Soluble uric acid inhibits ß2 integrin-mediated neutrophil recruitment in innate immunity.

Neutrophils are key players during host defense and sterile inflammation. Neutrophil dysfunction is a characteristic feature of the acquired immunodeficiency during kidney disease. We speculated that the impaired renal clearance of the intrinsic purine metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-12 mg/dL) related or unrelated to kidney dysfunction significantly diminished neutrophil adhesion and extravasation in mice with crystal- and coronavirus-related sterile inflammation using intravital microscopy and an air pouch model. This impaired neutrophil recruitment was partially reversible by depleting UA with rasburicase. We validated these findings in vitro using either neutrophils or serum from patients with kidney dysfunction-related HU with or without UA depletion, which partially normalized the defective migration of neutrophils. Mechanistically, sUA impaired ß2 integrin activity and internalization/recycling by regulating intracellular pH and cytoskeletal dynamics, physiological processes that are known to alter the migratory and phagocytic capability of neutrophils. This effect was fully reversible by blocking intracellular uptake of sUA via urate transporters. In contrast, sUA had no effect on neutrophil extracellular trap formation in neutrophils from healthy subjects or patients with kidney dysfunction. Our results identify an unexpected immunoregulatory role of the intrinsic purine metabolite sUA, which contrasts the well-known immunostimulatory effects of crystalline UA. Specifically targeting UA may help to overcome certain forms of immunodeficiency, for example in kidney dysfunction, but may enhance sterile forms of inflammation.

The Impact of the SARS-CoV-2 Pandemic on Healthcare Provision in Italy to non-COVID Patients: a Systematic Review.

BACKGROUND: Italy has been one of the countries most affected by the SARS-CoV-2 pandemic, and the regional healthcare system has had to quickly adapt its organization to meet the needs of infected patients. This has led to a drastic change in the routine management of non-communicable diseases with a potential long-term impact on patient health care. Therefore, we investigated the management of non-COVID-19 patients across all medical specialities in Italy. METHODS: A PRISMA guideline-based systematic review of the literature was performed using PubMed, Embase, and Scopus, restricting the search to the main outbreak period in Italy (from February 20 to June 25 2020). We selected articles in English or Italian that detailed changes in the Italian hospital care for non-COVID-19 patients due to the pandemic. Our keywords included all medical specialities combined with our geographical focus (Italy) and COVID-19. RESULTS: Of the 4643 potentially eligible studies identified by the search, 247 were included. A decrease in the management of emergencies in non-COVID patients was found together with an increase in mortality. Similarly, non-deferrable conditions met a tendency toward decreased diagnosis. All specialities have been affected by the re-organization of healthcare provision in the hub-and-spoke system and have benefited from telemedicine. CONCLUSIONS: Our work highlights the changes in the Italian public healthcare system to tackle the developing health crisis due to the COVID-19 pandemic. The findings of our review may be useful to analyse future directions for the healthcare system in the case of new pandemic scenarios.

Novel Criteria for When and How to Exit a COVID-19 Pandemic Lockdown.

In the first month of 2020, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus spreading quickly via human-to-human transmission, caused the coronavirus disease 2019 (COVID-19) pandemic. Italy installed a successful nationwide lockdown to mitigate the exponential increase of case numbers, as the basic reproduction number R0 reached 1 within 4 weeks. But is R0 really the relevant criterion as to whether or not community spreading is under control? In most parts of the world, testing largely focused on symptomatic cases, and we thus hypothesized that the true number of infected cases and relative testing capacity are better determinants to guide lockdown exit strategies. We employed the SEIR model to estimate the numbers of undocumented cases. As expected, the estimated numbers of all cases largely exceeded the reported ones in all Italian regions. Next, we used the numbers of reported and estimated cases per million of population and compared it with the respective numbers of tests. In Lombardy, as the most affected region, testing capacity per reported new case seemed between two and eight most of the time, but testing capacity per estimated new cases never reached four up to April 30. In contrast, Veneto's testing capacity per reported and estimated new cases were much less discrepant and were between four and 16 most of the time. As per April 30 also Marche, Lazio and other Italian regions arrived close to 16 ratio of test capacity per new estimated infection. Thus, the criterion to exit a lockdown should be decided at the level of the regions, based on the local testing capacity that should reach 16 times the estimated true number of newly infected cases as predicted.

The COVID-19 infection: lessons from the Italian experience.

The first case of the new coronavirus, COVID-19, was reported in China on 17 November 2019. By the end of March 2020, the rapid global spread of infection affected over 1 million people. Italy is one of the countries most impacted, with over 100,000 positive cases identified. The first detected cases were reported on 21 February 2020 in two Italian towns: Vo' Euganeo in the Province of Padua, Veneto region, and Codogno, in the Province of Lodi, Lombardy. In the next weeks the epidemic spread quickly across the country but mainly in the north of Italy. The two regions: Veneto and Lombardy, implemented different strategies to control the viral spread. In Veneto, health personnel tested both symptomatic and asymptomatic subjects, while in Lombardy only symptomatic cases were investigated. We analyzed the evolution of the epidemic in these regions and showed that testing both symptomatic and asymptomatic cases is a more effective strategy to mitigate the epidemic impact. We strongly recommend that decision-makers: ensure early isolation of symptomatic patients and rapid identification of their contacts; maximize testing rapidly, especially among people with multiple daily contacts with infected populations, high exposure to the public in essential services; rapidly increase diagnostic capacity by mobilizing trained personnel capable of performing rRT-PCR on respiratory samples; equip the population with protective masks.