Neurological diagnoses in hospitalized COVID-19 patients associated with adverse outcomes: A multinational cohort study

Meghan R. Hutch, Jiyeon Son, Trang T. Le, Chuan Hong, Xuan Wang, Zahra Shakeri Hossein Abad, Michele Morris, Alba Gutiérrez-Sacristán, Jeffrey G. Klann, Anastasia Spiridou, Ashley Batugo, Riccardo Bellazzi, Vincent Benoit, Clara-Lea Bonzel, William A. Bryant, Lorenzo Chiudinelli, Kelly Cho, Priyam Das, Tomás González González, David A. Hanauer, Darren W. Henderson, Yuk-Lam Ho, Ne Hooi Will Loh, Adeline Makoudjou, Simran Makwana, Alberto Malovini, Bertrand Moal, Danielle L. Mowery, Antoine Neuraz, Malarkodi Jebathilagam Samayamuthu, Fernando J. Sanz Vidorreta, Emily R. Schriver, Petra Schubert, Jeffery Talbert, Amelia L. M. Tan, Byorn W. L. Tan, Bryce W. Q. Tan, Valentina Tibollo, Patric Tippman, Guillaume Verdy, William Yuan,Paul Avillach, Nils Gehlenborg, Gilbert S. Omenn, The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), Shyam Visweswaran, Tianxi Cai, Yuan Luo, Zongqi Xia

Few studies examining the patient outcomes of concurrent neurological manifestations during acute COVID-19 leveraged multinational cohorts of adults and children or distinguished between central and peripheral nervous system (CNS vs. PNS) involvement. Using a federated multinational network in which local clinicians and informatics experts curated the electronic health records data, we evaluated the risk of prolonged hospitalization and mortality in hospitalized COVID-19 patients from 21 healthcare systems across 7 countries. For adults, we used a federated learning approach whereby we ran Cox proportional hazard models locally at each healthcare system and performed a meta-analysis on the aggregated results to estimate the overall risk of adverse outcomes across our geographically diverse populations. For children, we reported descriptive statistics separately due to their low frequency of neurological involvement and poor outcomes.

After exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), both adults and children experience a wide range of acute neurological manifestations. Following the start of the pandemic, early case series [1–5] and small cohort studies from single healthcare systems [6–9] reported the occurrence of acute neurological manifestations in adults with Coronavirus-19 (COVID-19). Neurological diagnoses during acute COVID-19 such as ischemic stroke [10], intracranial hemorrhage [3], seizures [4], or meningoencephalitis [5] were associated with adverse clinical outcomes in adults, including higher rates of in-hospital mortality [6,9,11] and lower rates of home discharge [6]. Additionally, altered mental status and stroke significantly increased in-hospital mortality regardless of disease severity [9].

Each participating healthcare system obtained Institutional Review Board (IRB) approval from local governing ethics committee, each with an approval of a waiver of informed consent for both adults and children, because access of de-identified data and external sharing of summary statistics (without interaction with the patients) are deemed minimal risk.

IRB Approval was obtained at Assistance Publique—Hôpitaux de Paris, Boston Children’s Hospital, Bordeaux University Hospital, Great Ormond Street Hospital for Children, ASST Papa Giovanni XXIII Bergamo, Istituti Clinici Scientifici Maugeri, Hospital Universitario 12 de Octubre, Madrid, Spain, Massachusetts General Brigham, National University Hospital, Northwestern University, Medical Center at University of Freiburg, University of Kentucky, University of Pittsburgh/UPMC, VA North Atlantic, VA Southwest, VA Midwest, VA Continental, and VA Pacific. An exempt determination was made by the IRB at University of California Los Angeles, University of Michigan, and University of Pennsylvania.

Patient characteristics
We analyzed data from 106,229 PCR-confirmed hospitalized patients with acute COVID-19 from 21 healthcare systems across 7 countries (Table 1, Fig 2, S1 Table). The US Veterans Affairs hospital system (comprising 170 hospitals) was divided into five regional healthcare systems, capturing broad geographic representations within the US. Males represented 65% of the overall study population. While 79% of the patients were 50 years or older, the study included 2,198 (2%) patients who were younger than 18 years of age.

Leveraging a large, geographically diverse, multinational cohort, we investigated the clinical outcomes of hospitalized COVID-19 patients with concurrent neurological diagnoses. Our unique study design adopted a federated framework in which local clinician and informatics experts at each participating healthcare system ensured critical EHR data quality control while preserving data confidentiality. The consistent findings across geographically diverse healthcare systems support the generalizability and validity of our study.

In this large multinational and geographically diverse cohort with a federated framework for leveraging locally curated EHR data for clinical discovery, we analyzed the clinical outcomes of both hospitalized adult and pediatric COVID-19 patients with concurrent CNS or PNS diagnosis. Adults with concurrent CNS diagnosis during COVID-19 hospitalization harbored greater burden of pre-existing health conditions and had greater risk of poor clinical outcomes (prolonged hospitalization and death) when compared to those with PNS diagnosis or no neurological diagnosis. We observed similar patterns in children though the overall low frequency of events prohibited a formal survival analysis.

Citation: Hutch MR, Son J, Le TT, Hong C, Wang X, Shakeri Hossein Abad Z, et al. (2024) Neurological diagnoses in hospitalized COVID-19 patients associated with adverse outcomes: A multinational cohort study. PLOS Digit Health 3(4): e0000484.

Editor: Jie Xu, University of Florida, UNITED STATES

Received: August 17, 2023; Accepted: March 6, 2024; Published: April 15, 2024

Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: The 4CE does not have permission from each contributing healthcare system to release patient-level electronic health records (EHR) data for public access. We have made it publicly available the summary statistics provided by each contributing healthcare system and a data dictionary as well as the code for the analysis (

Funding: MM and SV are supported by National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) UL1 TR001857. RB is supported by EU PROJECT H2020 PERISCOPE – 101016233. KC is supported by VA MVP000 and CIPHER. DAH is supported by NCATS UL1TR002240. DWH and JT are supported by NIH UL1TR001998. DLM is supported by NCATS UL1-TR001878. FJSV is supported by NCATS UL1TR001881. BWQT is supported by National Medical Research Council Research Training Fellowship (MOH-000195-00). WY is supported by NIH T32HD040128. GSO is supported by NIH P30ES017885; U24CA210967. YL is supported by NCATS U01TR003528 and National Library of Medicine (NLM) 1R01LM013337. ZX is supported by National Institute of Neurological Disorders and Stroke (NINDS) R01NS098023 and R01NS124882. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: All authors report no competing interests or conflicts of interest. JGK reports a consulting relationship with the i2b2-tranSMART Foundation through Invocate, Inc. RB reports being a shareholder of Biomeris s.r.l. and Engenome s.r.l. DAH reports entitled to royalties from the University of Michigan for licensing of the EMERSE "synonyms". AM’s work is being funded by the Federal Ministry of Education and Research (BMBF) in Germany in the framework of the MIRACUM Consortium. AM reports being a shareholder of Biomeris s.r.l. BM reports being co-founder and equity owner from DESKI. DLM has received research support from the National Institutes of Health, Department of Veteran Affairs, and the University of Pittsburgh/Pittsburgh Health Data Alliance outside of this work. PA reports consulting for CCHMC and BCH. NG is a co-founder and equity owner of Datavisyn. ZX has served as a Consultant for Genentech/Roche. The institution of ZX has received research support from the National Institute of Health, the National Multiple Sclerosis Society, Food and Drug Administration, the Pittsburgh Foundation, the PNC Charitable Trust, the Ethel Vincent Trust, and Genentech / Roche.