Objectives Aim of our study was to describe the incidence and predictive factors of secondary infections in patients with COVID-19. Methods Cohort study on patients hospitalized with COVID-19 at IRCCS San Raffaele Hospital between February 25 th and April 6th, 2020 (NCT04318366). We considered secondary bloodstream (BSIs) or possible lower respiratory tract infections (pLRTIs) occurred after 48 hours since hospital admission until death or discharge. We calculated multivariable Fine-Gray models, to assess factors associated with risk of secondary infections. Results Among 731 patients, a secondary infection was diagnosed in 68 patients (9.3%): 58/731 patients (7.9%) had at least one BSI and 22/731 patients (3.0%) at least one pLRTI. Overall 28-day cumulative incidence was 16.4% (95% CI 12.4% - 21.0%). The majority of BSIs was due to gram-positive pathogens (76/106 isolates, 71.7%), specifically coagulase-negative staphylococci (53/76, 69.7%), while among gram-negatives (23/106, 21.7%) Acinetobacter baumanii (7/23, 30.4%) and Escherichia coli (5/23, 21.7%) predominated. pLRTIs were mainly caused by gram-negative pathogens (14/26, 53.8%). Eleven patients were diagnosed with putative invasive aspergillosis. At multivariable analysis, factors associated with secondary infections were low baseline lymphocyte count ( < 0.7 vs >0.7 per 10 9 /L: subdistribution hazard ratios (sdHRs) 1.93 [95% CI 1.11-3.35]), baseline PaO 2 /FiO 2 (per 100-points lower: sdHRs 1.56 [95% CI 1.21-2.04]), and intensive-care unit (ICU) admission in the first 48 hours (sdHR 2.51 [95% CI 1.04-6.05]). Conclusions Patients hospitalized with COVID-19 had a high incidence of secondary infections. At multivariable analysis, early need for ICU, respiratory failure, and severe lymphopenia, were identified as risk factors for secondary infections.

Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV) infection of oligodendrocytes, may develop in patients with immune disorders following reactivation of chronic benign infection. Mutations of JCV capsid viral protein 1 (VP1), the capsid protein involved in binding to sialic acid cell receptors, might favor PML onset. Cerebrospinal fluid sequences from 37/40 PML patients contained one of several JCV VP1 amino acid mutations, which were also present in paired plasma but not urine sequences despite the same viral genetic background. VP1-derived virus-like particles (VLPs) carrying these mutations lost hemagglutination ability, showed different ganglioside specificity, and abolished binding to different peripheral cell types compared with wild-type VLPs. However, mutants still bound brain-derived cells, and binding was not affected by sialic acid removal by neuraminidase. JCV VP1 substitutions are acquired intrapatient and might favor JCV brain invasion through abrogation of sialic acid binding with peripheral cells, while maintaining sialic acid-independent binding with brain cells.

TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.

Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.