Figure - available from: Viruses
This content is subject to copyright.
White matter pathology. (A–C) Multiple subacute hemorrhagic lesions throughout the white matter with hemosiderin-laden macrophages, surrounding Waller degeneration with axonal and myelin vacuolation ((B), luxol fast blue), proliferation of macrophages and activated microglia ((C), left panel anti-HLA-DR immunohistochemistry) and isolated CD8+ T-lymphocytes ((C), right panel; case 4). (D) Focal cellular infiltrates of CD8+ T-lymphocytes in the white matter (case 2) and prominent diffuse microglial activation, particularly in the white matter, independently of T-cell infiltrates ((E,F), anti-HLA-DR immunohistochemistry (ctx: cortex; wm: white matter). (G–I) mild to moderate diffuse vacuolation of white matter, better identified on luxol-fast-blue-stained sections, without signs of demyelination (H) and diffuse microglial activation, accentuated at the perivascular spaces ((I), anti-HLA-DR immunohistochemistry) ((G–I), case 5). Scale bars: (A,C) right panel, (I) 20 μm; (B,C) left panel, (D,F–H) 50 μm; (E) 100 μm.
Source publication
Background:
There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms.
Methods:
We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19...
Citations
... It may well be that one measure taken at one time is extremely effective but when taken at a later point in time hardly shows an effect. Finally, neurologists seem to play a vital role in such pandemics, because of the potential acute involvement of the nervous system, which controls all vital functions and thus involves the nervous system as end organ, but also because of late manifestations that need to be recognized and treated [26]. ...
One hundred years ago, an influenza pandemic swept across the globe that coincided with the development of a neurological condition, named "encephalitis lethargica" for the occurrence of its main symptom, the sudden onset of sleepiness that either developed into coma or gradually receded. Between 1917 and 1920, mortality of the flu was >20 million and of encephalitis lethargica approximately 1 million. For lessons to be learned from this pandemic, it makes sense to compare it with the COVID‐19 pandemic, which occurred 100 years later. Biomedical progress had enabled testing, vaccinations, and drug therapies accompanied by public health measures such as social distancing, contact tracing, wearing face masks, and frequent hand washing. From todays' perspective, these public health measures are time honored but not sufficiently proven effective, especially when applied in the context of a vaccination strategy. Also, the protective effects of lockdowns of schools, universities, and other institutions and the restrictions on travel and personal visits to hospitals or old‐age homes are not precisely known. Preparedness is still a demand for a future pandemic. Clinical trials should determine the comparative effectiveness of such public health measures, especially for their use as a combination strategy with vaccination and individual testing of asymptomatic individuals. It is important for neurologists to realize that during a pandemic the treatment possibilities for acute stroke and other neurological emergencies are reduced, which has previously led to an increase of mortality and suffering. To increase preparedness for a future pandemic, neurologists play an important role, as the case load of acute and chronic neurological patients will be higher as well as the needs for rehabilitation. Finally, new chronic forms of postviral disease will likely be added, as was the case for postencephalitic parkinsonism a century ago and now has occurred as long COVID.
... Neuro-invasion of SARS-CoV-2 occurs via transcribrial (nose) route with damage to olfactory mucosa, and olfactory nerves, ultimately manifesting into anosmia (loss of smell) 197,198 . COVID-19 patients also display diffused white matter damage, microglial activation, and neuroinflammation at different CNS regions with olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%) 199 . Reactive gliosis, astrocytosis, and microglial activation, along with neuroinflammation gradually advances from COVID-19 to PASC 200 . ...
SARS‐CoV‐2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is criticalfor the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. Thissingle-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates aplethora of virus–host protein–protein interactions in the human body. These extensive viral proteininteractions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well asaltered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectiousprocess, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases,TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL)for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectiousoutcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acuteCOVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii)hyperferritinemia (‘cytokine storm’), and (iii) thrombocytosis (coagulopathy). The mean incubation period forCOVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The meanviral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients,respectively. However, about 25–70% of virus-free COVID-19 survivors continue to sustain virus-inducedHMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new ‘onset’ clinicalincidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patientsexperience several debilitating clinical condition(s) with >200 different and overlapping symptoms that maylast for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-relatedpathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innatehost responses. Based on HMRD and virus-free clinical impairments of different human organs/systems,PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%)with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxietydisorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4(10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viralhijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage tomultiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. Wehave also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precisionnutrients to reset HMRD for health recovery of PASC patients.
(
... Given the almost negligible detection of viral RNA in the cerebrospinal fluid or brain tissue sections of patients with COVID-19, 40 researchers are more inclined to attribute changes in brain structure to indirect brain damage rather than virus-specific damage. 41 The invasion of SARS-CoV-2 induces a pro-inflammatory cytokine response that elevates mediators such as interleukin-6, tumor necrosis factor and IFNc, activating immune responses involving CD8þ cytotoxic T cells, CD4þ helper T cells and B cells. 42,43 The peripheral immune system communicates bidirectionally with the central nervous system through cytokines and other pro-inflammatory mediators that penetrate the bloodbrain barrier, inducing neuroinflammation in the brain. ...
Background
Observational studies have reported structural changes in the brains of patients with coronavirus disease 2019 (COVID-19); it remains unclear whether these associations are causal.
Aim
We evaluated the causal effects of COVID-19 susceptibility, hospitalization and severity on cortical structures.
Design
Mendelian randomization (MR) study.
Methods
Data on the different COVID-19 phenotypes were obtained from the latest large-scale genome-wide association study (R7) of the COVID-19 Host Genetics Initiative. Brain structure data, including cortical thickness (TH) and surface area (SA), were obtained from the ENIGMA Consortium. Additionally, we employed the round 5 dataset released in January 2021 as the validation cohort. The inverse-variance weighted (IVW) method was used as the primary analysis in MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. We performed enrichment analysis on the MR analyses that passed the sensitivity analysis filtering.
Results
After IVW and sensitivity analyses, we observed causal associations between COVID-19 susceptibility and rostral middle frontal SAw (P = 0.0308, β = −39.1236), cuneus THw (P = 0.0170, β = −0.0121), medial orbitofrontal THw (P = 0.0002, β = 0.0225), postcentral THw (P = 0.0217, β = −0.0106), temporal pole THw (P = 0.0077, β = 0.0359), medial orbitofrontal SAnw (P = 0.0106, β = −24.0397), medial orbitofrontal THnw (P = 0.0007, β = 0.0232), paracentral SAnw (P = 0.0483, β = −20.1442), rostral middle frontal SAnw (P = 0.0368, β = −81.9719) and temporal pole THnw (P = 0.0429, β = 0.0353). COVID-19 hospitalization had causal effects on medial orbitofrontal THw (P = 0.0053, β = 0.0063), postcentral THw (P = 0.0143, β = −0.0042), entorhinal THnw (P = 0.0142, β = 0.0142), medial orbitofrontal THnw (P = 0.0147, β = 0.0065) and paracentral SAnw (P = 0.0119, β = −7.9970). COVID-19 severity had causal effects on rostral middle frontal SAw (P = 0.0122, β = −11.8296), medial orbitofrontal THw (P = 0.0155, β = 0.0038), superior parietal THw (P = 0.0291, β = −0.0021), lingual SAnw (P = 0.0202, β = −11.5270), medial orbitofrontal THnw (P = 0.0290, β = 0.0039), paracentral SAnw (P = 0.0180, β = −5.7744) and pars triangularis SAnw (P = 0.0151, β = −5.4520).
Conclusion
Our MR results demonstrate a causal relationship between different COVID-19 phenotypes and cortical structures.
... Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen for COVID-19, demonstrates a predilection for binding to angiotensin-converting enzyme 2 (ACE2) [21], a receptor found across multiple organ systems, including neural tissues [22]. Previous studies have reported cases of cranial nerve infections following COVID-19, as well as cognitive impairment due to diffuse white matter damage [23,24]. Symptoms such as loss of smell and Bell's palsy also result from olfactory and facial nerve involvement [25,26]. ...
Background and Objectives: Patients recovering from mild coronavirus disease (COVID-19) reportedly have dysphagia or difficulty in swallowing. We compared the prevalence of dysphagia between patients diagnosed with mild COVID-19 and those diagnosed with aspiration pneumonia alone. Materials and Methods: A retrospective study was conducted from January 2020 to June 2023 in 160 patients referred for a videofluoroscopic swallowing study (VFSS) to assess for dysphagia. The cohort included 24 patients with mild COVID-19 and aspiration pneumonia, 30 with mild COVID-19 without aspiration pneumonia, and 106 with aspiration pneumonia alone. We reviewed the demographic data, comorbidities, and VFSS results using the penetration–aspiration scale (PAS) and functional dysphagia scale (FDS). Results: In a study comparing patients with mild COVID-19 (Group A) and those with aspiration pneumonia alone (Group B), no significant differences were observed in the baseline characteristics, including the prevalence of dysphagia-related comorbidities between the groups. Group A showed milder dysphagia, as evidenced by lower PAS and FDS scores, shorter oral and pharyngeal transit times (p = 0.001 and p = 0.003, respectively), and fewer residues in the vallecula and pyriform sinuses (p < 0.001 and p < 0.03, respectively). When Group A was subdivided into those with COVID-19 with (Group A1) and without aspiration pneumonia (Group A2), both subgroups outperformed Group B in terms of specific VFSS metrics, such as oral transit time (p = 0.01), pharyngeal transit time (p = 0.04 and p = 0.02, respectively), and residue in the vallecula (p = 0.04 and p = 0.02, respectively). However, Group B showed improved triggering of the pharyngeal swallowing reflex compared with Group A2 (p = 0.02). Conclusion: Mild COVID-19 patients showed less severe dysphagia than those with aspiration pneumonia alone. This finding was consistent across VFSS parameters, even when the COVID-19 group was subdivided based on the status of aspiration pneumonia.
... Somit ist von einer persistierenden Infektion des ZNS NICHT auszugehen. Eine rezente Studie zeigt, dass inflammatorische Komponenten im Gehirn indirekte Ursache einer SARS-CoV-2-Infektion sind [106] und es sich nicht um ein neurotropes Virus handelt [105]. ...
... Auf der anderen Seite weisen sie in den Limitationen jedoch auch darauf hin, dass sich bei Hinzuziehen von weiteren Messmethoden auch andere Ergebnisse zeigen könnten[104]. Dem heutigen Stand entsprechend, ist SARS-CoV-2 kein neurotropes Virus[105], entsprechende Auffälligkeiten im Gehirn dürften auf eine indirekte Entzündungsreaktion zurückzuführen sein[106].Zusammenfassend bestehen derzeit unterschiedliche Hypothesen zur Pathogenese des Post-COVID-Zustandes wie virale Persistenz und Reaktivierung, autoimmunologische Mechanismen, hormonelle Dysfunktion, Mikrobiom-und Metabolomveränderungen sowie endotheliale Störungen, die möglicherweise auch gleichzeitig auftreten könnten. Es könnten somit bei einer Person verschiedene Ursachen für die bestehenden Symptome zu finden sein, wodurch die weitere Beforschung der adäquaten Patient:innenstratifizierung herausfordernd ist. ...
Zusammenfassung
Die vorliegende Leitlinie S1 ist die Aktualisierung und Weiterentwicklung der Leitlinie S1 Long COVID: Differenzialdiagnostik und Behandlungsstrategien. Sie fasst den Stand der Kenntnis zu postviralen Zuständen anhand des Beispiels Long/Post COVID zum Zeitpunkt des Redaktionsschlusses zusammen. Aufgrund der starken Dynamik der Wissensentwicklung versteht sie sich als „living guideline“. Der Schwerpunkt liegt auf der praktischen Anwendbarkeit auf der Ebene der hausärztlichen Primärversorgung, die als geeignete Stelle für den Erstzutritt und für die primäre Betreuung und Behandlung verstanden wird. Die Leitlinie gibt Empfehlungen zum Versorgungsgang, zu Differenzialdiagnostik der häufigsten Symptome, die in der Folge einer Infektion wie mit SARS-CoV‑2 auftreten können, zu therapeutischen Optionen, zu Patient:innenführung und -betreuung sowie zur Wiedereingliederung in den Alltag und zur Rehabilitation. Entsprechend des Krankheitsbildes ist die Leitlinie in einem interdisziplinären und interprofessionellen Prozess entstanden und gibt Empfehlungen zu Schnittstellen und Kooperationsmöglichkeiten.
... Also of utmost importance is the causal plausibility and, thus, diagnostic certainty of whether the reported neurological complaints are due to a previous SARS-CoV-2 infection or to another medical (e.g., concomitant or new disease) or nonmedical (e.g., psychosocial factors related to the pandemic crisis) cause. Currently, there is no evidence of SARS-CoV-2 being a neurotropic virus [10,11]. Several publications suggested psychological mechanisms behind the symptoms [12,13]. ...
... Fleischer et al. [7], and are covered by scientific progress. Currently, it is believed that SARS-CoV-2 is not a neurotropic virus and does not cause damage to olfactory sensory neurons, which have been considered a migration gateway to the central nervous system [10,11]. Based on postmortem findings in 85 corona-afflicted patients, they suggest that actually the sustentacular (supporting) cells of the epithelium are transiently damaged, which causes transient anosmia and ageusia [50]. ...
Introduction:
Following increasing demands of patients with suspected neurological symptoms after infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the Department of Neurology at the Medical University of Vienna established a new outpatient clinic to systematically assess, diagnose and document neurological complaints potentially associated with a prior SARS-CoV-2 infection.
Methods:
The data presented here include prospectively collected 156 outpatients from May 2021 to April 2022. Patients underwent semi-standardized interviewing about symptoms with reported onset after SARS CoV-2 infection, neurological examination, and comprehensive diagnostic workup.
Results:
Reported new-onset symptoms after infection included fatigue (77.6%), subjective cognitive impairment (72.4%), headache (47.7%), loss of smell and/or taste (43.2%), and sleep disturbances (42.2%). Most patients had a mild coronavirus disease (COVID-19) disease course (84%) and reported comorbidities (71%), thereof the most frequent were psychiatric disorders (34%). Frequency of symptoms was not associated with age, sex, or severity of COVID-19 course. A comprehensive diagnostic workup revealed no neurological abnormalities in the clinical examination, electrophysiological, or imaging assessments in the majority of patients (n=143, 91.7%). Neuropsychological assessment of a subgroup of patients (n = 28, 17.9%) showed that cognitive impairments in executive functions and attention, anxiety, depression, and somatization symptoms were highly common.
Conclusion:
In this systematic registry we identified fatigue, cognitive impairment, and headache as the most frequently reported persisting complaints after SARS-CoV-2 infection. Structural neurological findings were rare. We suspect a link between the growing burden of the COVID pandemic on personal lives and the increase in reported neurological and psychiatric complaints.
Background
Long COVID presents persistent neurological symptoms, including brain fog, with limited therapeutic options. Intravenous Laser Irradiation of Blood (ILIB) has been proposed as a potential intervention. This pilot study explores the efficacy of ILIB in alleviating brain fog symptoms and examines the underlying molecular mechanisms.
Aim
To evaluate the effectiveness of ILIB in improving cognitive function in long COVID patients with brain fog and to investigate the molecular pathways involved.
Design
A prospective, single-center pilot study involving six long COVID patients with brain fog who underwent ILIB therapy.
Methods
Patients received 30 ILIB sessions over eight weeks. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and Athens Insomnia Scale (AIS) at baseline, post-treatment, and one-month follow-up. RNA sequencing and pathway enrichment analyses (KEGG, Gene Ontology) identified differentially expressed genes and molecular pathways influenced by ILIB.
Results
MoCA and AIS scores significantly improved post-ILIB, suggesting enhanced cognitive function and sleep quality. RNA sequencing revealed 141 upregulated and 130 downregulated genes. Upregulated pathways were associated with mitochondrial electron transport and oxidative phosphorylation, while immune response and inflammatory pathways were downregulated. Notably, the glutathione metabolism pathway was significantly altered, suggesting reduced oxidative stress.
Conclusions
ILIB shows potential in alleviating brain fog symptoms in long COVID patients, possibly through modulation of oxidative stress, mitochondrial function, and inflammation. However, larger randomized controlled trials are needed to confirm these findings and establish ILIB as a viable therapeutic option.
SARS‐CoV‐2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is critical for the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. This single-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates a plethora of virus–host protein–protein interactions in the human body. These extensive viral protein interactions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as altered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectious process, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii) hyperferritinemia (‘cytokine storm’), and (iii) thrombocytosis (coagulopathy). The mean incubation period for COVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The mean viral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients, respectively. However, about 25–70% of virus-free COVID-19 survivors continue to sustain virus-induced HMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new ‘onset’ clinical incidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patients experience several debilitating clinical condition(s) with >200 different and overlapping symptoms that may last for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-related pathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innate host responses. Based on HMRD and virus-free clinical impairments of different human organs/systems, PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%) with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viral hijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage to multiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. We have also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precision nutrients to reset HMRD for health recovery of PASC patients.
Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later stages, yet the mechanisms that contribute to this remain unclear. Here we profiled single-nucleus transcriptomes and proteomes of brainstem tissue from deceased individuals at various stages of COVID-19. We detected an inflammatory type I interferon response in acute COVID-19 cases, which resolves in the late disease phase. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation, one neuronal with a direct focus on cranial nerve nuclei and a separate diffuse pattern affecting the whole brainstem. The latter reflects a bystander effect of the respiratory infection that spreads throughout the vascular unit and alters the transcriptional state of mainly oligodendrocytes, microglia and astrocytes, while alterations of the brainstem nuclei could reflect the connection of the immune system and the central nervous system via, for example, the vagus nerve. Our results indicate that even without persistence of severe acute respiratory syndrome coronavirus 2 in the central nervous system, local immune reactions are prevailing, potentially causing functional disturbances that contribute to neurological complications of COVID-19.
