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1.
Microorganisms ; 10(6)2022 Jun 10.
Article in English | MEDLINE | ID: covidwho-1884281

ABSTRACT

The severity of coronavirus disease 2019 (COVID-19) may be influenced by pre-existing immune responses against endemic coronaviruses, but conflicting data have been reported. We studied 148 patients who were hospitalised because of a confirmed diagnosis of COVID-19, classified mild in 58, moderate in 44, and severe in 46. The controls were 27 healthy subjects. At admission, blood samples were collected for the measurement of biomarkers of disease severity and levels of the IgG against the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and pre-existing coronaviruses OC43, HKU1, NL63 and 229E. Higher levels of IgG antibodies against the RBD of pre-existing coronavirus (with the highest significance for anti-HKU1 IgG, p = 0.01) were found in patients with mild disease, compared with those with moderate or severe disease. Multivariable logistic regression confirmed the association of high levels of antibodies to pre-existing coronavirus with mild disease and showed their associations with low levels of the complement activation marker SC5b-9 (p range = 0.007-0.05). High levels of anti-NL63 antibodies were associated with low levels of the coagulation activation marker D-dimer (p = 0.04), while high levels of IgG against 229E were associated with low levels of the endothelial activation marker von Willebrand factor (p = 0.05). Anti-SARS-CoV-2-neutralising activity of plasma positively correlated with anti-SARS-CoV-2 IgG (r = 0.53, p = 0.04) and with anti-HKU1 IgG (r = 0.51, p = 0.05). In hospitalised patients with COVID-19, high levels of antibodies to pre-existing coronaviruses are associated with mild disease, suggesting that their measurement could be useful in predicting the severity of the disease.

2.
J Allergy Clin Immunol ; 149(4): 1137-1149, 2022 04.
Article in English | MEDLINE | ID: covidwho-1773412

ABSTRACT

Urticarial vasculitis (UV) is a rare cutaneous vasculitis of small vessels characterized by recurrent episodes of wheal-like lesions that tend to last more than 24 hours, healing with a residual ecchymotic postinflammatory hyperpigmentation. The histopathologic pattern of UV is that of leukocytoclastic vasculitis, consisting of fibrinoid necrosis of dermal vessels' walls and neutrophil-rich perivascular inflammatory infiltrates. Although its etiopahogenesis remains still undefined, UV is now regarded as an immune complex-driven disease with activation of the complement cascade, leading to exaggerated production of anaphylatoxins that are responsible for neutrophil recruitment and activation. This condition can be categorized into 2 main entities according to serum complement levels: normocomplementemic UV and hypocomplementemic UV, the latter being associated with circulating anti-C1q autoantibodies and possible extracutaneous manifestations. Systemic multiorgan involvement may be seen particularly in syndromic hypocomplementemic UV, also known as McDuffie syndrome. This review summarizes the clinicopathological and laboratory features as well as the underlying pathophysiological mechanisms of UV. A focus on its main differential diagnoses is provided, that is, chronic spontaneous urticaria, bullous pemphigoid, IgA (Henoch-Schönlein purpura) and IgM/IgG immune complex vasculitis, lupus erythematous tumidus, Wells syndrome, erythema multiforme, cutaneous mastocytosis, cryopyrin-associated periodic syndromes, and coronavirus disease 2019-associated and anti-severe acute respiratory syndrome coronavirus 2-vaccine-associated urticarial eruptions.


Subject(s)
COVID-19 , Urticaria , Vasculitis, Leukocytoclastic, Cutaneous , Vasculitis , Antigen-Antibody Complex , Complement System Proteins , Diagnosis, Differential , Humans , Vasculitis/pathology , Vasculitis, Leukocytoclastic, Cutaneous/diagnosis , Vasculitis, Leukocytoclastic, Cutaneous/pathology
3.
Med Lav ; 112(6): 477-485, 2021 Dec 23.
Article in English | MEDLINE | ID: covidwho-1667925

ABSTRACT

BACKGROUND: In Italy, healthcare workers (HCWs) were among the first to receive COVID-19 vaccination. Aim of the present study is to evaluate frequency and severity of adverse events (AEs) following the second dose of BNT162b2 vaccine among HCWs of a large university hospital in Milan, Italy. METHODS: One month after having received the second dose of vaccine, HCWs filled-in a form about type, severity, and duration of post-vaccination local and systemic symptoms. We calculated the overall frequency of AEs and used multivariable Poisson regression models (adjusted for sex, age, BMI, smoking, allergy history, previous SARS-CoV-2 infection, anti-hypertensive therapy, and occupation) to calculate risk ratios (RR) and 95% confidence intervals (CI) of AEs according to selected variables. RESULTS: We included 3659 HCWs. Overall, 2801 (76.6%) experienced at least one local event, with pain at injection site being the most frequent (2788, 76.2%). Systemic events were reported by 2080 (56.8%) HCWs, with fatigue (52.3%), muscle pain (42.2%), headache (37.7%), joint pain (31.9%), and fever (26.2%) being the most frequent. Risks of systemic events were associated with female gender (RR=1.14, CI: 1.06-1.23), age (strong decrease with increasing age, p-trend<0.001), allergy history (RR=1.13, CI: 1.05-1.20), and current smoking (RR=0.90, CI: 0.84-0.97). HCWs with previous SARS-CoV-2 infection (even if symptomatic) were not at increased risk. CONCLUSIONS: Both local and systemic acute effects after second dose of BNT162b2 vaccine were frequently reported. However, symptoms were mostly light/mild and of short duration. Thus, our findings support the safety of COVID-19 vaccination in adults in relatively good health.


Subject(s)
COVID-19 Vaccines , COVID-19 , Adult , Female , Health Personnel , Hospitals , Humans , RNA, Messenger , SARS-CoV-2
4.
J Autoimmun ; 124: 102728, 2021 11.
Article in English | MEDLINE | ID: covidwho-1440155

ABSTRACT

Extremely rare reactions characterized by thrombosis and thrombocytopenia have been described in subjects that received ChAdOx1 nCoV-19 vaccination 5-16 days earlier. Although patients with vaccine-induced thrombotic thrombocytopenia (VITT) have high levels of antibodies to platelet factor 4 (PF4)-polyanion complexes, the exact mechanism of the development of thrombosis is still unknown. Here we reported serum studies as well as proteomics and genomics analyses demonstrating a massive complement activation potentially linked to the presence of anti-PF4 antibodies in a patient with severe VITT. At admission, complement activity of the classical and lectin pathways were absent (0% for both) with normal levels of the alternative pathway (73%) in association with elevated levels of the complement activation marker sC5b-9 (630 ng/mL [n.v. 139-462 ng/mL]) and anti-PF4 IgG (1.918 OD [n.v. 0.136-0.300 OD]). The immunoblotting analysis of C2 showed the complete disappearance of its normal band at 110 kDa. Intravenous immunoglobulin treatment allowed to recover complement activity of the classical pathway (91%) and lectin pathway (115%), to reduce levels of sC5b-9 (135 ng/mL) and anti-PF4 IgG (0.681 OD) and to normalize the C2 pattern at immunoblotting. Proteomics and genomics analyses in addition to serum studies showed that the absence of complement activity during VITT was not linked to alterations of the C2 gene but rather to a strong complement activation leading to C2 consumption. Our data in a single patient suggest monitoring complement parameters in other VITT patients considering also the possibility to target complement activation with specific drugs.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Complement C2 , Complement Membrane Attack Complex , Complement Pathway, Classical , Complement Pathway, Mannose-Binding Lectin , Purpura, Thrombotic Thrombocytopenic , SARS-CoV-2 , Adult , Autoantibodies/blood , COVID-19 Vaccines/administration & dosage , Complement C2/genetics , Complement C2/metabolism , Complement Membrane Attack Complex/genetics , Complement Membrane Attack Complex/metabolism , Complement Pathway, Classical/drug effects , Complement Pathway, Classical/genetics , Complement Pathway, Mannose-Binding Lectin/drug effects , Complement Pathway, Mannose-Binding Lectin/genetics , Female , Humans , Platelet Factor 4/blood , Purpura, Thrombotic Thrombocytopenic/blood , Purpura, Thrombotic Thrombocytopenic/chemically induced , Purpura, Thrombotic Thrombocytopenic/genetics
5.
Vaccines (Basel) ; 9(9)2021 Sep 11.
Article in English | MEDLINE | ID: covidwho-1411056

ABSTRACT

Urticarial eruptions and angioedema are the most common cutaneous reactions in patients undergoing mRNA COVID-19 vaccinations. The vasoactive peptide bradykinin has long been known to be involved in angioedema and recently also in urticaria. Bradykinin is mainly catabolized by angiotensin-converting enzyme (ACE), which is inhibited by ACE inhibitors, a commonly employed class of antihypertensive drugs. We evaluated the risk of developing urticaria/angioedema after inoculation with the BNT162b2 mRNA COVID-19 vaccine in a population of 3586 health care workers. The influences of ACE inhibitors and selected potential confounding variables (sex, age, previous SARS-CoV-2 infection, and allergy history) were evaluated by fitting univariate and multivariable Poisson regression models. The overall cumulative incidence of urticaria/angioedema was 1.8% (65 out of 3586; 95% CI: 1.4-2.3%). Symptoms were mild, and no subject consulted a physician. Subjects taking ACE inhibitors had an adjusted three-fold increased risk of urticaria/angioedema (RR 2.98, 95% CI: 1.12-7.96). When we restricted the analysis to those aged 50 years or more, the adjusted RR was 3.98 (95% CI: 1.44-11.0). In conclusion, our data indicate that subjects taking ACE inhibitors have an increased risk of urticaria/angioedema after vaccination with the BNT162b2 mRNA COVID-19 vaccine. Symptoms are mild and self-limited; however, they should be considered to adequately advise subjects undergoing vaccination.

8.
Adv Ther ; 38(5): 2709-2716, 2021 05.
Article in English | MEDLINE | ID: covidwho-1163169

ABSTRACT

INTRODUCTION: At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, controversial data were reported concerning angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) that induced a number of physicians to stop using them in patients with COVID-19. Although large-scale studies have ruled out this concern, it is common experience that patients with COVID-19 taking ACE inhibitors or ARBs are at increased risk of death. The aim of this study was to investigate the reasons for this apparently high mortality rate. METHODS: During the first wave of the pandemic, we conducted a field study of 427 consecutive patients with COVID-19 upon their admission to the emergency department of a hospital in one of the most severely hit cities in northern Italy, and 30 days later. The disease was defined as being mild, moderate or severe on the basis of clinical, laboratory and imaging data, and a multivariate model was used to analyse the determinants of mortality. RESULTS: Within 30 days of admission, 31.6% of the patients treated with ACE inhibitors or ARBs and 15.2% of those not treated with these drugs had died. Multivariate analysis showed that the determinants of mortality were age (p = 0.0001), hypertension (p = 0.0120) and diabetes (p = 0.0129), whereas ACE inhibitors or ARBs had no effect on mortality. There was no significant difference between the patients treated with ACE inhibitors and those treated with ARBs. CONCLUSION: The apparently increased mortality of patients with COVID-19 receiving long-term treatment with ACE inhibitors or ARBs is not due to the drugs themselves, but to the conditions associated with their use.


Subject(s)
COVID-19 , Hypertension , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Humans , Hypertension/drug therapy , Italy/epidemiology , Renin-Angiotensin System , SARS-CoV-2
9.
J Autoimmun ; 117: 102595, 2021 02.
Article in English | MEDLINE | ID: covidwho-1014585

ABSTRACT

BACKGROUND: Genetic variation at a multigene cluster at chromosome 3p21.31 and the ABO blood group have been associated with the risk of developing severe COVID-19, but the mechanism remains unclear. Complement activation has been associated with COVID-19 severity. OBJECTIVE: The aim of this study was to examine whether chromosome 3p21.31 and the ABO variants are linked to the activation of the complement cascade in COVID-19 patients. METHODS: We considered 72 unrelated European hospitalized patients with genetic data and evaluation of circulating C5a and soluble terminal complement complex C5b-9 (SC5b-9). Twenty-six (36.1%) patients carried the rs11385942 G>GA variant and 44 (66.1%) non-O blood group associated with increased risk of severe COVID-19. RESULTS: C5a and SC5-b9 plasma levels were higher in rs11385949 GA carriers than in non-carriers (P = 0.041 and P = 0.012, respectively), while C5a levels were higher in non-O group than in O group patients (P = 0.019). The association between rs11385949 and SC5b-9 remained significant after adjustment for ABO and disease severity (P = 0.004) and further correction for C5a (P = 0.018). There was a direct relationship between upper airways viral load and SC5b-9 in carriers of the rs11385949 risk allele (P = 0.032), which was not observed in non-carriers. CONCLUSIONS: The rs11385949 G>GA variant, tagging the chromosome 3 gene cluster variation and predisposing to severe COVID-19, is associated with enhanced complement activation, both with C5a and terminal complement complex, while non-O blood group with C5a levels. These findings provide a link between genetic susceptibility to more severe COVID-19 and complement activation.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/genetics , Chromosomes, Human, Pair 3/genetics , Complement Activation/genetics , Genotype , Multigene Family/genetics , Aged , Complement C5a/genetics , Disease Progression , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Hospitalization , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk , SARS-CoV-2/physiology , Viral Load
10.
J Autoimmun ; 116: 102560, 2021 01.
Article in English | MEDLINE | ID: covidwho-899086

ABSTRACT

BACKGROUND: Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet. OBJECTIVE: To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients. METHODS: In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma. RESULTS: The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels. CONCLUSIONS: Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.


Subject(s)
Biomarkers/blood , COVID-19/blood , Complement Activation/physiology , Endothelium, Vascular/physiopathology , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Male , Middle Aged , SARS-CoV-2
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