Molecular Analysis of Prothrombotic Gene Variants in Patients with Acute Ischemic Stroke and with Transient Ischemic Attack.

Background and objectives: ischemic stroke (IS) is among the most frequent causes of death worldwide; thus, it is of paramount relevance to know predisposing factors that may help to identify and treat the high-risk subjects. Materials and Methods:we tested nine variants in genes involved in thrombotic pathway in 282 patients that experienced IS and 87 that had transient ischemic attacks (TIA) in comparison to 430 subjects from the general population (GP) of the same geographic area (southern Italy). We included cases of young and child IS to evaluate the eventual differences in the role of the analyzed variants. Results: we did not observe significant differences between TIA and the GP for any of the variants, while the allele frequencies of methylene-tetrahydrofolate reductase (MTHFR) C677T, beta-fibrinogen -455G>A and factor (FXIII) V34L were significantly higher in patients with IS than in the subjects from the GP. No significant interaction was observed with sex. Conclusions: the present data argue that some gene variants have a role in IS and this appears to be an interesting possibility to be pursued in large population studies to help design specific strategies for IS prevention.

Influence of pancreatic status on circulating plasma sterols in patients with cystic fibrosis.

Background Patients with cystic fibrosis (CF) have a reduced intestinal absorption of cholesterol and in a preliminary study we observed differences in plasma sterol profile between patients with pancreatic sufficiency (PS) and those with pancreatic insufficiency (PI). Therefore, we hypothesized that the sterol analysis may contribute to study the digestion and absorption state of lipids in patients with CF. To this aim we evaluated plasma sterols in a significant number of adult patients with CF in relation to the pancreatic status. Methods Beside cholesterol, we measured phytosterols and lathosterol as markers of intestinal absorption and hepatic biosynthesis, respectively, by gas-chromatography in plasma of adult CF patients with pancreatic sufficiency (PS-CF, n = 57), insufficiency (PI-CF, n = 97) and healthy subjects (control group, CT, n = 71). Results PI-CF patients had cholesterol and phytosterols levels significantly lower than PS-CF and CT (p < 5 × 10-10) suggesting a reduced intestinal absorption of sterols related to PI. Instead, lathosterol was significantly higher in PI-CF patients than PS-CF and CT (p < 0.0003) indicating an enhanced cholesterol biosynthesis. In PI-CF patients, phytosterols positively correlate with vitamin E (p = 0.004). Both the classes of molecules need cholesterol esterase for the intestinal digestion, thus the reduced levels of such lipids in serum from PI-CF patients may depend on a reduced enzyme activity, despite the pancreatic enzyme supplementation in all PI-CF patients. Conclusions A plasma sterols profile may be useful to evaluate the metabolic status of lipids in adult patients with CF and could help to manage the pancreatic enzyme supplementation therapy.

Two CFTR mutations within codon 970 differently impact on the chloride channel functionality.

Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By complementary DNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of messenger RNA (mRNA) from patient's cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level to determine if the pharmacotherapy of CFTR basic defect is appropriate.

Adiponectin Expression Is Modulated by Long-Term Physical Activity in Adult Patients Affected by Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disease characterized by progressive decline of lung function and chronic airway inflammation. Adipose tissue, through adiponectin and leptin, exerts several effects on energy metabolism and inflammatory processes. This study evaluated the levels of adiponectin and leptin in adult healthy subjects, in patients with CF and their correlation with long-term physical activity. CF patients were divided into two groups (sedentary versus active) based on their regular physical activity over 3 years. Anthropometric and serum biochemical profiles of CF patients and controls were evaluated and compared. Total serum adiponectin and leptin levels were measured by ELISA; adiponectin oligomeric profiles were analysed by western blot. Adiponectin levels were significantly higher while leptin levels were lower in patients with CF than in healthy controls. Furthermore, adiponectin was significantly lower in active compared to sedentary CF (p = 0.047), while leptin was slightly increased in active compared to sedentary CF. In addition, C-reactive protein levels were significantly lower in active than in sedentary CF patients (p = 0.048). Interestingly, only in the active group adiponectin levels were inversely correlated with forced expiratory volume (FEV) 1% decrease/year and FEV1% decrease. Moreover, adiponectin levels negatively correlated with lipid profiles. Our findings indicated that regular, long-term physical activity in CF improves respiratory function, metabolism, and inflammation status. These improvements in patients' conditions are associated with immunometabolic processes involving adiponectin, leptin, and C-reactive protein. Therefore, we propose that both adipokines may be a useful biomarker in the evaluation of metabolic and inflammatory status in patients with CF.

Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles.

BACKGROUND: The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. OBJECTIVES: To describe the genotype-phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator (CFTR) complex alleles. METHODS: We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele. RESULTS: The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I-II mutation. Their CFTR activity on NEC was comparable with patients with two class I-II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I-II mutation in trans, or CFTR-related disorders (CFTR-RD) in three having in trans a class IV-V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I-II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I-II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3-36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I-II mutation had mild CF or CFTR-RD (gating activity: 18.5-19.0%). CONCLUSIONS: The effect of complex alleles partially depends on the mutation in trans. Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction.

Twelve Novel Mutations in the SLC26A3 Gene in 17 Sporadic Cases of Congenital Chloride Diarrhea.

OBJECTIVES: We aimed to improve the knowledge of pathogenic mutations in sporadic cases of congenital chloride diarrhea (CCD) and emphasize the importance of functional studies to define the effect of novel mutations. METHODS: All member 3 of solute carrier family 26 (SLC26A3) coding regions were sequenced in 17 sporadic patients with CCD. Moreover, the minigene system was used to analyze the effect of 2 novel splicing mutations. RESULTS: We defined the SLC26A3 genotype of all 17 patients with CCD and identified 12 novel mutations. Using the minigene system, we confirmed the in silico prediction of a complete disruption of splicing pattern caused by 2 of these novel mutations: the c.971+3_971+4delAA and c.735+4_c.735+7delAGTA. Moreover, several prediction tools and a structure-function prediction defined the pathogenic role of 6 novel missense mutations. CONCLUSIONS: We confirm the molecular heterogeneity of sporadic CCD adding 12 novel mutations to the list of known pathogenic mutations. Moreover, we underline the importance, for laboratories that offer molecular diagnosis and genetic counseling, to perform fast functional analysis of novel mutations.

Identification of miR-494 direct targets involved in senescence of human diploid fibroblasts.

Cellular senescence is a permanent cell cycle arrest triggered by different stimuli. We recently identified up-regulation of microRNA (miR)-494 as a component of the genetic program leading to senescence of human diploid IMR90 fibroblasts. Here, we used 2-dimensional differential gel electrophoresis (2D-DIGE) coupled to mass spectrometry to profile protein expression changes induced by adoptive overexpression of miR-494 in IMR90 cells. miR-494 induced robust perturbation of the IMR90 proteome by significantly (P≤0.05) down-regulating a number of proteins. Combination of mass spectrometry-based identification of down-regulated proteins and bioinformatic prediction of the miR-494 binding sites on the relevant mRNAs identified 26 potential targets of miR-494. Among them, computational analysis identified 7 potential evolution-conserved miR-494 targets. Functional miR-494 binding sites were confirmed in 3'-untranslated regions (UTRs) of 4 of them [heterogeneous nuclear ribonucleoprotein A3 (hnRNPA3), protein disulfide isomerase A3 (PDIA3), UV excision repair protein RAD23 homolog B (RAD23B), and synaptotagmin-binding cytoplasmic RNA-interacting protein (SYNCRIP)/heterogeneous nuclear ribonucleoprotein Q (hnRNPQ)]. Their reduced expression correlated with miR-494 up-regulation in senescent cells. RNA interference-mediated knockdown of hnRNPA3 and, to a lesser extent, RAD23B mirrored the senescent phenotype induced by miR-494 overexpression, blunting cell proliferation and causing up-regulation of SA-ß-galactosidase and DNA damage. Ectopic expression of hnRNPA3 or RAD23B slowed the appearance of the senescent phenotype induced by miR-494. Overall, these findings identify novel miR-494 direct targets that are involved in cellular senescence.

Age and sex mediated effects of estrogen and Β3-adrenergic receptor on cardiovascular pathophysiology.

Sex differences are consistently identified in determining the prevalence, manifestation, and response to therapies in several systemic disorders, including those affecting the cardiovascular (CV), skeletal muscle, and nervous system. Interestingly, such differences are often more noticeable as we age. For example, premenopausal women experience a lower risk of CV disease than men of the same age. While at an advanced age, with menopause, the risk of cardiovascular diseases and adverse outcomes increases exponentially in women, exceeding that of men. However, this effect appears to be reversed in diseases such as pulmonary hypertension, where women are up to seven times more likely than men to develop an idiopathic form of the disease with symptoms developing ten years earlier than their male counterparts. Explaining this is a complex question. However, several factors and mechanisms have been identified in recent decades, including a role for sex hormones, particularly estrogens and their related receptors. Furthermore, an emerging role in these sex differences has also been suggested for ß-adrenergic receptors (ßARs), which are essential regulators of mammalian physiology. It has in fact been shown that ßARs interact with estrogen receptors (ER), providing further demonstration of their involvement in determining sexual differences. Based on these premises, this review article focused on the ß3AR subtype, which shows important activities in adipose tissue but with new and interesting roles in regulating the function of cardiomyocytes and vascular cells. In detail, we examined how ß3AR and ER signaling are intertwined and whether there would be sex- and age-dependent specific effects of these receptor systems.

The relevance of prothrombotic genetic variants in women who experienced pregnancy loss or embryo implantation failure: A retrospective analysis of 1922 cases.

OBJECTIVE: The aim of our study was that to assess the allelic and genotype frequencies of nine prothrombotic gene variants in patients with a history of pregnancy loss and recurrent pregnancy loss (RPL). Women who underwent assisted reproductive technology (ART) with ongoing pregnancy and those with recurrent implantation failure (RIF) were also included. METHODS: Nine prothrombotic gene variants were evaluated: factor V Leiden (FVL), factor V, H1299R variant (FVR2), factor II (FII) G20210A, methylene-tetrahydrofolate reductase (MTHFR) C677T and A1298C, beta-fibrinogen -455G>A, factor XIII (FXIII) V34L, human platelet antigen-1 (HPA-1) L33P variants, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G. The following study groups were assessed: (1) women who experienced one (n = 334) or two (n = 264) episodes of pregnancy loss; (2) 468 women who experienced RPL; (3) 214 women who underwent ART followed by ongoing pregnancies; and (4) 282 women who experienced RIF after ART, that is, three or more consecutive implantation failures following high-quality embryo transfers to the uterus with an appropriate endometrium. As control group, 430 subjects from the general population were enrolled. RESULTS: FVL, the -455G>A variant of beta-fibrinogen, and PAI-1 4G were associated with a higher risk of developing RPL compared with the general population. Furthermore, FVL, FVR2, FII G20210A and MTHFR C677T conferred a significantly higher risk of RIF in women who performed ART compared with the general population. No statistical differences between the general population and other study groups were observed. CONCLUSIONS: Specific prothrombotic genetic variants are more frequently expressed in women with RPL and RIF, supporting their role in the development of polimicrothrombosis and impairing the invasion during embryo implantation.

Inducible Nitric Oxide Synthase (iNOS): Why a Different Production in COVID-19 Patients of the Two Waves?

Profound clinical differences between the first and second waves of COVID-19 were observed in Europe. Nitric oxide (NO) may positively impact patients with Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection. It is mainly generated by inducible nitric oxide synthase (iNOS). We studied serum iNOS levels together with serum interleukin (IL)-6 and IL-10 in patients with SARS-CoV-2 infection in the first wave (n = 35) and second wave (n = 153). In the first wave, serum iNOS, IL-6, IL-10 levels increased significantly, in line with the World Health Organization (WHO) score severity, while in the second wave, iNOS did not change with the severity. The patients of the second wave showed lower levels of iNOS, IL-6, and IL-10, as compared to the corresponding subgroup of the first wave, suggesting a less severe outcome of COVID-19 in these patients. However, in the severe patients of the second wave, iNOS levels were significantly lower in patients treated with steroids or azithromycin before the hospitalization, as compared to the untreated patients. This suggests an impairment of the defense mechanism against the virus and NO-based therapies as a potential therapy in patients with low iNOS levels.

Matrix metalloproteinases (MMP) 3 and 9 as biomarkers of severity in COVID-19 patients.

The molecular basis of the wide clinical heterogeneity of Coronavirus disease 2019 (COVID-19) is still unknown. Matrix metalloproteinases (MMPs) may have a role in the lung damage and regeneration that occur in severe patients. We studied serum MMP3 and MMP9 as potential biomarkers of COVID-19 severity, in 108 hospitalized patients with different World Health Organization (WHO) severity stage and in 48 controls. At hospital admission, serum MMP3 was increased in COVID-19 patients with a significant trend along the progression of the WHO stage, while serum levels of MMP9 were significantly increased in COVID-19 patients with no correlation with disease severity. At 1 week from hospitalization, MMP3 was reduced, suggesting an early pathogenic role of the protein in lung inflammation, while MMP9 levels were further increased, indicating a late role of the protein in the inflammatory process, specifically during the repairing phase. Furthermore, serum MMP9 was positively correlated with serum interleukin-6, myeloperoxidase, and circulating neutrophils and monocytes number. In conclusion, serum MMP3 may help to early predict the severity of COVID-19 and both proteins, MMP3 and MMP9, may contribute to define severe COVID-19 patients that may benefit from a targeted therapy on MMPs.

NGS Gene Panel Analysis Revealed Novel Mutations in Patients with Rare Congenital Diarrheal Disorders.

Congenital diarrheal disorders (CDDs) are early-onset enteropathies generally inherited as autosomal recessive traits. Most patients with CDDs require rapid diagnosis as they need immediate and specific therapy to avoid a poor prognosis, but their clinical picture is often overlapping with a myriad of nongenetic diarrheal diseases. We developed a next-generation sequencing (NGS) panel for the analysis of 92 CDD-related genes, by which we analyzed patients suspect for CDD, among which were (i) three patients with sucrose-isomaltase deficiency; (ii) four patients with microvillous inclusion disease; (iii) five patients with congenital tufting enteropathy; (iv) eight patients with glucose-galactose malabsorption; (v) five patients with congenital chloride diarrhea. In all cases, we identified the mutations in the disease-gene, among which were several novel mutations for which we defined pathogenicity using a combination of bioinformatic tools. Although CDDs are rare, all together, they have an incidence of about 1%. Considering that the clinical picture of these disorders is often confusing, a CDD-related multigene NGS panel contributes to unequivocal and rapid diagnosis, which also reduces the need for invasive procedures.

Elexacaftor-Tezacaftor-Ivacaftor Therapy for Cystic Fibrosis Patients with The F508del/Unknown Genotype.

The new CFTR modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta) was approved by the FDA in October 2019 for treatment of Cystic Fibrosis in patients 6 years of age or older who have at least one F508del mutation in one allele and a minimal-function or another F508del mutation in the other allele. However, there is a group of patients, in addition to those with rare mutations, in which despite the presence of a F508del in one allele, it was not possible to identify any mutation in the other allele. To date, these patients are excluded from treatment with Trikafta in Italy, where the CF patients carrying F508del/unknown represent about 1.3% (71 patients) of the overall Italian CF patients. In this paper we show that the Trikafta treatment of nasal epithelial cells, derived from F508del/Unknown patients, results in a significant rescue of CFTR activity. Based on our findings, we think that the F508del/Unknown patients considered in this study could obtain clinical benefits from Trikafta treatment, and we strongly suggest their eligibility for this type of treatment. This study, adding further evidence in the literature, once again confirms the validity of functional studies on nasal cells in the cystic fibrosis theratyping and personalized medicine.

Lung Microbiome in Cystic Fibrosis.

The defective mucociliary clearance due to CFTR malfunctioning causes predisposition to the colonization of pathogens responsible for the recurrent inflammation and rapid deterioration of lung function in patients with cystic fibrosis (CF). This has also a profound effect on the lung microbiome composition, causing a progressive reduction in its diversity, which has become a common characteristic of patients affected by CF. Although we know that the lung microbiome plays an essential role in maintaining lung physiology, our comprehension of how the microbial components interact with each other and the lung, as well as how these interactions change during the disease's course, is still at an early stage. Many challenges exist and many questions still to be answered, but there is no doubt that manipulation of the lung microbiome could help to develop better therapies for people affected by CF.

Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508). METHODS: Cholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin. RESULTS: Before the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced. CONCLUSIONS: These data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.

Age-Related Differences in the Expression of Most Relevant Mediators of SARS-CoV-2 Infection in Human Respiratory and Gastrointestinal Tract.

Background: Clinical features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seem to differ in children compared to that in adults. It has been hypothesized that the lower clinical severity in children could be influenced by differential expression of the main host functional receptor to SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), but data are still conflicting. To explore the origin of age-dependent clinical features of coronavirus disease 2019 (COVID-19), we comparatively evaluated the expression in children and adult subjects of the most relevant mediators of the SARS-CoV-2 infection: ACE2, angiotensin-converting enzyme 1 (ACE1), transmembrane serine protease-2 (TMPRSS2), and neuropilin-1 (NRP1), at upper respiratory tract and small intestine level. Methods: The expression of ACE2, ACE1, TMPRSS2, and NRP1 in nasal epithelium and in small intestine epithelium was investigated by quantitative real-time PCR analysis. Results: We found no differences in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium comparing children and adult subjects. In contrast, nasal epithelium NRP1 expression was lower in children compared to that in adults. Intestinal ACE2 expression was higher in children compared to that in adults, whereas intestinal ACE1 expression was higher in adults. Intestinal TMPRSS2 and NRP1 expression was similar comparing children and adult subjects. Conclusions: The lower severity of SARS-CoV-2 infection observed in children may be due to a different expression of nasal NRP1, that promotes the virus interaction with ACE2. However, the common findings of intestinal symptoms in children could be due to a higher expression of ACE2 at this level. The insights from these data will be useful in determining the treatment policies and preventive measures for COVID-19.

Corrigendum: Age-Related Differences in the Expression of Most Relevant Mediators of SARS-CoV-2 Infection in Human Respiratory and Gastrointestinal Tract.

[This corrects the article DOI: 10.3389/fped.2021.697390.].

A Transient Increase in the Serum ANCAs in Patients with SARS-CoV-2 Infection: A Signal of Subclinical Vasculitis or an Epiphenomenon with No Clinical Manifestations? A Pilot Study.

A relationship is emerging between SARS-CoV-2 infections and ANCA-associated vasculitis (AAV) because: (i) the pulmonary involvement of COVID-19 may mimic that observed in patients with AAV; (ii) the two diseases may occur together; (iii) COVID-19 may trigger AAV. However, few cases of AAV have been identified so far in COVID-19 patients. To define the frequency of ANCA autoimmunity in patients with SARS-CoV-2 infection, we analyzed the serum ANCAs and the serum PR3 and MPO antigens by immunoassays in 124 adult patients with a diagnosis of SARS-CoV-2 infection (16 were asymptomatic and 108 were hospitalized) and 48 control subjects. The serum ANCAs were significantly higher in the hospitalized patients compared with either the controls or the asymptomatic patients and increased with the progression of the COVID-19 severity. After one week of hospitalization, the values were significantly lower. In contrast, no differences emerged among the controls, asymptomatic and hospitalized patients for the PR3 and MPO serum levels. None of the patients had clinical signs of AAV with the exception of a severe pulmonary involvement. Further studies are necessary to define whether the increase in the serum ANCAs might mask subclinical vasculitis in a percentage of patients with SARS-CoV-2 infection or it is an epiphenomenon of SARS-CoV-2 infection with no clinical manifestations.

Further Findings Concerning Endothelial Damage in COVID-19 Patients.

Systemic vascular damage with micro/macro-thrombosis is a typical feature of severe COVID-19. However, the pathogenesis of this damage and its predictive biomarkers remain poorly defined. For this reason, in this study, serum monocyte chemotactic protein (MCP)-2 and P- and E-selectin levels were analyzed in 204 patients with COVID-19. Serum MCP-2 and P-selectin were significantly higher in hospitalized patients compared with asymptomatic patients. Furthermore, MCP-2 increased with the WHO stage in hospitalized patients. After 1 week of hospitalization, MCP-2 levels were significantly reduced, while P-selectin increased in patients in WHO stage 3 and decreased in patients in WHO stages 5-7. Serum E-selectin was not significantly different between asymptomatic and hospitalized patients. The lower MCP-2 levels after 1 week suggest that endothelial damage triggered by monocytes occurs early in COVID-19 disease progression. MCP-2 may also predict COVID-19 severity. The increase in P-selectin levels, which further increased in mild patients and reduced in severe patients after 1 week of hospitalization, suggests that the inactive form of the protein produced by the cleavage of the active protein from the platelet membrane is present. This may be used to identify a subset of patients that would benefit from targeted therapies. The unchanged levels of E-selectin in these patients suggest that endothelial damage is less relevant.