A myriad of neurological symptoms has been associated with COVID-19. Thus, we conducted the first age- and sex-matched neuropathology study of COVID-19 ARDS cases to controls to investigate if SARS-CoV-2 confers a higher risk of ABI in COVID-19 vs. non-COVID-19 ARDS. Our study showed no difference in the frequency of ABI on postmortem examination of COVID-19 and non-COVID-19 ARDS patients.
The high frequency of ABI in both groups can potentially be a complication of severe ARDS, and not the specific etiology of lung injury. The brain-lung crosstalk, along with systemic inflammation and hypoxemia, is often offered as an explanation for neurological complications seen in ARDS.3 Prior clinical and autopsy studies have documented neurological complications in non-COVID-19 ARDS.3 In a matched case-control study, Shoskes et al. did not find a difference in ischemic and hemorrhagic ABI on brain MRI between COVID-19 and non-COVID-19 ARDS patients, with the exception of disseminated hemorrhagic leukoencephalopathy being more common in COVID-19 ARDS patients.6 Similarly, our study does not show a difference in ABI between patients that died of COVID-19 and non-COVID-19 ARDS.
Others have suggested that COVID-19 may have a predilection for the brainstem, with autopsy studies documenting pronounced neuro-inflammatory changes in COVID-19 infratentorial specimens.4 Immune dysfunction and vascular activation seen in these critical areas of the central nervous system may be responsible for some of the short- and long-term neurological symptoms.7 Although limited to basic histopathologic examination, our study found no differences between patients with ARDS due to COVID-19 versus other causes. Potential COVID-19-specific brainstem pathology might not be easily identifiable by standard brain autopsies and could require ancillary testing. Therefore, whether these reported brainstem-associated findings are specific to COVID-19 remains unknown.
Interestingly, intracapillary megakaryocytes have been reported in brain autopsies of COVID-19 patients,8 and were seen in 30% of COVID-19 cases in our study. Though previously hypothesized to be a potential contributor to COVID-19 related neurological complications, McMullen et al. reported that intracapillary megakaryocytes were not a specific marker of COVID-19, but instead seen in a multitude of acute lung pathologies.9 It seems unlikely that autopsy reports in the pre-pandemic era reported on this finding since they were only recently reported in literature.8 However, caution should be taken as this is a retrospective case-control study that may be biased to report more findings in COVID-19 samples.
COVID-19 ARDS patients had a higher frequency of vasculopathy noted on brain pathology in our study. COVID-19 has been associated with endothelial cell inflammation and vasculitis in both systemic and central nervous system (CNS).10 On review of vasculopathy cases in our study, majority of vasculopathy was attributed to long term arteriosclerotic changes and no acute vascular changes were noted on pathology. While COVID-19 has been associated with CNS vasculitis in a few case reports, our study did not find any evidence of CNS vasculitis in COVID-19 ARDS patients.
One major limitation of our study was the difference in PMI time between COVID-19 and non-COVID-19 ARDS patients. Concern about the risk of exposure to COVID-19, particularly at the start of the pandemic, was likely the main factor for prolonged PMI in the COVID-19 group. Prolonged PMI may have resulted in degradation of brain tissue and underestimation of ABI.11 Our study only reviewed autopsy reports, slides were not revaluated, and further staining for specific markers was not pursued for the purpose of the study. Though, it is standard for our pathologists to evaluate for inflammation on basic hematoxylin and eosin stains (H&E) and pursue further staining for specific markers if there is any concern. Intracapillary megakaryocytes in COVID-19 were also first identified on H&E and subsequent staining was only done to confirm their presence. While the process to evaluate all slides was similar, there may be a bias where pathologists were hypervigilant about any changes in COVID-19 patients.
While this is one of the first matched case-control study evaluating ABI in COVID-19 ARDS patients, the study is limited by a small sample size and single center structure. We did see a trend of higher events of infratentorial ABI, ischemic infarcts, herniation and edema in the COVID-19 group, though no established association with COVID-19 could be made. The small sample size can potentially miss certain brain pathologies related to COVID-19, so further assessment in a larger population is warranted.