In a recent study published in the journal Brain, researchers reported that brain injury is common in coronavirus disease 2019 (COVID-19) and influenza.
COVID-19 has been linked to neurological complications such as stroke, autoimmune encephalitis and Guillain-Barré syndrome. Although physical brain injury is evident in neurological syndromes related to COVID-19, such as encephalitis and stroke, several reports suggest that brain injury associated with COVID-19 could occur even in the absence of of a concomitant neurological diagnosis. In addition, the exaggerated inflammatory response during COVID-19 could lead to progression to severe disease.
Study: Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses. Image credit: sfam_photo / Shutterstock
About the study
In the present study, the researchers investigated host markers of the dysregulated immune response. We included polymerase chain reaction (PCR)-positive COVID-19 patients admitted to University Hospital Cambridge between March 2020 and March 2021. In addition, the patient cohort was supplemented with a sample of convenience for patients with COVID-19 at Sahlgrenska University Hospital, Sweden.
Healthy subjects were recruited before the COVID-19 pandemic as controls. Pooled clinical and plasma data from patients with influenza from an independent trial were used as an additional control cohort. A small positive control group was included as a reference for the magnitude of brain injury biomarker elevations. This group consisted of patients with acute severe traumatic brain injury.
Serum samples were collected from admission and convalescence to three time points: acute stages (< 14 dies), subagudes (de 15 a 70 dies) i de convalescència (> 80 days; ambulatory). Influenza/COVID-19 patients were divided into three severity groups (mild, moderate, and severe) based on treatment during the acute phase. Mild patients did not require supplemental oxygen, moderate patients required supplemental oxygen, and severe patients required mechanical ventilation.
Glial fibrillary acidic protein (GFAP), neurofilament lumen (NfL), and total tau concentrations were measured in sera from patients with COVID-19 or plasma from patients with influenza. Autoantibodies were screened using a custom CNS protein microarray. In addition, serum concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-10, interferon (IFN)-γ, and IL-6 were quantified using multiplexed particle-based flow cytometry.
discoveries
The researchers obtained 250 samples from 175 patients with COVID-19 and control samples from 59 healthy subjects and 45 patients with influenza. Seventy patients with COVID-19 had mild disease, 72 had moderate disease, and 33 patients had severe disease. GFAP, total tau and NfL concentrations were above the functional lower limit of quantification for most healthy control and COVID-19 patient samples.
Notably, serum concentrations of GFAP and NfL increased with severity of COVID-19 at acute and subacute time points, consistent with levels observed in subjects with severe traumatic brain injury. No differences in total tau levels were observed between patients and controls. Longitudinal samples were available for 67 patients, allowing study of temporal dynamics.
The authors noted that NfL and GFAP concentrations decreased over time, although some patients showed increased NfL concentration between acute and subacute periods. Serum GFAP concentrations were not different between patients and controls at the time of convalescence. However, serum NfL concentrations at the time of convalescence were higher in patients with moderate or severe disease than in controls.
The increase in total tau concentration did not vary with disease severity. Convalescence levels of serum GFAP and NfL correlated with paired samples collected between 15 and 42 days, whereas total tau concentrations did not. In addition, GFAP and NfL concentrations in plasma collected from severely ill influenza patients were elevated to levels comparable to those in patients with COVID-19.
Patients with COVID-19 showed obvious IgG reactivity to spike and nucleocapsid proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in particular to lung surfactant protein A (SFTPA1). SFTPA1 reactivity was higher in subacute samples from moderate and severe patients than in mild patients or healthy controls. This autoantibody has not been described in the context of COVID-19.
In addition, autoantibody profiles of cohorts were compared by determining the number and targets of positive autoantibody hits to specific antigens. Patients with COVID-19 had more IgG and IgM autoantibody hits than healthy controls. Antimyelin-associated glycoprotein (anti-MAG) was the most common IgG autoantibody, followed by anti-SFTPA1 autoantibody detected in 9.6% and 8.8% of COVID-19 samples, respectively . Both autoantibodies were not detected in healthy controls.
Increased serum cytokine levels were observed in subacute samples and many convalescent samples had elevated cytokine concentrations above the normal range. Patients with moderate and severe COVID-19 had elevated levels of pro-inflammatory cytokines. The team then investigated associations between biomarkers of brain injury and inflammatory profiles (cytokine and autoantibody responses).
There was a positive correlation between serum levels of NfL and GFAP and the number of IgG hits. However, total tau concentrations were not associated with IgG hits or cytokine profiles. The number of IgM hits correlated with serum levels of NfL, but not with total tau or GFAP concentrations. Of note, the researchers found a correlation between the number of IgM hits and all brain injury biomarkers, especially total tau levels, during convalescence.
Conclusions
The present study demonstrated elevated concentrations of brain injury biomarkers in patients with COVID-19, which increased with disease severity during acute infection. These elevations correlate with the presence of autoantibodies and proinflammatory cytokines. Furthermore, there was evidence of a dysregulated immune response even after four months. Notably, autoantibodies against brain antigens did not predict stronger brain injury than those against non-brain antigens.
This meant that the brain injury occurred due to general dysregulated immunity and not due to directly pathogenic autoantibodies. In addition, data from influenza patients indicated that brain injury during acute SARS-CoV-2 infection was not unique to COVID-19. Overall, the findings revealed the association of brain injury biomarkers with dysregulated immunity in COVID-19.