Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19 (preprint)

The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble alpha-synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) frequently experience hyposmia. We previously hypothesized that alpha-synuclein and tau misprocessing could occur following host responses to microbial triggers. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19+ patients (n=22), individuals with Lewy body disease (e.g., PD and dementia with Lewy bodies (DLB; n=6)), Alzheimer disease (AD; n=3), other non-synucleinopathy-linked degenerative diseases (e.g., progressive supranuclear palsy (PSP; n=2) and multisystem atrophy (MSA; n=1)). Further, we included neurologically healthy controls (HCO; n=9) and those with an inflammation-rich brain disorder as neurological controls (NCO; n=7). When probing for inflammatory changes focusing on anterior olfactory nuclei (AON) using anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, inflammation on average was not significantly altered in COVID19+ patients relative to controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-alpha-Syn and phospho-tau signals were detected in the AON of tauopathy- and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes, when present, in the rostral, intracranial portion of the olfactory circuitry generally reflected neurodegenerative processes seen elsewhere in the brain. In general, inflammation correlated best with the degree of Alzheimer's-linked tauopathy and declined with progression of age in COVID19+ patients.

Seed amplification assay of nasal swab extracts for accurate and non-invasive molecular diagnosis of neurodegenerative diseases.

Nasal swabs are non-invasive testing methods for detecting diseases by collecting samples from the nasal cavity or nasopharynx. Dysosmia is regarded as an early sign of coronavirus disease 2019 (COVID-19), and nasal swabs are the gold standard for the detection. By nasal swabs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acids can be cyclically amplified and detected using real-time reverse transcriptase-polymerase chain reaction after sampling. Similarly, olfactory dysfunction precedes the onset of typical clinical manifestations by several years in prion diseases and other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In neurodegenerative diseases, nasal swab tests are currently being explored using seed amplification assay (SAA) of pathogenic misfolded proteins, such as prion, α-synuclein, and tau. These misfolded proteins can serve as templates for the conformational change of other copies from the native form into the same misfolded form in a prion-like manner. SAA for misfolded prion-like proteins from nasal swab extracts has been developed, conceptually analogous to PCR, showing high sensitivity and specificity for molecular diagnosis of degenerative diseases even in the prodromal stage. Cyclic amplification assay of nasal swab extracts is an attractive and feasible method for accurate and non-invasive detection of trace amount of pathogenic substances for screening and diagnosis of neurodegenerative disease.

COVID-19 mRNA Vaccines: From Inflammation to Hyperinflammation (preprint)

Each injection of any known vaccine results in a strong expression of pro-inflammatory cytokines. This is the result of the innate immune system activation, without which no adaptive response to the injection of vaccines is possible. COVID-19 mRNA vaccines would not escape this rule. Unfortunately, the degree of inflammation produced by these vaccines is variable, probably depending on the genetic background and previous immune experiences, which through epigenetic modifications, could have made the innate immune system of each individual tolerant or reactive to subsequent immune stimulations.We hypothesize that we can move from a limited pro-inflammatory condition to conditions of increasing expression of pro-inflammatory cytokines that can culminate in multisystem hyperinflammatory syndromes following COVID-19 mRNA vaccines (MIS-V). We have graphically represented this idea in a hypothetical inflammatory pyramid (IP) and we have correlated the time factor to the degree of inflammation produced after the injection of vaccines. Furthermore, we have placed the clinical manifestations within this hypothetical IP, correlating them to the degree of inflammation produced. Surprisingly, excluding the possible presence of an early MIS-V, the time factor and the complexity of clinical manifestations are correlated to the increasing degree of inflammation: symptoms, heart disease and syndromes (MIS-V).

EAACI statement on the pathogenesis, immunology, and immune-targeted management of the Multisystem Inflammatory Syndrome in Children (MIS-C) or Pediatric Inflammatory Multisystem Syndrome (PIMS). (preprint)

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately four weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

The impact of a home-based personalized computerized training program on cognitive dysfunction associated with Long COVID: a before-and-after feasibility study (preprint)

Background: Long COVID, also known as post-acute sequelae of COVID-19 or PASC,is a systemic syndrome affecting a large number of persons in the aftermath of the pandemic. Cognitive dysfunction (or brain fog) is one of its most common manifestations of PACS, and there are no effective interventions to mitigate it. Home-based personalized computerized cognitive training (CCT), which has shown effectiveness to improve other conditions, could offer hope to relieve the cognitive dysfunction in people with a previous history of COVID-19. Objective: To evaluate the feasibility and potential benefit of a personalized CCT intervention to improve cognitive function among people living with PACS. Methods: Adult individuals who self-reported cognitive dysfunction more than 3 months after a diagnosis of COVID-19 were recruited through an online platform designed for the study. Those who were eligible assessed their general cognitive function before completing as many cognitive daily training sessions as they wished during an 8-week period, using a personalized CCT application at home. The sessions included gamified tasks that tapped into five cognitive domains (attention, coordination, memory, perception and reasoning) and were tailored to the specific cognitive strengths and weaknesses detected at each point. At the end of this period, participants repeated the general cognitive function assessment. The differences between the scores at 8 weeks and baseline was the main outcome, complemented with analyses of the changes based on age, training time, self-reported health level at baseline and time since the initial COVID-19 infection. Cognitive assessment scores were also computed in terms of percentiles according to the normative database of the test, considering their corresponding age- and gender-based reference sample. Results: The participants had significant cognitive dysfunction at baseline, even though 80% of them had had the initial episode of COVID-19 more than a year before enrolling in the study. Eighty nine percent reported negative levels of self-reported health at baseline. On average, 51 training sessions (range: 10 to 251) were completed over a mean time of 435 minutes (range 78 to 2448). Most of the participants obtained higher scores after CCT in each of the domains as compared with baseline (attention: 81% of the sample; memory: 86%; coordination: 82%; perception: 88%; reasoning: 77%). The magnitude of the score increase at post-test was high across domains (attention: 31% of change; memory: 37%; coordination: 52%; perception: 42%; reasoning: 26%). Following CCT, there were also improvements in the percentile data in all the domains (attention: 14 points; memory: 18 points; coordination: 18 points; perception: 17 points; reasoning: 11 points). Conclusions: This study suggests that a self-administered CCT based on gamified cognitive tasks could be an effective way to ameliorate cognitive dysfunction in persons with PASC.

COVID-19 pandemic and the international classification of functioning in multiple system atrophy: a cross-sectional, nationwide survey in Japan.

The present study aimed to determine the magnitude of and risk factors for the effects of the COVID-19 pandemic on the international classification of functioning, disability and health (ICF) in patients with multiple system atrophy (PwMSA). The study was part of a cross-sectional, nationwide, multipurpose mail survey for Japanese PwMSA from October to December, 2020. The primary outcome was the impact of the early COVID-19 pandemic on ICF functioning, consisting of body function, activity, and participation. Age, sex, disease type, disease duration, and dwelling place were asked as participants' characteristics, and the multiple system impairment questionnaire (MSIQ), patient health questionnaire-2, modified rankin scale, barthel index, life-space assessment (LSA), and EuroQoL were examined. Multivariate logistic regression analyses were performed to identify independent risk factors for a worse function score due to the COVID-19 pandemic for each ICF functioning domain. A total of 155 patients (mean age 65.6 [SD 8.1] years; 43.9% women; mean disease duration 8.0 [SD 6.2] years; 65% MSA with cerebellar ataxia, 13% MSA with parkinsonism, 9% MSA with predominant autonomic features) were analyzed. Of the ICF functioning domains, the respondents reported that the early COVID-19 pandemic affected body function in 17.4%, activity in 17.6%, and participation in 46.0%. The adjusted multivariate model identified MSIQ and LSA as the two variables that independently contributed to all domains. The COVID-19 pandemic affected ICF functioning of PwMSA in Japan, and the severity of disease-related impairments and a large daily living space were common risk factors. These results help support the focus on patient characteristics for medical and social welfare support.

Objective and Subjective Clinical Swallowing Outcomes via Telehealth: Reliability in Outpatient Clinical Practice.

Purpose The COVID-19 pandemic has drastically increased the use of telehealth. Prior studies of telehealth clinical swallowing evaluations provide positive evidence for telemanagement of swallowing. However, the reliability of these measures in clinical practice, as opposed to well-controlled research conditions, remains unknown. This study aimed to investigate the reliability of outcome measures derived from clinical swallowing tele-evaluations in real-world clinical practice (e.g., variability in devices and Internet connectivity, lack of in-person clinician assistance, or remote patient/caregiver training). Method Seven raters asynchronously judged clinical swallowing tele-evaluations of 12 movement disorders patients. Outcomes included the Timed Water Swallow Test (TWST), Test of Masticating and Swallowing Solids (TOMASS), and common observations of oral intake. Statistical analyses were performed to examine inter- and intrarater reliability, as well as qualitative analyses exploring patient and clinician-specific factors impacting reliability. Results Forty-four trials were included for reliability analyses. All rater dyads demonstrated "good" to "excellent" interrater reliability for measures of the TWST (intraclass correlation coefficients [ICCs] ≥ .93) and observations of oral intake (≥ 77% agreement). The majority of TOMASS outcomes demonstrated "good" to "excellent" interrater reliability (ICCs ≥ .84), with the exception of the number of bites (ICCs = .43-.99) and swallows (ICCs = .21-.85). Immediate and delayed intrarater reliability were "excellent" for most raters across all tasks, ranging between ICCs of .63 and 1.00. Exploratory factors potentially impacting reliability included infrequent instances of suboptimal video quality, reduced camera stability, camera distance, and obstruction of the patient's mouth during tasks. Conclusions Subjective observations of oral intake and objective measures taken from the TWST and the TOMASS can be reliably measured via telehealth in clinical practice. Our results provide support for the feasibility and reliability of telehealth for outpatient clinical swallowing evaluations during COVID-19 and beyond. Supplemental Material https://doi.org/10.23641/asha.13661378.

Therapeutic plasma exchange: A potential management strategy for critically ill MIS-C patients in the pediatric intensive care unit.

This study aimed to evaluate the effectiveness and the role of therapeutic plasma exchange (TPE) in treatment of children with severe MIS-C. In addition, we assessed demographic data, clinical features, laboratory abnormalities, underlying conditions, treatments, and outcomes. Patients with severe MIS-C who were admitted to the pediatric intensive care unit (PICU) between September 01 and October 05, 2020 were included in this observational, descriptive, retrospective study. The data collected included the patients' demographic data, presenting symptoms, clinical features, laboratory parameters, diagnostic investigations, and medications. Of 27 children with MIS-C, 63 % were male. The median age of the patients was nine years. Intravenous immunoglobulin and corticosteroids were used for treatment in 100 % of the patients, anakinra in 51.8 %, vasopressors in 85.1 %, noninvasive mechanical ventilation in 25.9 %, and invasive mechanical ventilation in 18.5 %. Ten of the 27 patients (37 %) underwent TPE. In the patients who underwent TPE, the median PELOD score was 21 (IQR: 11-30.25) before TPE and 10 (IQR: 10-11) after TPE (p < 0.001). Moreover, their median left ventricular ejection fraction (LVEF) was 52 % (IQR: 49.25 %-55 %) before TPE and median LVEF was 66.5 (IQR: 58 %-68.5 %) after TPE (p = 0.012). The median number of TPE sessions was three (IQR: 2-4.75). The mortality rate of the patients with severe MIS-C admitted to the PICU was 7.4 %. We suggest that TPE should be considered as a therapeutic option in children with severe MIS-C. Early initiation of TPE followed by immunomodulatory therapy in critically ill children with MIS-C may help improve clinical and laboratory outcomes.

CoSIR: Optimal control of SIR epidemic dynamics by mapping to Lotka-Volterra System (preprint)

Multiple macro-phenomena such as disease epidemics, online information propagation, and economic activity can be well-approximated using simple dynamical systems. Shaping these phenomena with adaptive control of key levers has long been the holy grail of policymakers. In this paper, we focus on optimal control of transmission rate in epidemic systems following the widely applicable SIR dynamics. We first demonstrate that the SIR model with infectious patients and susceptible contacts (i.e., product of transmission rate and susceptible population) interpreted as predators and prey respectively reduces to a Lotka-Volterra (LV) predator-prey model. The modified SIR system (LVSIR) has a stable equilibrium point, an “energy” conservation property, and exhibits bounded cyclic behavior. We exploit this mapping using a control-Lyapunov approach to design a novel adaptive control policy (CoSIR) that nudges the SIR model to the desired equilibrium. Combining CoSIR policy with data-driven estimation of parameters and adjustments for discrete transmission levels yields a control strategy with practical utility. Empirical comparison with periodic lockdowns on simulated and real COVID-19 data demonstrates the efficacy and adaptability of our approach.

COVID-19 ocular findings in paediatric population (preprint)

Purpose To investigate and describe ocular findings in COVID-19 paediatric patients. Methods A total of 17 COVID-19 patients aged between 0 and 17 years old were recruited at the Paediatric Hospital of La Paz University Hospital (Madrid, Spain). A complete ophthalmological examination was performed in all patients.  Results Of 17 patients, 50% had a known COVID-19 previous exposure. PCR from nasopharyngeal swabs was positive in 35.29%, whereas IgM and/or IgG serology tests were positive in 81%. Clinical manifestations were: 6 COVID-19associated Paediatric Inflammatory Multisystem Syndrome (PIMS), 7 pneumonias and 2 cutaneous purpura and/or chilblains. Ocular findings were ocular hyperaemia (5 patients), as bilateral acute conjunctivitis (3 patients) or unilateral episcleritis (2 patients). Mean best corrected visual acuity was 1/1 in all tested cases. Only one patient, presenting unilateral optic neuritis, had visual symptoms as unilateral inferior temporal quadrantanopsy. Retinal involvement was found in one patient, where ocular fundus exam showed unilateral retinal vasculitis. Conclusion SARS-CoV-2 infection could produce ocular pathology in children, frequently presented weeks after the acute phase of the disease. We should take into account COVID-19 when performing differential diagnosis of children presenting with conjunctivitis, episcleritis, retinal vasculitis and/or optic neuritis, meanwhile this world-wide pandemic lasts.   

Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; The APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study) (preprint)

Background and Aims: COVID-19 is a dominant pulmonary disease, with multisystem involvement, depending upon co morbidities. Its profile in patients with pre-existing chronic liver disease (CLD) is largely unknown. We studied the liver injury patterns of SARS-Cov-2 in CLD patients, with or without cirrhosis. Methods: Data was collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19. Result: Altogether, 228 patients [185 CLD without cirrhosis and 43 with cirrhosis] were enrolled, with comorbidities in nearly 80%. Metabolism associated fatty liver disease (113, 61%) and viral etiology (26, 60%) were common. In CLD without cirrhosis, diabetes [57.7% vs 39.7%, OR=2.1(1.1-3.7), p=0.01] and in cirrhotics, obesity, [64.3% vs. 17.2%, OR=8.1(1.9-38.8), p=0.002) predisposed more to liver injury than those without these. Forty three percent of CLD without cirrhosis presented as acute liver injury and 20% cirrhotics presented with either acute-on-chronic liver failure [5(11.6%)] or acute decompensation [4(9%)]. Liver related complications increased (p<0.05) with stage of liver disease; a Child-Turcotte Pugh score of 9 or more at presentation predicted high mortality [AUROC-0.94, HR=19.2(95CI 2.3-163.3), p<0.001, sensitivity 85.7% and specificity 94.4%). In decompensated cirrhotics, the liver injury was progressive in 57% patients, with 43% mortality. Rising bilirubin and AST/ALT ratio predicted mortality among cirrhosis. Conclusions: SARS-Cov-2 infection causes significant liver injury in CLD patients, decompensating one fifth of cirrhosis, and worsening the clinical status of the already decompensated. The CLD patients with diabetes and obesity are more vulnerable and should be closely monitored.