Dementia and Cognitive Concerns are Risk Factors for Mortality in People with Human Immunodeficiency Virus and COVID-19

Background. Despite higher prevalence of cognitive disorders in people with human immunodeficiency virus (PWH) and dementia being a risk factor for COVID-19 mortality, the association between dementia and adverse outcomes in PWH with COVID-19 has not been well established. Methods. This was a matched case-control study (1:10) of patients with and without HIV at an academic institution with documented SARS-CoV-2 polymerase chain reaction (PCR) positivity from March 2020-March 2021. Data were extracted from the electronic health record data registry. PWH were matched to people without HIV (PWoH) by age, sex, race, and zip code. The primary exposures were dementia (identified using International Classification of Diseases, Tenth Revision codes) and cognitive concerns, defined as documentation of possible cognitive impairment up to 12 months prior to COVID-19 diagnosis and ascertained using a semi-automated natural language processing annotation tool. VACS 2.0 Index (including age, sex, body mass index, CD4+ T-cell count and HIV-1 RNA) was calculated. Logistic regression models assessed the effect of dementia and cognitive concerns on the odds of death (OR [95% confidence interval]), adjusted for VACS 2.0 Index. Results. Sixty-four (0.45%) PWH were identified among 14129 patients with COVID-19 and were matched to 463 PWoH. Among PWH, 59% were virally suppressed, and 14% had CD4< 200 cells/muL. Compared to 463 matched PWoH, PWH had higher prevalence of dementia (16% vs. 6%, p=0.01) and cognitive concerns (22% vs. 16%, p=0.04). Death was more frequent in PWH (17% vs. 6%, p< 0.01) and at younger ages (58 vs. 66 years, p=0.03). Cognitive concerns (2.5 [1.1-5.9], p=0.03) and dementia (3.4 [1.3-8.1], p=0.01) were significantly associated with increased adjusted odds of death in the overall group. Among PWH, cognitive concerns (7.2 [1.1-48], p=0.04) and dementia (6.0 [0.8-43.8], p=0.08) remained associated with mortality. Conclusion. Dementia and cognitive concerns were associated with mortality among PWH with COVID-19. The magnitude of the effect of cognitive impairment on COVID-19 outcomes may be greater in HIV, and additional studies with larger cohorts will help to assess this association further. Assessment of cognitive status is an important component to care for aging PWH in the COVID-19 era.

Intrathecal inflammatory responses in the absence of SARS-CoV-2 nucleic acid in the CSF of COVID-19 hospitalized patients

Objective: Evaluate SARS-CoV-2 RNA and inflammatory cytokines and chemokines in the CSF of patients with acute COVID-19 and neurologic symptoms, and to compare these to controls and patients with known neurotropic pathogens. Background: Neurologic symptoms have been described in 30-60% of hospitalized patients with Coronavirus Disease 2019 (COVID-19). However, little is known about CSF profiles in these patients. Design/Methods: CSF from twenty-seven consecutive patients with COVID-19 and neurological symptoms was assayed for SARS-CoV-2 RNA using quantitative reverse transcription PCR (RT-qPCR) and unbiased metagenomic sequencing. Assays for blood brain barrier (BBB) breakdown (CSF:serum albumin ratio (Q-Alb)), and proinflammatory cytokines and chemokines (IL-6, IL-8, IL-15, IL-16, monocyte chemoattractant protein -1 (MCP-1) and monocyte inhibitory protein - 1β (MIP-1β)) were performed in 23 patients and compared to CSF from patients with HIV-1 (16 virally suppressed, 5 unsuppressed), West Nile virus (WNV) (n=4) and 16 healthy controls (HC). Results: Median CSF cell count for COVID-19 patients was 1 white blood cell/μL;two patients were infected with a second pathogen (Neisseria, Cryptococcus neoformans). No CSF samples had detectable SARS-CoV-2 RNA by either detection method. In patients with COVID-19 only, CSF IL-6, IL-8, IL-15, and MIP-1β levels were higher than HC and suppressed HIV (corrected-p < 0.05). MCP-1 and MIP-1β levels were higher, while IL-6, IL-8, IL-15 were similar in COVID-19 compared to WNV patients. Q-Alb correlated with all proinflammatory markers, with IL-6, IL-8, and MIP-1β (r≥0.6, p<0.01) demonstrating the strongest associations. Conclusions: Lack of SARS-CoV-2 RNA in CSF is consistent with pre-existing literature. Evidence of intrathecal proinflammatory markers in a subset of COVID-19 patients with BBB breakdown despite minimal CSF pleocytosis is atypical for neurotropic pathogens.

Neuropathological Features of COVID-19

Objective: To report neuropathological findings and quantify SARS-CoV-2 viral burden for 18 consecutive coronavirus disease 2019 (COVID-19) autopsies. Background: COVID-19 is a respiratory disease caused by SARS-CoV-2, a virus known to infect lung epithelial cells, yet data about SARS-CoV-2 neuropathology in human brain autopsies is limited. Design/Methods: Brain tissue specimens were sampled from 18 subjects (10 standard areas), fixed in formalin, and stained with hematoxylin and eosin for histopathological analysis. SARSCoV-2 immunohistochemistry and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were performed on 10 brain sections from 2 subjects and 2 sections (medulla and frontal lobe with olfactory nerve) from the remaining 16 subjects. Results: Median age was 62 years (interquartile range, 53 to 75), and 14 patients (78%) were men. Presenting neurologic symptoms were myalgia (n=3), headache (n=2), and decreased taste (n=1);11 received mechanical ventilation. Acute hypoxic injury was detected in cerebrum, hippocampus, and cerebellum in all patients;rare foci of perivascular lymphocytes (n=2) or focal leptomeningeal inflammation (n=1) were also detected. RT-qPCR showed limited evidence of viral RNA. In 10 unique specimens from two subjects, results were equivocal (viral load <5.0 copies/mm3) in 4 and 5 sections, respectively. In the remaining 16 patients, 3 medulla sections and 3 frontal lobe and olfactory sections were positive (5.0 to 59.4 copies/mm3) while the rest were equivocal or negative. SARS-CoV-2 viral load did not correlate with the interval between the onset of symptoms and death or histopathological findings. Immunohistochemical staining for SARS-CoV-2 nucleocapsid protein was negative in neurons, glia, endothelium, and immune cells. Conclusions: Histopathology of brain specimens revealed hypoxia with limited evidence of direct viral damage, including no viral protein. Concordantly, although SARS-CoV-2 was detected by RT-qPCR in some sections, viral load was low and did not correlate with other pathological features.

Prolonged intubation in patients with prior cerebrovascular disease and COVID-19

Objective: To determine the odds of critical illness by day 28 and duration of mechanical ventilation (MV) over 45-day observation period in patients with history of cerebrovascular disease and COVID-19. Background: COVID-19-associated morbidity is correlated with multiple factors including age, comorbidities, and host response to the virus. Our understanding of the risk of critical illness due to prior neurological conditions remains limited. Here, we hypothesized that prior cerebrovascular disease is a risk factor for severe outcomes in COVID-19, including increased duration of MV. Design/Methods: A cross-sectional study of 1128 consecutive adult patients admitted to a tertiary care center in Boston, Massachusetts, and diagnosed with laboratory-confirmed COVID-19. The association between history of cerebrovascular disease and critical illness defined as MV or death was examined using logistic regression with inverse probability weighting of the propensity score. Cumulative incidence of successful extubation without death over 45 days was examined using competing risk analysis. Results: Of the 1128 adults admitted with COVID-19, 350 (36%) were critically ill by day 28. The median age was 59 years (standard deviation: 18 years), 640 (57%) were men, and 401 (36%) were Latinx ethnicity. As of June 2nd, 2020, 127 (11%) patients died. A total of 257 (23%) of patients had a prior neurological diagnosis;most common was cerebrovascular disease (16%). Prior cerebrovascular disease was significantly associated with critical illness (OR 1.54 [95% CI: 1.14 - 2.07]), lower rate of successful extubation (cause-specific HR 0.57 [95% CI: 0.33-0.98]), and increased duration of intubation (restricted mean time difference 4.02 days [95% CI: 0.34- 10.92]) compared to patients without cerebrovascular disease. Conclusions: History of cerebrovascular disease adversely affects COVID-19 outcomes including increased risk of critical illness and prolonged intubation. Further studies are needed to define measures that reduce risk of poor outcomes in this subpopulation.

Ethnic factors and symptomatic predictors of headache in COVID-19

Objective: We retrospectively analyzed clinical data of patients who were diagnosed with COVID-19 for the predictors of headache development. Background: COVID-19, a multisystemic infection caused by the SARS-CoV2 virus, is associated with significant mortality and neurologic morbidity, including stroke, encephalopathy and neuromuscular disorders as well as less severe symptoms like headaches, muscle aches and anosmia that are important for case recognition and diagnosis. Little is known about the predictors and associations of headache in COVID-19. Design/Methods: We performed retrospective chart review of patients positive for SARS-CoV2 by nasopharyngeal swab in March and April 2020 at MGH, Boston, Massachusetts. This study was approved by our institutional review board. Demographic, medical comorbidity, radiologic and laboratory data were collected by electronic medical record review. Clinical manifestations were included starting on the date of COVID-19 onset, as identified by the patient's clinical notes. Data was analyzed based on age, racial/ethnic background, body mass index, and associated symptoms. Results: We identified 440 patients, 202 (45.9%) male and 238 (54%) female. Males more likely required admissions for inpatient treatment, had abnormal chest imaging or a clinical diagnosis of pneumonia. There is significantly different headache prevalence between patients aged below 50 (15.9%) and aged 50 or above (18.9%, p=0.0086). There was no difference in headache prevalence between BMI groups. Patients who had headaches were significantly more likely to also have had non-specific viral symptoms, including nausea/vomiting, nasal congestion, myalgia, ear pain, eye pain, and fatigue as well as neurological symptoms of anosmia, hypogeusia, and dizziness. Hispanics had significantly more headaches, nausea/vomiting, anosmia, myalgia, and nasal congestion than non-Hispanics, while non-Hispanics had significantly more fatigue. Conclusions: Our results demonstrated age and ethnic predisposing factors for headache in COVID-19. In addition, certain neurological symptoms are positive predictors for headache in COVID-19.

Clinical, Imaging, and Lab Correlates of Severe COVID-19 Leukoencephalopathy.

BACKGROUND AND PURPOSE: Patients infected with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) can develop a spectrum of neurological disorders, including a leukoencephalopathy of variable severity. Our aim was to characterize imaging, lab, and clinical correlates of severe coronavirus disease 2019 (COVID-19) leukoencephalopathy, which may provide insight into the SARS-CoV-2 pathophysiology. MATERIALS AND METHODS: Twenty-seven consecutive patients positive for SARS-CoV-2 who had brain MR imaging following intensive care unit admission were included. Seven (7/27, 26%) developed an unusual pattern of "leukoencephalopathy with reduced diffusivity" on diffusion-weighted MR imaging. The remaining patients did not exhibit this pattern. Clinical and laboratory indices, as well as neuroimaging findings, were compared between groups. RESULTS: The reduced-diffusivity group had a significantly higher body mass index (36 versus 28 kg/m2, P < .01). Patients with reduced diffusivity trended toward more frequent acute renal failure (7/7, 100% versus 9/20, 45%; P = .06) and lower estimated glomerular filtration rate values (49 versus 85 mL/min; P = .06) at the time of MRI. Patients with reduced diffusivity also showed lesser mean values of the lowest hemoglobin levels (8.1 versus 10.2 g/dL, P < .05) and higher serum sodium levels (147 versus 139 mmol/L, P = .04) within 24 hours before MR imaging. The reduced-diffusivity group showed a striking and highly reproducible distribution of confluent, predominantly symmetric, supratentorial, and middle cerebellar peduncular white matter lesions (P < .001). CONCLUSIONS: Our findings highlight notable correlations between severe COVID-19 leukoencephalopathy with reduced diffusivity and obesity, acute renal failure, mild hypernatremia, anemia, and an unusual brain MR imaging white matter lesion distribution pattern. Together, these observations may shed light on possible SARS-CoV-2 pathophysiologic mechanisms associated with leukoencephalopathy, including borderzone ischemic changes, electrolyte transport disturbances, and silent hypoxia in the setting of the known cytokine storm syndrome that accompanies severe COVID-19.

Brain MR Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary Observations.

Brain multivoxel MR spectroscopic imaging was performed in 3 consecutive patients with coronavirus disease 2019 (COVID-19). These included 1 patient with COVID-19-associated necrotizing leukoencephalopathy, another patient who had a recent pulseless electrical activity cardiac arrest with subtle white matter changes, and a patient without frank encephalopathy or a recent severe hypoxic episode. The MR spectroscopic imaging findings were compared with those of 2 patients with white matter pathology not related to Severe Acute Respiratory Syndrome coronavirus 2 infection and a healthy control subject. The NAA reduction, choline elevation, and glutamate/glutamine elevation found in the patient with COVID-19-associated necrotizing leukoencephalopathy and, to a lesser degree, the patient with COVID-19 postcardiac arrest, follow a similar pattern as seen with the patient with delayed posthypoxic leukoencephalopathy. Lactate elevation was most pronounced in the patient with COVID-19 necrotizing leukoencephalopathy.