Phenotyping the Chronic Neurological Sequelae of Acute SARS-CoV-2 Infections

Objective: To phenotype the neurological dysfunction in post-acute sequelae SARS-CoV-2 infection. Background: Neurological complications of SARS-CoV-2 infection can arise acutely but can also emerge and persist weeks and months after acute infection. These symptoms can affect up to 80% of those with post-acute sequelae SARS-CoV-2 infection (PASC). The University of Pennsylvania Neuro-COVID Clinic (PNCC) was established to provide care for patients with PASC and to obtain standardized clinical metrics to better define the neurological complications attributed to PASC. Design/Methods: Retrospective analysis of charts from the first 94 patients seen at the PNCC. Demographics as well as standardized clinical histories were reviewed. Standardized cognitive testing including the Montreal Cognitive Assessment (MOCA version 8.2), Trails A and B, and digit span (forward and reverse) were performed and analyzed with summary statistics. Results: Mean age of this patient population was 50 years (range 21 - 75yrs) and 67% were female. 30% of patients were admitted to inpatient care during their acute infection (4% required ICU level care). The average time from acute infection to first visit at the PNCC was 234 days (range: 40 - 509 days). The most frequent primary neurological complaint was brain fog (68%) and 91% of patients endorsed some level of brain fog. Abnormal testing (> 4 missed points) on MOCA testing was measured in 39% of patients. Abnormal testing on Trails B (below the age-adjusted 9 percentile) was measured in 16% of patients. Conclusions: Neurological manifestations of PASC are common even in non-hospitalized patients and brain fog is a frequent symptom. Discrepancies between subjective experience and standardized cognitive testing suggest a multifactorial cause to brain fog in PASC. Co-occurrence of mood symptoms, poor sleep, and medication side effects may exacerbate more direct effects of COVID-19. The long-term trajectory of neurological symptoms in PASC will be determined with longitudinal follow-up of this patient cohort. th.

Characterizing Concussion Using Brain Derived Exosomes

Traumatic brain injury (TBI) currently afflicts 357,000 enlisted military men and women in the US Armed Services. For the most common form of TBI, Mild Traumatic Brain Injury (mTBI) most patients recover within a year following the incident, but 10-20 of mild cases result in a long-term disability including seizures and emotional and behavioral issues. Although much has been learned about molecular changes in the brain following injury, access to these biomarkers following mTBI is lacking. The accurate diagnosis and precise individual clinical management of traumatic brain injury (TBI) is limited by the lack of accessible molecular biomarkers that are informative regarding the unique mixture of injury mechanisms in each TBI patient.

Neurological biomarkers in COVID-19: Comparing patient biomarkers across hospital discharge status

Objective: Evaluate the use of neurological biomarkers to predict discharge outcomes in COVID-19 patients. Background: Altered levels of brain-derived molecular biomarkers in patients with nonneurological critical illness associates with worse outcomes following these systemic insults. We hypothesized that COVID-19 critical illness would increase expression of brain-derived biomarkers and portend worse outcomes. Design/Methods: 38 adults admitted for COVID-19 at a single tertiary care medical center were prospectively enrolled (M = 63.63 ±19.51, 53% female, 71% requiring ICU admission) and clinical information collected including discharge disposition to home/rehabilitation (n=18) or expired/skilled nursing facility (SNF;n=20). Plasma GFAP, Tau, NfL, and UCHL1 were measured by digital ELISA. Results: COVID-19 patients admitted to the ICU exhibited significantly higher levels of NfL (p=0.003, d=1.25) and GFAP (p=0.03, d=0.88). We used binary logistic regression to determine if biomarkers predicted discharge outcome. Models were examined for best fit using biomarker level, age, ICU status, and history of prior neurological disease. A model including NfL level (Wald's χ =6.614, p=0.010, OR=1.043, 95%CI (1.010, 1.076)) predicting disposition was significant (χ = 22.247, p<0.001, Nagelkerke R = .591). The model's prediction success was 84.2% (90.0% for home/rehab and 77.8% for SNF/expired) A model including GFAP level (Wald's χ =3.055, p=0.080, OR=1.003, 95%CI (1.000, 1.007)) and ICU status (Wald's χ =4.073, p=0.044, OR=0.096, 95%CI (0.010, 0.935)) on disposition was also significant (χ = 17.377, p<0.01, Nagelkerke R = .490). The model successfully predicted disposition status at 78.9% (85% for home/rehab and 72.2% for SNF/expired). Adding age, ICU status, or prior neurological history did not improve outcome prediction. Conclusions: COVID-19 patients requiring ICU admission exhibit increases in circulating brainderived proteins. Higher levels of GFAP and NfL is associated with worse discharge outcomes, even after controlling for age, ICU status and prior neurological disease. Future work examining COVID-19 recovery will help determine if these biomarkers are predictive of long-term neurological consequences.

Persistent dyspnea and accompanying negative emotions after COVID-19 associated respiratory failure

INTRODUCTION: Dyspnea is common and distressing in patients with acute critical illness who require mechanical ventilation (MV), and is often a presenting symptom for COVID-19. However, little is known about the long-term persistence of dyspnea or its impact on patients recovering from mechanical ventilation. This study sought to evaluate early and persistent dyspnea, and its emotional impact, among survivors of respiratory failure due to COVID-19. METHODS: We conducted a prospective observational cohort study at Beth Israel Deaconess Medical Center. We identified ICU survivors who underwent at least 48 hours of MV for COVID-19. We contacted eligible patients via telephone at 6 months post-hospital discharge. We assessed the presence and severity of dyspnea throughout their illness (ICU, hospital floor, hospital discharge, 6 months post-discharge) using components of the Multidimensional Dyspnea Profile (MDP), a validated instrument. Additionally, we asked patients with persistent dyspnea at the time of follow up whether dyspnea triggered specific emotional responses, using the MDP. Data are means + standard deviation or number (percent). RESULTS: Forty of 43 patients contacted by telephone completed interviews and 3 declined. Twenty-three patients (58%) were male, 7 (18%) had COPD, 9 (22%) had obstructive sleep apnea, and 11 (28%) had active tobacco use. The duration of invasive MV was 14+7.1 days and hospital length of stay was 24.7+9.6 days. Six-month post-discharge data revealed 25 patients (62.5%) with any dyspnea, and 10 (25%) with moderate to severe dyspnea (10-point severity scale score > 4). Among patients with persistent dyspnea at 6 months, the majority reported fear (60%), anxiety (57.5%), or frustration (52.5%). Depression was the most common severe emotional response accompanying dyspnea (10-point severity scale score of 7-10), reported by 9 patients (22.5%). CONCLUSIONS: Six months after COVID-19-associated respiratory failure, dyspnea was persistent in the majority of patients and commonly associated with negative emotions. Fear and anxiety were most commonly reported. Prior to COVID-19, long-term dyspnea had been described in up to 40% of patients after respiratory failure, though data are limited. Thus dyspnea appears as, or more, common after COVID-19. In addition to the typical components of post-intensive care syndrome (PICS), dyspnea and the negative emotional states it evokes may impair quality-of-life for COVID-19 survivors and should be specifically assessed during post-hospital care visits.

Long-term impairment in cognition, mental health, and physical function following covid-19-associated respiratory failure

RATIONALE: Prior to the emergence of coronavirus disease 2019 (COVID-19), critical illness survivors were known to suffer long-term impairments in physical function, mental health, and cognition. These deficits, collectively termed the post-intensive care syndrome (PICS), impact health-related quality-of-life. Survivors of COVID-19-associated respiratory failure may be at particularly high risk of PICS due to delirium and prolonged mechanical ventilation, and factors unique to the pandemic, including physical isolation from medical staff, lack of in-hospital family presence, limited post-acute care rehabilitation, and widespread economic recession. Given this context, we describe the prevalence of PICS 6 months following hospital discharge among survivors of COVID-19-associated respiratory failure. METHODS: We conducted a multicenter prospective cohort study from March to December 2020 at Beth Israel Deaconess Medical Center and the Hospital of the University of Pennsylvania. We identified ICU survivors who underwent at least 48 hours of mechanical ventilation for COVID-19. We contacted eligible patients via telephone at 6 months post-hospital discharge. Sample size was determined by thematic saturation of interviews within a concurrent qualitative assessment. We used the Society of Critical Care Medicine international consensus recommendations for PICS assessment. We assessed anxiety, depression, and post-traumatic stress disorder (PTSD) using the Hospital Anxiety and Depression Scale and Impact-of-Events Scale, respectively. We assessed physical impairment with the EQ-5D questionnaire, and cognitive impairment using the Montreal Cognitive Assessment-Blind. Data are means + standard deviation or number (percent). RESULTS: We completed telephone interviews with 50 of 173 eligible patients (53 contacted, 3 declined). Age was 57+13 years, duration of invasive mechanical ventilation was 14+8.2 days and PaO2:FiO2 ratio at intubation was 174±46. Delirium developed in 35 patients (70%). Six months post-discharge, 38 patients (76%) met criteria for PICS, with 1 or more domains impaired. Among patients with PICS, 22 (44%) were impaired in at least 2 domains, and 9 (18%) impaired in all 3 domains. PTSD was present in 17 patients (34%), anxiety in 19 (38%), and depression in 20 (40%). Twenty-four patients (48%) had impairments in activities of daily living. Nineteen patients (37%) demonstrated cognitive impairment. CONCLUSIONS Over three quarters of COVID-19-associated respiratory failure survivors demonstrated PICS 6 months after hospital discharge. Patients were commonly impaired in at least two domains. These estimates of PICS prevalence appear broadly similar to those reported in the pre-COVID-19 literature and should drive focused efforts to identify COVID-19 survivors at high risk for PICS prior to discharge.