system of people living with HIV (PLWH) is unclear. We therefore studied the effects of COVID-19 infection or vaccination on functional immune responses and systemic inflammation in PLWH. Method(s): Between 2019 and 2021, 1985 virally suppressed, asymptomatic PLWH were included in the Netherlands in the 2000HIV study (NCT039948350): 1514 participants enrolled after the start of the COVID-19 pandemic were separated into a discovery and validation cohort. PBMCs were incubated with different stimuli for 24 hours: cytokine levels were measured in supernatants. ~3000 targeted plasma proteins were measured with Olink Explore panel. Past COVID-19 infection was proven when a positive PCR was reported or when serology on samples from inclusion proved positive. Compared were unvaccinated PLWH with and without past COVID-19 infection, and PLWH with or without anti-COVID-19 vaccination excluding those with past COVID-19 infection. Result(s): 471 out of 1514 participants were vaccinated (median days since vaccination: 33, IQR 16-66) and 242 had a past COVID-19 infection (median days since +PCR: 137, IQR 56-206). Alcohol, smoking, drug use, BMI, age, latest CD4 count and proportion with viral blips were comparable between groups. Systemic inflammation as assessed by targeted proteomics showed 89 upregulated and 43 downregulated proteins in the vaccinated participants. In contrast, individuals with a past COVID-19 infection display lower levels of 138 plasma proteins compared to the uninfected group (see figure). 'Innate immune system' and 'cell death' were upregulated in pathway analysis in vaccinated PLWH, but downregulated in COVID-19 infected participants. The increased systemic inflammation of the COVID-19 vaccinated group was accompanied by lower TNF-alpha and IL-1beta production capacity upon restimulation with a range of microbial stimuli, while production of IL-1Ra was increased. In COVID-19 infected PLWH only a reduced production of TNF-alpha to S. pneumonia was significant. Vaccinated PLWH also showed upregulation of platelet aggregation pathways. Conclusion(s): COVID-19 vaccination in PLWH leads to an increased systemic inflammation, but less effective cytokine production capacity of its immune cells upon microbial stimulation. This pattern is different from that of COVID-19 infection that leads to a decreased inflammatory profile and only minimal effects on cytokine production capacity. (Figure Presented).

Sustained endothelial, coagulation and inflammatory cytokine activation without macrovascular dysfunction at 3 months after COVID-19: A reflection on SARS-CoV-2 induced thrombo-inflammation

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).

Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19.

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.

COVID-19-associated Aspergillus tracheobronchitis: the interplay between viral tropism, host defence, and fungal invasion

Invasive pulmonary aspergillosis is emerging as a secondary infection in patients with COVID-19, which can present as alveolar disease, airway disease (ie, invasive Aspergillus tracheobronchitis), or both. Histopathology of invasive Aspergillus tracheobronchitis in patients with severe COVID-19 confirms tracheal ulcers with tissue invasion of Aspergillus hyphae but without angioinvasion, which differs from patients with severe influenza, where early angioinvasion is observed. We argue that aggregation of predisposing factors (eg, factors that are defined by the European Organisation for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium or genetic polymorphisms), viral factors (eg, tropism and lytic effects), immune defence factors, and effects of concomitant therapies will determine whether and when the angioinvasion threshold is reached. Management of invasive Aspergillus tracheobronchitis should include reducing viral lytic effects, rebalancing immune dysregulation, and systemic and local antifungal therapy . Future study designs should involve approaches that aim to develop improved diagnostics for tissue invasion and airways involvement and identify the immune status of the patient to guide personalised immunotherapy.

Late Breaking Abstract - Plasma cells and endothelitis in COVID-19 lung pathology

Histopathology is a powerful tool to understand the COVID-19 pathogenesis and come up with rational treatment strategies. We present lung histopathological features of biopsies of fatal COVID-19 cases together with anakinra (Kineret®) 11-1 a and IL-1ß receptor blocking treatment of the disease. Lung biopsy of 8 cases were scored for alveolar, vascular and inflammatory features on a 4-point scale (none-severe) by 3 lung pathologists;consensus scores were used. Anakinra was given in off-label setting to 3 COVID-19 cases receiving ICU treatment including mechanical ventilation. Lung pathology includes 1. Extensive epithelial damage with regenerative metaplasia with co-localization of neutrophils and macrophages, together with organizing pneumonia and scarring, 2. Alveolar edema, hemorrhage, diffuse alveolar damage and a dominant pattern of acute and chronic arterial thrombosis in all cases as manifestations of vascular leakage and its sequelae, and 3. plasma cell orT cell endothelitis of the pulmonary arteries as a characteristic feature to COVID-19 in six out of eight cases, indicating a role for plasma cells (fig.1) orT cells in its vascular pathology. The temporal heterogeneity of both the epithelial damage and repair and the thrombosis and thrombotic arteriopathy within in all cases indicated ongoing disease. The anakinra-treated cases showed a rapid response with extubation in 2-4 days and a drop in fever and inflammatory parameters. We propose that these distinctive features of COVID-19 are initiated through the IL-1 innate immunity pathway and operated by plasma cells. We further provide proof of concept that the IL-1 receptor antagonist anakinra was beneficial in the late and severe stage of COVID-19 disease.

Does BCG vaccination protect against COVID-19? 'Trained immunity' against viral infections

A number of clinical trials are currently underway worldwide to see whether BCG, the long-standing vaccine against tuberculosis, can protect against covid-19. In this article we briefly outline the background, the immunological mechanisms (in particular induction of 'innate immune memory' or 'trained immunity'), and the further perspectives for the use of BCG against viral and other infections.

[Is it possible that BCG vaccine protects against COVID-19?]

A number of clinical trials are currently underway worldwide to assess whether BCG, the old vaccine against tuberculosis, can protect against COVID-19 infection. In this Perspective, we briefly outline the background, the immunological mechanisms (in particular induction of 'innate immune memory' or 'trained immunity'), and further considerations for the potential future use of BCG against viral and other infections.

Cardiac function in relation to myocardial injury in hospitalised patients with COVID-19.

BACKGROUND: Previous studies have reported on myocardial injury in patients with coronavirus infectious disease 19 (COVID-19) defined as elevated cardiac biomarkers. Whether elevated biomarkers truly represent myocardial dysfunction is not known. The aim of this study was to explore the incidence of ventricular dysfunction and assess its relationship with biomarker analyses. METHODS: This cross-sectional study ran from April 1 to May 12, 2020, and consisted of all consecutively admitted patients to the Radboud university medical centre nursing ward for COVID-19. Laboratory assessment included high-sensitivity Troponin T and N­terminal pro-B-type natriuretic peptide (NT-proBNP). Echocardiographic evaluation focused on left and right ventricular systolic function and global longitudinal strain (GLS). RESULTS: In total, 51 patients were included, with a median age of 63 years (range 51-68 years) of whom 80% was male. Troponin T was elevated (>14 ng/l) in 47%, and a clinically relevant Troponin T elevation (10â€¯× URL) was found in three patients (6%). NT-proBNP was elevated (>300 pg/ml) in 24 patients (47%), and in four (8%) the NT-proBNP concentration was >1,000 pg/ml. Left ventricular dysfunction (ejection fraction <52% and/or GLS >-18%) was observed in 27%, while right ventricular dysfunction (TAPSE <17 mm and/or RV S' < 10 cm/s) was seen in 10%. There was no association between elevated Troponin T or NT-proBNP and left or right ventricular dysfunction. Patients with confirmed pulmonary embolism had normal right ventricular function. CONCLUSIONS: In hospitalised patients, it seems that COVID-19 predominantly affects the respiratory system, while cardiac dysfunction occurs less often. Based on a single echocardiographic evaluation, we found no relation between elevated Troponin T or NT-proBNP, and ventricular dysfunction. Echocardiography has limited value in screening for ventricular dysfunction.