Immunogenicity and Safety of the BNT162b2 COVID-19 Vaccine in Patients with Cystic Fibrosis with or without Lung Transplantation.

Cystic fibrosis (CF) is characterized by a progressive decline in lung function, which may be further impaired by viral infections. CF is therefore considered a comorbidity of coronavirus disease 2019 (COVID-19), and SARS-CoV-2 vaccine prioritization has been proposed for patients with (pw)CF. Poor outcomes have been reported in lung transplant recipients (LTR) after SARS-CoV-2 infections. LTR have also displayed poor immunization against SARS-CoV-2 after mRNA-based BNT162b2 vaccination, especially in those undergoing immunosuppressive treatment, mostly those receiving mycophenolate mofetil (MMF) therapy. We aimed to determine here the immunogenicity and safety of the BNT162b2 vaccine in our cohort of 260 pwCF, including 18 LTR. Serum levels of neutralizing anti-SARS-CoV-2 IgG and IgA antibodies were quantified after the administration of two doses. PwCF displayed a vaccine-induced IgG and IgA antiviral response comparable with that seen in the general population. We also observed that the immunogenicity of the BNT162b2 vaccine was significantly impaired in the LTR subcohort, especially in patients undergoing MMF therapy. The BNT162b2 vaccine also caused minor adverse events as in the general population, mostly after administration of the second dose. Overall, our results justify the use of the BNT162b2 vaccine in pwCF and highlight the importance of a longitudinal assessment of the anti-SARS-CoV-2 IgG and IgA neutralizing antibody response to COVID-19 vaccination.

High Plasma Levels of Activated Factor VII-Antithrombin Complex Point to Increased Tissue Factor Expression in Patients with SARS-CoV-2 Pneumonia: A Potential Link with COVID-19 Prothrombotic Diathesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), in which coagulation abnormalities and endothelial dysfunction play a key pathogenic role. Tissue factor (TF) expression is triggered by endothelial dysfunction. Activated factor VII-antithrombin (FVIIa-AT) complex reflects indirectly FVIIa-TF interaction and has been proposed as a potential biomarker of prothrombotic diathesis. FVIIa-AT plasma concentration was measured in 40 patients (30 males and 10 females; 64.8 ± 12.3 years) admitted with SARS-CoV-2 pneumonia during the first pandemic wave in Italy. Two sex- and age-matched cohorts without COVID-19, with or without signs of systemic inflammation, were used to compare FVIIa-AT data. The FVIIa-AT plasma levels in COVID-19 patients were higher than those in non-COVID-19 subjects, either with or without inflammation, while no difference was observed among non-COVID-19 subjects. The association between COVID-19 and FVIIa-AT levels remained significant after adjustment for sex, age, C-reactive protein, renal function, fibrinogen, prothrombin time and activated partial thromboplastin time. Our results indicate that SARS-CoV-2 infection, at least during the first pandemic wave, was characterized by high FVIIa-AT levels, which may suggest an enhanced FVIIa-TF interaction in COVID-19, potentially consistent with SARS-CoV-2-induced endotheliopathy.

Heparin: The Journey from Parenteral Agent to Nasal Delivery.

Although the worldwide usage of direct oral anticoagulants has continuously increased over the past decade, heparin remains an important weapon in the current arsenal of anticoagulant drugs. Parenteral heparin administration (i.e., either intravenously or subcutaneously) has represented for decades the only possible route for generating a significant anticoagulant effect, although being notoriously associated with some important drawbacks such as discomfort and risk of low compliance, thus paving the way to searching for more amenable means of administration. We provide here an updated analysis of animal and human studies that have explored the feasibility, suitability, and efficiency of heparin administration through the unconventional nasal route, as a possible alternative to the more traditional parenteral injection. The major hurdles that contribute to impair intranasal absorption and systemic delivery of heparin are represented by its relatively high molecular weight and negative charge. Therefore, although pure drug administration would not be associated with efficient nasal adsorption, or by systemic biological activity (i.e., anticoagulant effect), the combination of low molecular weight heparins and absorption enhancers such as surfactants, mucoadhesive, cyclodextrins, polyethylenimines and encapsulation into (nano)carriers seems effective to at least partially improve drug transport through the nasal route and allow systemic delivery in animals. Besides generating anticoagulant effects, intranasal heparin administration can also produce local pleiotropic effects, mostly related to anti-inflammatory properties, such as attenuating airway allergic inflammation or inhibiting the binding of the spike protein of some coronaviruses (including severe acute respiratory syndrome coronavirus 2) to their host cell receptors. This preliminary evidence represents a valuable premise for planning future studies in humans aimed at establishing the pharmacokinetics and biological activity of locally and systemically delivered intranasal heparin formulations.

Homocysteine in coronavirus disease (COVID-19): a systematic literature review.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) is a life-threatening infectious disorder characterized by a sustained prothrombotic state. Since homocysteine is a potential biomarker of thrombotic diseases, the aim of this article is to provide an updated overview on the possible role played by hyperhomocysteinemia in influencing an unfavorable COVID-19 progression. METHODS: We carried out an electronic search in Medline (PubMed interface) using the keywords ("COVID-19" OR "SARS-CoV-2") AND "homocysteine", between 2019 and the present time, with no language restrictions, to identify all articles which explored the concentration of homocysteine in COVID-19 patients with or without unfavorable disease progression. RESULTS: Three studies, totaling 694 hospitalized COVID-19 patients, were included in our systematic review. Overall, the differences between the mean homocysteine values in non-severe vs. severe COVID-19 patients were always positive (i.e., 15.1%, 24.1% and 22.8%, generating a positive weight mean difference of 1.75 µmol/L (95%CI, 1.26-2.25 µmol/L; p=0.011), which translates into a cumulative difference of approximately ∼1.2 µmol/L. CONCLUSIONS: Despite the limited evidence that has been garnered so far, increased homocysteine ​​levels may be a potentially useful marker for predicting the risk of unfavorable progression in patients with COVID-19.

Artificial intelligence at the time of COVID-19: who does the lion's share?

OBJECTIVES: The development and use of artificial intelligence (AI) methodologies, especially machine learning (ML) and deep learning (DL), have been considerably fostered during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Several models and algorithms have been developed and applied for both identifying COVID-19 cases and for assessing and predicting the risk of developing unfavourable outcomes. Our aim was to summarize how AI is being currently applied to COVID-19. METHODS: We conducted a PubMed search using as query MeSH major terms "Artificial Intelligence" AND "COVID-19", searching for articles published until December 31, 2021, which explored the possible role of AI in COVID-19. The dataset origin (internal dataset or public datasets available online) and data used for training and testing the proposed ML/DL model(s) were retrieved. RESULTS: Our analysis finally identified 292 articles in PubMed. These studies displayed large heterogeneity in terms of imaging test, laboratory parameters and clinical-demographic data included. Most models were based on imaging data, in particular CT scans or chest X-rays images. C-Reactive protein, leukocyte count, creatinine, lactate dehydrogenase, lymphocytes and platelets counts were found to be the laboratory biomarkers most frequently included in COVID-19 related AI models. CONCLUSIONS: The lion's share of AI applied to COVID-19 seems to be played by diagnostic imaging. However, AI in laboratory medicine is also gaining momentum, especially with digital tools characterized by low cost and widespread applicability.

Performance of non-invasive respiratory function indices in predicting clinical outcomes in patients hospitalized for COVID-19 pneumonia in medical and sub-intensive wards: a retrospective cohort study.

Coronavirus disease 2019 (COVID-19) is a newly recognized infectious disease which can lead to acute respiratory distress syndrome requiring ventilatory support and intensive care unit admission. The aim of our study is to evaluate the performance of two non-invasive respiratory function indices (the ROX index and the SatO2/FiO2 ratio), as compared to the traditional PaO2/FiO2 ratio, in predicting a clinically relevant composite outcome (death or intubation) in hospitalized patients for COVID-19 pneumonia. Four hospital centers in Northern Italy conducted an observational retrospective cohort study during the first wave of COVID-19 pandemic. Four hundred and fifty-six patients with COVID-19 pneumonia admitted to medical or sub-intensive wards were enrolled. Clinical, laboratory, and respiratory parameters, for the calculation of different indices, were measured at hospital admission. In medical wards (Verona and Padua) the PaO2/FiO2 ratio, ROX index and SatO2/FiO2 ratio were able to predict intubation or death with good accuracy (AUROC for the PaO2/FiO2 ratio, ROX index and SatO2/FiO2 ratio of 75%, 75% and 74%, respectively). Regarding sub-intensive wards (Milan and Mantua), none of the three respiratory function indices was significantly associated with the composite outcome. In patients admitted to medical wards for COVID-19 pneumonia, the ROX index and the SatO2/FiO2 ratio demonstrated not only good performance in predicting intubation or death, but their accuracy was comparable to that of the PaO2/FiO2 ratio. In this setting, where repeated arterial blood gas tests are not always feasible, they could be considered a reliable alternative to the invasive PaO2/FiO2 ratio.

Variation of Forehead Temperature during Routine Working Shift in Hospital Laboratory Personnel: Implications for SARS-CoV-2 Screening.

BACKGROUND: Scarce information is available on circadian body temperature fluctuation in healthy healthcare workers. METHODS: Forehead temperature was measured with an infrared thermometer in 33 ostensibly healthy laboratory professionals (mean age, 43 ± 13 years; 76% females) throughout a regular working shift, from 800 AM to 300 PM, at 1-hour intervals. RESULTS: A significant difference was found at different times of the day by 1-way analysis of variance (F statistics, 13.79; p < 0.001). The lowest mean forehead temperature was 36.2 ± 0.3℃, recorded at 100 PM, whilst the highest was 36.7 ± 0.3℃, at 900 AM. The mean difference between forehead temperature at acrophase and nadir was 0.5℃ (95% CI, 0.3-0.6℃; p < 0.001). The forehead temperature measured between 900-1200 AM was also significantly higher than that measured between 100-300 PM (0.3℃; 95% CI, 0.2-0.4℃; p < 0.001). The mean intra-individual variation of forehead temperature was higher but not significantly different in men (1.0 ± 0.2%) compared to women (0.8 ± 0.3%; p = 0.112). CONCLUSION: Fever screening protocols for purposes of coronavirus disease 2019 (COVID-19) and other infectious diseases monitoring should consider normal daily fluctuations in forehead temperature.

Comparison of five commercial anti-SARS-CoV-2 total antibodies and IgG immunoassays after vaccination with BNT162b2 mRNA.

BACKGROUND: Since universal vaccinations represents the most effective strategy to mitigate coronavirus disease 2019 (COVID-19), baseline assessment and post-vaccine monitoring of anti-SARS-CoV-2 neutralizing antibodies are essential to vaccination programs. Therefore, this study aimed to compare data of five commercial anti-SARS-CoV2 immunoassays after administration of an mRNA vaccine. METHODS: Venous blood was collected from three healthcare workers, receiving a double (30 g) dose of BNT162b2 mRNA Covid-19 vaccine (Comirnaty, Pfizer), on the day of the first vaccine dose and then at fixed intervals for the following 2 months. Anti-SARS-CoV-2 neutralizing antibody response was assayed with Roche Total Ig anti-RBD (receptor binding domain), DiaSorin TrimericS IgG (spike trimer), Beckman Coulter IgG anti-RBD, SNIBE IgG anti-RBD and Technogenetics IgG anti-N/S1. RESULTS: A total number of 45 samples were drawn at the end of the 2-month study period. The Spearman's correlations of absolute anti-SARS-CoV-2 antibodies were always excellent (all p<0.001), comprised between 0.967-0.994. Satisfactory results were also observed when absolute antiSARS-CoV-2 antibodies values of the five methods were compared with the mean consensus value, with correlations always higher than 0.979 (all p<0.001). The agreement of anti-SARS-CoV-2 antibodies positivity versus the consensus median positivity ranged between 0.764 and 1.000 (always p<0.001), but become always >0.900 after readjustment of one assay cutoff. CONCLUSIONS: All the immunoassays evaluated in this study appear suitable for monitoring anti-SARS-CoV-2 neutralizing antibodies response in subjects undergoing mRNA COVID-19 vaccination.

Comprehensive assessment of humoral response after Pfizer BNT162b2 mRNA Covid-19 vaccination: a three-case series.

OBJECTIVES: Since universal vaccination is a pillar against coronavirus disease 2019 (COVID-19), monitoring anti-SARS-CoV-2 neutralizing antibodies is essential for deciphering post-vaccination immune response. METHODS: Three healthcare workers received 30 µg BNT162b2 mRNA Covid-19 Pfizer Vaccine, followed by a second identical dose, 21 days afterwards. Venous blood was drawn at baseline and at serial intervals, up to 63 days afterwards, for assessing total immunoglobulins (Ig) anti-RBD (receptor binding domain), anti-S1/S2 and anti-RBD IgG, anti-RBD and anti-N/S1 IgM, and anti-S1 IgA. RESULTS: All subjects were SARS-CoV-2 seronegative at baseline. Total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG levels increased between 91 and 368 folds until 21 days after the first vaccine dose, then reached a plateau. The levels raised further after the second dose (by ∼30-, ∼8- and ∼8-fold, respectively), peaking at day 35, but then slightly declining and stabilizing ∼50 days after the first vaccine dose. Anti-S1 IgA levels increased between 7 and 11 days after the first dose, slightly declined before the second dose, after which levels augmented by ∼24-fold from baseline. The anti-RBD and anti-N/S1 IgM kinetics were similar to that of anti-S1 IgA, though displaying substantially weaker increases and modest peaks, only 4- to 7-fold higher than baseline. Highly significant inter-correlation was noted between total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG (all r=0.99), whilst other anti-SARS-CoV-2 antibodies displayed lower, though still significant, correlations. Serum spike protein concentration was undetectable at all-time points. CONCLUSIONS: BNT162b2 mRNA vaccination generates a robust humoral immune response, especially involving anti-SARS-Cov-2 IgG and IgA, magnified by the second vaccine dose.