The impact of COVID-19 and vaccination status on outcomes in veterans with head and neck squamous cell carcinoma.

BACKGROUND: The impact of both COVID-19 infection and vaccination status on patients with head and neck squamous cell carcinoma (HNSCC) remains unknown. OBJECTIVE: To determine the impact of COVID-19 infection and vaccination status on 60-day mortality, cardiovascular, and respiratory complications in patients with a prior diagnosis of HNSCC. METHODS: This was a retrospective cohort study through the Veterans Affairs (VA) Corporate Data Warehouse of Veterans with HNSCC who were tested for COVID-19 during any inpatient VA medical center admission. A cohort of patients was created of Veterans with a diagnosis of HNSCC of the oral cavity,oropharynx, hypopharynx, larynx, and nasopharynx based on International Classification of Disease (ICD) codes. Data collected included clinical/demographic data, vaccination status, and incidence of 60-day mortality, 60-day cardiovascular complication (including myocardial infarction, venous thromboembolism, cerebrovascular accident), and 60-day respiratory complication (including acute respiratory failure, acute respiratory distress syndrome, and pneumonia). The interactions between COVID-19 infection, vaccination status, morbidity and mortality were investigated. RESULTS: Of the 14 262 patients with HNSCC who were tested for COVID-19 during inpatient admission, 4754 tested positive (33.3%), and 9508 (67.7%) tested negative. Patients who tested positive demonstrated increased 60-day mortality (4.7% vs. 2.0%, respectively; p < 0.001), acute respiratory failure (ARF; 15.4% vs. 7.1%, p < 0.001), acute respiratory distress syndrome (ARDS; 0.9% vs. 0.2%, p < 0.001), and pneumonia (PNA; 20.0% vs. 6.4%, p < 0.001) compared to those who never tested positive, respectively. Patients who received COVID-19 vaccination between 2 weeks and 6 months prior to a positive test demonstrated decreased rates of ARF (13.2% vs. 16.0%, p = 0.034) and PNA (16.7% vs. 20.9%, p = 0.003) compared to the unvaccinated group. A logistic regression of patients with COVID-19 infections who died within 60 days was performed, with no significant survival advantage among patients vaccinated between 2 weeks and 6 months prior to the positive test. CONCLUSION: COVID-19 infection may significantly increase rates of 60-day mortality and respiratory complications in patients with HNSCC. COVID-19 vaccination between 2 weeks and 6 months prior to infection may decrease severity of respiratory complications but did not show significant mortality benefits in this study. These data highlight the need for surveillance of respiratory infection and vaccination in this vulnerable population.

Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis.

Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n = 401) as well as a group with HS-aging without CTE (n = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.

Evolution of neuronal and glial tau isoforms in chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p-tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre-mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post-mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform-specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p-tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I-II), a 3R shift was observed in later stages (III-IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R-positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.

Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) consists of beta-amyloid deposition in the walls of the cerebrovasculature and is commonly associated with Alzheimer's disease (AD). However, the association of CAA with repetitive head impacts (RHI) and with chronic traumatic encephalopathy (CTE) is unknown. We evaluated the relationship between RHI from contact sport participation, CTE, and CAA within a group of deceased contact sport athletes (n = 357), a community-based cohort (n = 209), and an AD cohort from Boston University AD Center (n = 241). Unsupervised hierarchal cluster analysis demonstrated a unique cluster (n = 11) with increased CAA in the leptomeningeal vessels compared to the intracortical vessels (p < 0.001) comprised of participants with significantly greater frequencies of CTE (7/11) and history of RHI. Overall, participants with CTE (n = 251) had more prevalent (p < 0.001) and severe (p = 0.010) CAA within the frontal leptomeningeal vessels compared to intracortical vessels. Compared to those with AD, participants with CTE had more severe CAA in frontal than parietal lobes (p < 0.001) and more severe CAA in leptomeningeal than intracortical vessels (p = 0.002). The overall frequency of CAA in participants with CTE was low, and there was no significant association between contact sport participation and the presence of CAA. However, in those with CAA, a history of contact sports was associated with increased CAA severity in the frontal leptomeningeal vessels (OR = 4.01, 95% CI 2.52-6.38, p < 0.001) adjusting for AD, APOE ε4 status, and age. Participants with CAA had increased levels of sulcal tau pathology and decreased levels of the synaptic marker PSD-95 (p's < 0.05), and CAA was a predictor of dementia (OR = 1.75, 95% CI 1.02-2.99, p = 0.043) adjusting for age, sex, and comorbid pathology. Overall, contact sport participation and CTE were associated with more severe frontal and leptomeningeal CAA, and CAA was independently associated with worse pathological and clinical outcomes.