Dottorato in ADVANCES IN INFECTIOUS DISEASES, MICROBIOLOGY, LEGAL
MEDICINE AND PUBLIC HEALTH SCIENCES

Titolo della tesi: Monitoring CJD notification during COVID-19 pandemic in Italy (from 2017 to 2022)

Monitoring CJD notification during COVID-19 pandemic in Italy (from 2017 to 2022) Background: Creutzfeldt-Jakob disease (CJD) and related syndromes are rare human diseases belonging to the wide group of Transmissible spongiform encephalopathies (TSEs) or prion diseases. Humans TSEs include sporadic, genetic, iatrogenic and infectious forms. TSEs are caused by transmissible agents called prions wich replicates in the CNS leading to a characteristic neurodegenerative picture including spongiosis, glyosis, neuron loss and the deposition of the pathological prion protein (PrPTSE). Surveillance of human TSEs has been established in 1993 in Italy and contributed to the identification and recording of variant CJD in Europe and in Italy. Objectives: We conducted the retrospective study using the 2017-2022 Italian Creutzfeldt-Jakob disease register data to assess the incidence rate of CJD during this 5-year-period in Italy, and to identify the influence of the COVID-19 pandemic on the overall incidence rate, case notifications and survival time. Methods: A total of 1114 patients were included, (554 females), with 769 classified as Pre-COVID and 345 as Post-COVID. We collected all the cases ascertained by 14-3-3 positivity, a positive result in the real-time quaking-induced conversion (RT-QuIC) assay using CSF, the Prion protein gene (PRNP) testing, the range of PRNP mutations, brain MRI abnormalities, electroencephalogram findings and median survival time. Kaplan-Meier (KM) curves were used to estimate survival probabilities, with group differences evaluated via the log-rank test. The impact of covariates on survival was analyzed using a multivariable Cox proportional hazards model, with results reported as hazard ratios (HRs) and 95% confidence intervals (CIs). A p-value e <0.05 was considered statistically significant. All analyses were conducted using R software (version 4.4.2). Results: CJD notifications declined slightly in 2020 (16.3%) and 2021 (16.2%) and further decreased to 9.9% in 2022. We found that atypical EEG findings were more frequent in the pre-COVID period (60.5%) compared to post-COVID (49.1%). Conversely, both protein 14.3.3 positivity and RT-QuIC positivity increased in post-COVID period. Survival was significantly longer in the pre-COVID period (5.03 months) compared to 3.02 months in the post-COVID period. Males had a median survival of 4.01 months, while females had 4.99 months. Lastly, post-COVID cases exhibited a higher frequency of Met/Met PRNP polymorphism and 210 mutations. Conclusion: Even if CJD surveillance mechanisms have been optimised and diagnostic testing capabilities improved, nevertheless prognostication in sCJD remains a significant challenge. Moreover, we cannot rule out that COVID-19 infection might be implicated in fostering the clinical onset, but not disease pathogenesis in prion disease.