407 Phenotypic heterogeneity of COVID-19 pneumonia: clinical and phatophysiologic relevance of the vascular phenotype

Recent data support the existence of a distinctive ‘vascular’ phenotype with the involvement of both pulmonary parenchyma and its circulation in COVID-19 pneumonia. Its prompt identification is important for the accurate management of COVID-19 patients. The aim is to analyse the pro and contra of the different modalities to identify the ‘vascular’ phenotype. Chest computed tomography scan and angiogram may quantify both parenchyma and vascular damage, but the presence of thrombosis of pulmonary micro-circulation may be missed. Increased d-dimer concentration confirms a thrombotic state, but it cannot localize the thrombus. An elevation of troponin concentration nonspecifically reflects cardiac injury. Echocardiogram and electrocardiogram provide specific signs of right ventricular pressure overload. This is particularly relevant for the ‘vascular’ phenotype which does not necessarily represent the result of thromboembolic venous complications but, more frequently, it is the result of pulmonary microcirculation thrombosis in situ and needs immediate therapeutic action.

Cigarette Smoking Exacerbates Flu-Induced Thrombo-Inflammation

Rationale: Epidemiological evidence suggests that prior exposure to cigarette smoke (CS) or habitual smoking increases the risk of influenza A virus (IAV)-triggered respiratory failure (severe flu). Although emerging evidence supports the role of thrombo-inflammation in the development of CS and IAV-triggered lung injury, the innate immune mechanism that contributes to this morbidity remains poorly understood. Materials and methods: We have developed a two-hit model of CS-induced severe flu in mice. Mice were exposed to four weeks of room air (air) or CS followed by intra-nasal administration of A/PR/8/34 (H1N1) IAV. The body weight was measured every day for two weeks after IAV administration followed by assessment of lung injury at day 7 and 14. Lungs were harvested for histological assessment of lung injury and estimation of viral titer by RT-PCR. Quantitative fluorescence intravital lung microscopy (qFILM) was conducted at 2-, 3- and 4-days post IAV-infection to visualize dynamics of neutrophil and platelet recruitment in the lung of mice IV administered with fluorescent dextran, anti-Ly6G Ab and anti-CD49Ab. Results: Mice exposed to CS+IAV manifested significantly more weight loss, lung injury, lung congestion and alveolar hemorrhage compared to mice administered room-air+IAV. QFILM revealed that severity of lung injury was associated with significantly more entrapment of neutrophil-platelet aggregates within the pulmonary microcirculation and infiltration into the air spaces of CS+IAV than room-air+IAV administered mice. Conclusion: These initial results suggest that CS primes innate immune signaling in neutrophils and platelets to promote their recruitment in the lung following flu. Currently, studies are underway to identify innate immune pathways in neutrophils and platelets that drive this severe thrombo-inflammatory response. Disclosures Sundd: CSL Behring Inc: Research Funding; Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Changes in pulmonary microcirculation after COVID-19

The endothelium is a tissue most vulnerable to the SARS-CoV-2 virus. Systemic endothelial dysfunction leads to the development of endothelitis which causes the main manifestations of the disease and systemic disturbance of microcirculation in various organs. Pulmonary microcirculatory damage, the most striking clinical manifestation, was the reason to perform SPECT to detect microcirculation disorders.Aim. To assess microcirculatory changes in the lungs of patients who had no previous respiratory diseases and had a COVID-19 infection at different times from the onset of the disease.Methods. SPECT data were analyzed in 136 patients who had a proven coronavirus infection of varying severity from May 2020 to June 2021.Results. All patients showed changes in microcirculation in the lungs in the post-COVID period. The severity of microcirculation disorders had a significant correlation (rs = 0.76; p = 0.01) with the degree of damage to the pulmonary parenchyma and an average correlation (rs = 0.48; p = 0.05) with the timing of the post-COVID period and the degree of residual lesions on CT (rs = 0.49; p = 0.01). The examined patients with persistent clinical complaints had pulmonary microcirculatory lesions, which may indicate the development of vasculitis, at all stages of the post-COVID period. Despite regression of the lesions confirmed by CT in 3 to 6 months after the acute COVID-19 infection, specialists from Russian and other countries report that 30–36% of patients develop pulmonary fibrosis. Similar changes were identified in 19.1% of the examined patients in our study.Conclusion. Microcirculation disorders are detected in all patients in the post-COVID period, irrespective of the severity according to CT. Progressive decrease in microcirculation in the lower parts of the lungs, local zones of hypoperfusion with the critically low accumulation of radiopharmaceuticals, persistent areas of compaction of the lung tissue (so-called “ground glass”), reticular changes, and the development of traction bronchiectasis, a decrease in the diffusion capacity of the lungs and alveolar volume may indicate fibrotic lesions with subsequent development of virus-associated interstitial lung disease.

Intravital Assessment of Pre-capillary Pulmonary Arterioles of Type-1 Diabetic Mice Shows Oxidative Damage and Increased Tone in Response to NOS Inhibition

Microvascular dilation, important for peripheral tissue glucose distribution, also modulates alveolar perfusion and is inhibited by loss of bioavailable nitric oxide (NO) in diabetes mellitus (DM). We hypothesized that DM-induced oxidative stress decreases bioavailable NO and pulmonary pre-capillary arteriolar diameter, causing endothelial injury. We examined sub-pleural pulmonary arterioles after acute NO synthase (NOS) inhibition with L-NAME in streptozotocin (STZ) and saline (CTRL)-treated C57BL/6J mice. Microvascular changes were assessed by intravital microscopy in the right lung of anesthetized mice with open-chest and ventilated lungs. Arteriolar tone in pulmonary arterioles (27.2 to 48.7 µm diameter), increased in CTRL mice (18.0 ± 11% constriction p=0.034, n=5) but decreased in STZ (13.6 ± 7.5% dilation p= 0.009, n=5), after L-NAME. Lung tissue DHE fluorescence (superoxide), inducible NOS expression, and protein nitrosylation (3-nitrotyrosine) increased in STZ mice and correlated with increased glucose levels (103.8 ± 8.8 mg/dL). Fluorescently-labeled fibrinogen administration and fibrinogen immunostaining showed fibrinogen adhesion, indicating endothelial injury in STZ mice. In CTRL mice, vasoconstriction to L-NAME was likely due to the loss of bioavailable NO. Vasodilation in STZ mice may be due to decreased formation of a vasoconstrictor or emergence of a vasodilator. These findings provide novel evidence that DM targets the pulmonary microcirculation and that decreased NO bioavailability and increased precapillary arteriolar tone could potentially lead to ventilation-perfusion abnormalities, exacerbating systemic DM complications.

Prevalence of right ventricular dysfunction and impact on all-cause death in hospitalized patients with COVID-19: a systematic review and meta-analysis

The Coronavirus Disease (COVID-19) pandemic imposed a high burden of morbidity and mortality. In COVID-19, direct lung parenchymal involvement and pulmonary microcirculation dysfunction may entail pulmonary hypertension (PH). PH and direct cardiac injury beget right ventricular dysfunction (RVD) occurrence, which has been frequently reported in COVID-19 patients; however, the prevalence of RVD and its impact on outcomes during COVID-19 are still unclear. This study aims to evaluate the prevalence of RVD and associated outcomes in patients with COVID-19, through a Systematic Review and Meta-Analysis. MEDLINE and EMBASE were systematically searched from inception to 15th July 2021. All studies reporting either the prevalence of RVD in COVID-19 patients or all-cause death according to RVD status were included. The pooled prevalence of RVD and Odds Ratio (OR) for all-cause death according to RVD status were computed and reported. Subgroup analysis and meta-regression were also performed. Among 29 studies (3813 patients) included, pooled prevalence of RVD was 20.4% (95% CI 17.1–24.3%; 95% PI 7.8–43.9%), with a high grade of heterogeneity. No significant differences were found across geographical locations, or according to the risk of bias. Severity of COVID-19 was associated with increased prevalence of RVD at meta-regression. The presence of RVD was found associated with an increased likelihood of all-cause death (OR 3.32, 95% CI 1.94–5.70). RVD was found in 1 out of 5 COVID-19 patients, and was associated with all-cause mortality. RVD may represent one crucial marker for prognostic stratification in COVID-19; further prospective and larger are needed to investigate specific management and therapeutic approach for these patients.

The peculiarities of pulmonary macro- and microhemodynamics changes after treatment with agonists and blockers of cholinoceptors

Background. The pulmonary arterial and venous vessels are innervated by parasympathetic cholinergic nerves. However, the studies, performed on the isolated rings of pulmonary vessels, can not give answer to the question about the role of cholinergic mechanisms in the changes of pulmonary circulation in full measure. Aim. The comparative analysis of the changes of the pulmonary macro- and microhemodynamics after acetylcholine, atropine, pentamine and nitroglycerine treatment. Materials and methods. The study was carried out on the anesthetized rabbits in the condition of intact circulation with the measurement of the pulmonary artery pressure and flow, venae cavae flows, cardiac output, and also on isolated perfused lungs in situ with stabilized pulmonary flow with measurement of the perfused pulmonary artery pressure, capillary hydrostatic pressure, capillary filtration coefficient and calculation of the pulmonary vascular resistance, pre- and postcapillary resistances. Results. In the conditions of intact circulation after acetylcholine, pentamine and nitroglycerine treatment the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance did not change as a result of decreasing of pulmonary artery flow and left atrial pressure due to diminution of venous return and venae cavaе flows. On perfused isolated lungs acetylcholine caused the increasing of pulmonary artery pressure, capillary hydrostatic pressure, pulmonary vascular resistance, pre- and postcapillary resistance and capillary filtration coefficient. After M-blocker atropine treatment the indicated above parameters of pulmonary microcirculation increased, on the contrary, after N-blocker pentamine treatment they decreased. Nitroglycerine infusion caused less decreasing of the parameters of pulmonary microcirculation in comparison with effects of pentamine, but capillary filtration coefficient decreased to a greater extent. These data indicate that nitroglycerine decreases endothelial permeability of pulmonary microvessels. Conclusion. After activation or blockade of cholinergic mechanisms in the condition of intact circulation the calculated parameter of pulmonary vascular resistance is depended from the ratio of the pulmonary artery pressure and flow and left atrial pressure, which are determined by the venous return. The different character of the changes of pulmonary microcirculatory parameters after M-blocker atropine and N-blocker pentamine treatment is evidence of reciprocal relations of M- and N-cholinoceptors in the nervous regulation of the pulmonary microcirculatory bed.

Abstract 14228: Pericytes Within a Pulmonary Neurovascular Unit in Covid-19-elicited Pathologic Changes

A pericyte-centered hypothesis suggests that embolisms occurring within microvasculature of a neurovascular unit can result in either parenchymal hemorrhage or intravascular congestion. Dysfunctional microvascular pericytes are featured depending on their location in the neurovascular unit. I extend the hypothesis by proposing a concept of pulmonary neurovascular unit (pNVU). In simulating pathophysiology in pulmonary embolisms, acute high-altitude illness and COVID-19, an existing local regulation of microvascular blood flow is believable. This control balances blood flow with oxygen supply to maintain physiological blood oxygen saturation level. We have reported a working module for the neurovascular unit in the sexually dimorphic nucleus of the preoptic area. Pericytes, labeled with alpha-smooth muscle actin immunoreactivity, are significantly denser within the microvasculature of the neurovascular unit in males, signifying their biological functions or potential pathophysiological role in diseases. Noticeably, an illustration provides an explanation of how malfunction of microvascular pericytes causes pulmonary focal hemorrhage, edema or microvascular congestion and thrombi [Fig. 1]. A bypass existing in the pNVU would autonomically deviate blood flow from COVID-19-affected pNVU to other healthy pNVU. Consequentially, systematically applied medicines including chloroquine and/or hydroxychloroquine became valueless due to low concentration of the medicine in the COVID-19-affected regions. Alternatively, a preventive, early antiviral therapy may be efficacious because dysfunctional blood-air exchange precedents and malfunction of pulmonary microcirculation follows. While testing the hypothesis with experimental evidence is urgently needed, supporting therapy aimed at improvement of microcirculation or rebuilding of microvascular pericytes’ physiological function may be recommended during the COVID pandemic.