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.

A Single Center, Retrospective Analysis of Inpatient Neurologic Consultations of Patients Infected with SARS-CoV-2

Objective: To determine if inpatient neurological consultations differ between COVID-19 and non-COVID-19 respiratory infections. Background: The COVID-19 pandemic has posed challenges to healthcare systems across the world, and neurological complications of COVID-19 have garnered increased concern in medicine and the public. Neurological consultation for patients with viral-mediated disease is common;it is unknown whether the neurologist's approach to inpatient consultation of patients with COVID-19 should be altered. Design/Methods: We performed a retrospective chart analysis of inpatient neurologic consultations at three major hospitals comprising the University of Pennsylvania Health System. We compared the reason for neurologic consultation and final diagnosis of 62 patients with COVID-19 between March 2020 and April 2021 to 56 patients with non-COVID-19 respiratory virus (defined as Influenza A, Influenza B, Respiratory Syncytial Virus, Rhinovirus, or Adenovirus) between January 2019 and January 2020. Secondary metrics included mortality and level of care. A frequency and means analysis were completed to evaluate the relative difference between groups on all primary and secondary metrics. Results: Stroke was the only diagnosis more common in the COVID population as compared to the non-COVID virus population (14% vs. 9%). Neurology was consulted more frequently for altered mental status in the COVID-19 population (27% vs. 18%);however, the ultimate diagnosis was toxic-metabolic encephalopathy due to infection, not a consequence of COVID-19 itself. Neurology was consulted significantly later in the hospital course of COVID-19 (3.1 vs. 0.96 days), despite a higher mortality in the other population (30% vs. 19%). Conclusions: Patients requiring inpatient neurologic consultation with a diagnosis of COVID-19 or another respiratory virus were found to be remarkably similar in terms of their ultimate neurologic diagnosis, with the exception of stroke, which was more common in the COVID-19 population. These results suggest the neurological approach to patients with COVID-19 should be similar to that in patients with other respiratory infections.

Ocrelizumab infusion delays and radiologic relapse in multiple sclerosis

Introduction: Ocrelizumab is administered every 6 months due to expectations that this is necessary to control new disease activity. This dosing schedule is difficult in some settings, such as during the SARS-CoV-2 pandemic, which can lead to anxiety for patients and care teams. There is clinical evidence and mechanistic rationale that ocrelizumab may have a more durable treatment effect beyond the 6-month dosing interval;however, it is unclear whether infusion delays contribute to relapses. Objectives/Aims: To explore whether infusion delay, length of delay, and repeated delays are associated with radiologic relapse in patients on ocrelizumab, as part of a quality improvement project to improve departmental practices. Methods: Retrospective, single site (University of Pennsylvania) cohort study, that included 86 patients with relapsing-remitting multiple sclerosis (MS) treated with ocrelizumab for at least 2 years. Demographics and infusion dates were obtained through chart review. Routine clinical MRIs that included a 1mm3 isotropic T2/FLAIR sequence obtained at baseline (3-9 months after starting ocrelizumab) and follow-up (at least 2 years after starting ocrelizumab) were compared using in-house developed software that aids in detection of new lesions by registration and subtraction of MR images from two time points. New MS lesions were adjudicated by two neurologists. Statistical analysis was performed using Fisher's exact test. Results: Due to logistics of arranging infusions, 33 (38.4%) patients had at least 1 infusion interval longer than 7 months (210 days). Five patients (5.8%) had a radiologic relapse during two years of observation. Presence of an infusion interval longer than 7 months or 8 months (240 days) was not associated with radiologic relapse (p=1.00, p=0.43, respectively). Length of maximum infusion interval was not associated with radiologic relapse (p=0.52). Patients with multiple infusion delays had no increased risk of relapse (p=0.47). Conclusions: While underpowered to exclude a relationship between ocrelizumab infusion delays and new disease activity, our study is reassuring that a delay of up to 2 months is not associated with relapse. Prospective studies could confirm these findings and identify characteristics of patients who will have more prolonged disease control with ocrelizumab beyond the currently prescribed 6-month dosing interval.

Quinine Inhibits Infection of Human Cell Lines with SARS-CoV-2

While vaccination campaigns are ongoing worldwide, there is still a tremendous medical need for efficient antivirals against SARS-CoV-2 infection. Among several drug candidates, chloroquine (CQN) and hydroxychloroquine (H-CQN) were tested intensively, and any contentious therapeutic effect of both has been discussed controversially in the light of severe side effects and missing efficacy. Originally, H-CQN descended from the natural substance quinine, a medicinal product used since the Middle Ages, which actually is regulatory approved for various indications. We hypothesized that quinine also exerts anti-SARS-CoV-2 activity. In Vero cells, quinine inhibited SARS-CoV-2 infection more effectively than CQN, and H-CQN and was less toxic. In human Caco-2 colon epithelial cells as well as the lung cell line A549 stably expressing ACE2 and TMPRSS2, quinine also showed antiviral activity. In consistence with Vero cells, quinine was less toxic in A549 as compared to CQN and H-CQN. Finally, we confirmed our findings in Calu-3 lung cells, expressing ACE2 and TMPRSS2 endogenously. In Calu-3, infections with high titers of SARS-CoV-2 were completely blocked by quinine, CQN, and H-CQN in concentrations above 50 microM. The estimated IC₅₀s were ~25 microM in Calu-3, while overall, the inhibitors exhibit IC₅₀ values between ~3.7 to ~50 microM, dependent on the cell line and multiplicity of infection (MOI). Conclusively, our data indicate that quinine could have the potential of a treatment option for SARS-CoV-2, as the toxicological and pharmacological profile seems more favorable when compared to its progeny drugs H-CQN or CQN.