The impact of COVID-19 on people with bradykinin-mediated angioedema in the ITACA cohort

Background: The pandemic of Coronavirus disease 19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), has become a global challenge in the last two years. SARS-CoV- 2 enters the cells of the infected subjects through angiotensin converting enzyme 2 (ACE-2), leading to its depletion on cell surface. ACE-2 activity is involved in the catabolism of des-Arg( 9)-bradykinin and increases the expression of angiotensin converting enzyme (ACE) in animal models. ACE in turn inactivates bradykinin. The infection has therefore the potential to cause a deregulation of the contact system and its pro-inflammatory activity, which could also contribute to the pathogenesis of COVID-19. Since bradykinin-mediated angioedema is generally thought to be the result of a poorly regulated contact system, it has been speculated that these patients are prone to severe SARS-CoV- 2 infection and that COVID-19 can in turn elicit angioedema attacks. We examined these hypotheses in a large group of bradykinin-mediated angioedema patients. Method(s): W e c onducted a m ulticenter r etrospective s tudy t argeting all the patients with hereditary angioedema (HAE) or acquired angioedema due to C1 inhibitor deficiency followed up by the centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). All accessible patients underwent a telephone interview between January 1st and March 31st 2021;we collected data about demographic and angioedema features, the occurrence of SARS-CoV- 2 positivity and COVID-19 outcomes from the beginning of the pandemic until March 31st 2021. A digital diary of attacks developed by ITACA helped us to collect attacks data. 15 centers participated in the survey. Result(s): 677 patients were included;52/677 reported SARS-CoV- 2 positivity (48 with hereditary and 4 with acquired C1 inhibitor deficiency). The incidence was 7.68% (confidence interval 5,79-9,95%), similar to the general population (6.04%). 4/52 patients (7.7%) reported severe COVID-19;the median disease duration was 15 days. One patient suffered a pulmonary thromboembolism;no deaths were reported. 27/52 patients (51,9%) had angioedema attacks during the infection, with a median of 1 attack per patient;severity of COVID-19 predicted more frequent and more severe angioedema attacks in a multivariate analysis (p < 0.001). Conclusion(s): COVID-19 does not seem more severe in bradykinin-mediated angioedema than in the general population. SARS-CoV- 2 infection can elicit angioedema attacks.

Nitrogen dioxide pollution increases vulnerability to COVID-19 through altered immune function.

Previous ecological studies suggest the existence of possible interplays between the exposure to air pollutants and SARS-CoV-2 infection. Confirmations at individual level, however, are lacking. To explore the relationships between previous exposure to particulate matter < 10 µm (PM10) and nitrogen dioxide (NO2), the clinical outcome following hospital admittance, and lymphocyte subsets in COVID-19 patients with pneumonia. In 147 geocoded patients, we assessed the individual exposure to PM10 and NO2 in the 2 weeks before hospital admittance. We divided subjects according to the clinical outcome (i.e., discharge at home vs in-hospital death), and explored the lymphocyte-related immune function as an index possibly affecting individual vulnerability to the infection. As compared with discharged subjects, patients who underwent in-hospital death presented neutrophilia, lymphopenia, lower number of T CD45, CD3, CD4, CD16/56 + CD3 + , and B CD19 + cells, and higher previous exposure to NO2, but not PM10. Age and previous NO2 exposure were independent predictors for mortality. NO2 concentrations were also negatively related with the number of CD45, CD3, and CD4 cells. Previous NO2 exposure is a co-factor independently affecting the mortality risk in infected individuals, through negative immune effects. Lymphopenia and altered lymphocyte subsets might precede viral infection due to nonmodifiable (i.e., age) and external (i.e., air pollution) factors. Thus, decreasing the burden of air pollutants should be a valuable primary prevention measure to reduce individual susceptibility to SARS-CoV-2 infection and mortality.

Ongoing COVID-19 vaccination in Italy. Online survey of gender- and age-related side effects

Background: Evidences suggest that gender may influence the response to various vaccines in terms of immune response and side effects. Whether similar differences also occur with COVID-19 vaccine, is still uncertain. Materials and Methods: In March 2021, we advertised a short anonymous questionnaire (Google forms) to medical doctors, nurses, postgraduates, students and general public, consisting of 30 questions exploring 16 possible side effects (local pain or hardness, swelling, redness, allergic reaction, tiredness, headache, sleep disorders, myalgia, fever, enlarged lymph nodes, irritability, diarrhea, urticaria, vomiting, anaphylaxis). We recorded side effects after 1st dose, and within one week after 2nd dose. Data were analyzed according to gender and seven age groups. Results: We received 1,034 questionnaires from all over Italy (369 males, 665 females, age range 20-83 years). Injected vaccines were Pfizer-BioNTech (96.9%), Astra-Zeneca (2.4%), Moderna (0.7%). Major adverse events were absent. Minor adverse events occurred with both 1st dose (76.0%) and 2nd dose (78.0%) and were invariably higher in females than in males (1st dose: 79.4% vs 69.9% p = 0.0006;2nd dose: 81.8% vs 70.7%, p = 0.00004). The significant cluster of adverse events were local pain, redness, hardness at the injection site, fever, sleep disturbances, headache, lymph nodes enlargement following both doses (0.00001 < p < 0.02). Effects disappeared within 48hrs in 80% of cases (range 1-7 days). The gender difference was confirmed in the age class 30-39 after 1st dose (85.8% vs 70%, in females and males, respectively p = 0.03), and in the age classes 30-39 (84.6% vs 75.5%, in females and males, respectively p = 0.03) and 40-49 (74.8% vs 57.9%, in females and males, respectively p = 0.02) after 2nd dose. Fever tended to be more frequent in females after the 1st dose (6.5% vs 3.8%) and became significantly higher after the 2nd dose (32.9% vs 17.3%, p = 0.00001). After 50 years of age, the rate of all the recorded adverse events was similar between genders. Conclusions: COVID-19 vaccines generate frequent, although mild side effects with a gender (female) prevalence, especially in the age range 30-49 years. The gender difference disappears after 50 years of age, thus pointing to possible involvement of sex hormones and attenuated immune response.