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.

Analytical and clinical performances of five immunoassays for the detection of SARS-CoV-2 antibodies in comparison with neutralization activity.

BACKGROUND: Reliable high-throughput serological assays for SARS-CoV-2 antibodies are urgently needed for the effective containment of the COVID-19 pandemic, as it is of crucial importance to understand the strength and duration of immunity after infection, and to make informed decisions concerning the activation or discontinuation of physical distancing restrictions. METHODS: In 184 serum samples from 130 COVID-19 patients and 54 SARS-CoV-2 negative subjects, the analytical and clinical performances of four commercially available chemiluminescent assays (Abbott SARS-Cov-2 IgG, Roche Elecsys anti-SARS-CoV-2, Ortho SARS-CoV-2 total and IgG) and one enzyme-linked immunosorbent assay (Diesse ENZY-WELL SARS-CoV-2 IgG) were evaluated and compared with the neutralization activity achieved using the plaque reduction neutralization test (PRNT). FINDINGS: Precision results ranged from 0.9% to 11.8% for all assays. Elecsys anti-SARS-CoV-2 demonstrated linearity of results at concentrations within the cut-off value. Overall, sensitivity ranged from 78.5 to 87.7%, and specificity, from 97.6 to 100%. On limiting the analysis to samples collected 12 days after onset of symptoms, the sensitivity of all assays increased, the highest value (95.2%) being obtained with VITRO Anti-SARS-CoV-2 Total and Architect SARS-CoV-2 IgG. The strongest PRNT50 correlation with antibody levels was obtained with ENZY-Well SARS-CoV-2 IgG (R2adj = 0.569). INTERPRETATION: The results confirmed that all immunoassays had an excellent specificity, whereas sensitivity varied across immunoassays, depending strongly on the time interval between symptoms onset and sample collection. Further studies should be conducted to achieve a stronger correlation between antibody measurement and PRNT50 in order to obtain useful information for providing a better management of COVID-19 patients, effective passive antibody therapy, and developing a vaccine against the SARS-CoV-2 virus. FUNDING: None.

Diagnostic performances and thresholds: The key to harmonization in serological SARS-CoV-2 assays?

BACKGROUND: The evaluation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibody (Ab) assay performances is of the utmost importance in establishing and monitoring virus spread in the community. In this study focusing on IgG antibodies, we compare reliability of three chemiluminescent (CLIA) and two enzyme linked immunosorbent (ELISA) assays. METHODS: Sera from a total of 271 subjects, including 64 reverse transcription-polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 patients were tested for specific Ab using Maglumi (Snibe), Liaison (Diasorin), iFlash (Yhlo), Euroimmun (Medizinische Labordiagnostika AG) and Wantai (Wantai Biological Pharmacy) assays. Diagnostic sensitivity and specificity, positive and negative likelihood ratios were evaluated using manufacturers' and optimized thresholds. RESULTS: Optimized thresholds (Maglumi 2 kAU/L, Liaison 6.2 kAU/L and iFlash 15.0 kAU/L) allowed us to achieve a negative likelihood ratio and an accuracy of: 0.06 and 93.5% for Maglumi; 0.03 and 93.1% for Liaison; 0.03 and 91% for iFlash. Diagnostic sensitivities and specificities were above 93.8% and 85.9%, respectively for all CLIA assays. Overall agreement was 90.3% (Cohen's kappa = 0.805 and SE = 0.041) for CLIA, and 98.4% (Cohen's kappa = 0.962 and SE = 0.126) for ELISA. CONCLUSIONS: The results obtained indicate that, for CLIA assays, it might be possible to define thresholds that improve the negative likelihood ratio. Thus, a negative test result enables the identification of subjects at risk of being infected, who should then be closely monitored over time with a view to preventing further viral spread. Redefined thresholds, in addition, improved the overall inter-assay agreement, paving the way to a better harmonization of serologic tests.

IgA-Ab response to spike glycoprotein of SARS-CoV-2 in patients with COVID-19: A longitudinal study.

Validation studies of serological antibody tests must be properly designed for clinical, epidemiological and Public Health objectives such as confirmation of suspected COVID-19 cases, certification of seroconversion after infection, and epidemiological surveillance. We evaluated the kinetics of IgM, IgA and IgG SARS-CoV-2 antibodies in COVID-19 patients with confirmed (rRT-PCR) infection. We found that the IgA response appears and grows early, peaks at week 3, and it is stronger and more persistent than the IgM response. Further longitudinal investigations of virus-specific antibodies functions and of their protective efficacy over time are needed.