Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis

Abstract

Background: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome.

Methods: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models.

Results: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region.

Interpretation: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission.

Fig 1. PRISMA flow diagram.

IPD = individual patient data.

Fig 2. Characteristics of patients in the individual patient data (IPD) database.

Fig 3. Locations of 1979 patients from 83 studies providing individual patient data (IPD).

WHO regions are depicted in different colours. Countries from which we received IPD are depicted in a darker shade. Country names and numbers of patients for which we had IPD are displayed in boxes, grouped according to region.

Fig 4. Time-to-event analyses for secondary outcomes for patients with COVID-19 and neurological disease in the IPD database¹.

1. These figures show results of analyses for the whole IPD database (i.e., patients with any neurological disease diagnosis), and other than for A, the analyses use death as a competing risk. 2. A total of 1745 patients were included in this analysis. Of the 1979, 115 had no dates; 14 patients had no hospital admission date; 9 dead patients had no date of death; 88 alive patients had no discharge date; it was unknown if 8 patients were dead or alive. For time to death, individuals that were alive at discharge or last follow-up were censored. 3. This analysis uses date of hospital admission as day 0. A total of 1428 patients were included in this analysis: 404 patients had no dates; 17 had no hospital admission date; 123 (23 dead; 100 alive) patients had neither the date of admission to critical care or the date of commencement of invasive ventilation; 7 patients only had a hospital admission date, but it was unknown if they were dead or alive. For time to critical care admission, individuals who were alive at discharge or last follow-up and had not been admitted to intensive care were censored. Individuals who died without receiving critical care or invasive ventilation were treated as competing events in a competing risks analysis. 4. This analysis uses date of critical care admission as day 0. A total of 486 patients who were admitted critical care were included in this analysis: 1482 patients had no date of admission to critical care; 5 dead patients had no death date; 5 alive patients had no hospital discharge date; there were no dates for 1 patient. 5. For discharge from critical care, individuals that were alive and not yet discharged at last follow-up were censored. Individuals that died after admission to intensive care were treated as competing events in a competing risks analysis. 10. For length of hospital stay, individuals that were alive and not yet discharged at last follow-up were censored. Individuals that died were treated as competing events in a competing risks analysis.

Fig 5. Pooled proportions of all patients hospitalised with COVID-19 reported to have acute new-onset neurological disease.

Neurological disease = number of patients with neurological COVID-19 disease. All COVID-19 = number of patients with all COVID-19 disease hospitalised in the same centre over the same time period.