Italian good practice recommendations on management of persons with Long-COVID.

A significant number of people, following acute SARS-CoV-2 infection, report persistent symptoms or new symptoms that are sustained over time, often affecting different body systems. This condition, commonly referred to as Long-COVID, requires a complex clinical management. In Italy new health facilities specifically dedicated to the diagnosis and care of Long-COVID were implemented. However, the activity of these clinical centers is highly heterogeneous, with wide variation in the type of services provided, specialistic expertise and, ultimately, in the clinical care provided. Recommendations for a uniform management of Long-COVID were therefore needed. Professionals from different disciplines (including general practitioners, specialists in respiratory diseases, infectious diseases, internal medicine, geriatrics, cardiology, neurology, pediatrics, and odontostomatology) were invited to participate, together with a patient representative, in a multidisciplinary Panel appointed to draft Good Practices on clinical management of Long-COVID. The Panel, after extensive literature review, issued recommendations on 3 thematic areas: access to Long-COVID services, clinical evaluation, and organization of the services. The Panel highlighted the importance of providing integrated multidisciplinary care in the management of patients after SARS-CoV-2 infection, and agreed that a multidisciplinary service, one-stop clinic approach could avoid multiple referrals and reduce the number of appointments. In areas where multidisciplinary services are not available, services may be provided through integrated and coordinated primary, community, rehabilitation and mental health services. Management should be adapted according to the patient's needs and should promptly address possible life-threatening complications. The present recommendations could provide guidance and support in standardizing the care provided to Long-COVID patients.

Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6.

BACKGROUND: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. OBJECTIVE: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. METHODS: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. RESULTS: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean ± standard deviation 3.47 ± 1.90 vs. 8.03 ± 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels ≥ 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir. CONCLUSIONS: This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients.

Candidemia in Patients with Body Temperature Below 37°C and Admitted to Internal Medicine Wards: Assessment of Risk Factors.

BACKGROUND: An increasing number of candidemia episodes has been reported in patients cared for in internal medicine wards. These usually older and frail patients may not be suspected as having candidemia because they lack fever at the onset of the episode. To identify the risk factors associated with the lack of fever at the onset of candidemia (ie, the collection of the first positive blood culture for Candida spp.) in patients cared for in internal medicine wards, we compared 2 group of patients with or without fever. METHODS: We retrospectively review data charts from 3 tertiary care, university hospitals in Italy, comparing patients with or without fever at onset of candidemia. Consecutive candidemic episodes in afebrile patients and matched febrile controls were identified during the 3-year study period. Patient baseline characteristics and several infection-related variables were examined. Random forest analysis was used, given the number of predictors to be considered and the potential complexity of their relations with the onset of fever. RESULTS: We identified 147 candidemic episodes without fever at onset and 147 febrile candidemia episodes. Factors associated with the lack of fever at onset of candidemia were diabetes, Clostridium difficile infection, and a shorter delta time from internal medicine wards admission to the onset of candidemia. The only variable associated with fever was the use of intravascular devices. Quite unexpectedly, antifungal therapy was administered more frequently to patients without fever, and no differences on 30-day mortality rate were documented in the 2 study groups. CONCLUSIONS: Clinicians should be aware that an increasing number of patients with invasive candidiasis cared for in internal medicine wards may lack fever at onset, especially those with diabetes and C. difficile infection. Candidemia should be suspected in patients with afebrile systemic inflammatory response syndrome or in worsening clinical condition: blood cultures should be taken, and a timely and appropriate antifungal therapy should be considered.