May 2022 - Pathophysiology
This is a new literature review updated on may 2022. In case some essential information is missing, please contact us at: rafael@hcuge.ch.
The immunology and immunopathology of COVID-19
Merad M, Blish CA, Sallusto F, Iwasaki A. Science. 2022 Mar 11;375(6585):1122-1127. doi: 10.1126/science.abm8108. Epub 2022 Mar 10. PMID: 35271343.
Link to study: The immunology and immunopathology of COVID-19
SARS-CoV-2 is associated with changes in brain structure in UK Biobank
Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JLR, Griffanti L, Duff E, Jbabdi S, Taschler B, Keating P, Winkler AM, Collins R, Matthews PM, Allen N, Miller KL, Nichols TE, Smith SM. Nature. 2022 Mar 7. doi: 10.1038/s41586-022-04569-5. Epub ahead of print. PMID: 35255491.
Link to study SARS-CoV-2 is associated with changes in brain structure in UK Biobank
Alzheimer's-like signaling in brains of COVID-19 patients
Reiken S, Sittenfeld L, Dridi H, Liu Y, Liu X, Marks AR. Alzheimers Dement. 2022 Feb 3. doi: 10.1002/alz.12558. Epub ahead of print. PMID: 35112786.
De-identified human heart, lung, and brain tissue were obtained from the COVID BioBank at Columbia University for 10 patients. The cortex samples were from the mesial temporal lobe and the cerebellum samples were from the cerebellar cortex, lateral hemisphere. Age- and sex-matched controls exhibited absence of neurological disorders and cardiovascular or pulmonary diseases. Brain lysates from control and COVID-19 patients were analyzed for oxidative stress and inflammatory signaling pathway markers, and measurements of Alzheimer’s disease (AD)-linked signaling biochemistry. Post-translational modifications of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endoplasmic reticuli (ER), known to be linked to AD, were also measured by co-immunoprecipitation/immunoblotting of the brain lysates. Results showed an association between SARS-CoV-2 infection and the activation of TGF-β signaling and oxidative overload. The neuropathological pathways causing tau hyperphosphorylation typically associated with Alzheimer’s Dementia were also shown to be activated in COVID-19 patients. RyR2 in COVID-19 brains demonstrated a “leaky” phenotype, which can promote cognitive and behavioral defects. COVID-19 neuropathology includes Alzheimer Dementia-like features and leaky RyR2 channels could be a therapeutic target for amelioration of some cognitive defects associated with SARS-CoV-2 infection and long COVID.
Link to study: Alzheimer's-like signaling in brains of COVID-19 patients
A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications
Kell DB, Laubscher GJ, Pretorius E. Biochem J. 2022 Feb 17;479(4):537-559. doi: 10.1042/BCJ20220016. PMID: 35195253.
Authors evaluate extensive fibrin amyloid microclots that can persist in platelet-poor plasma (PPP) of individuals with Long COVID, can entrap other proteins, and may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, authors argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored 'triple' anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.
Link to study : A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications
Molecular imaging findings on acute and long-term effects of COVID-19 on the brain: A systematic review
Meyer PT, Hellwig S, Blazhenets G, Hosp JA. J Nucl Med. 2022 Feb 17:jnumed.121.263085. doi: 10.2967/jnumed.121.263085. Epub ahead of print. PMID: 35177424.
Authors provide a systematic review that summarizes the current literature on molecular imaging techniques like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) according to five predominant topics: 1. Few case reports suggest reversible cortical and subcortical metabolic alterations in rare cases with concomitant, para- or post-infectious encephalitis. 2. Imaging findings in single patients with first manifestations of parkinsonism in the context of COVID-19 resemble those in neurodegenerative parkinsonism (loss of nigrostriatal integrity), but scarceness of data and a lack of follow-up preclude further etiological conclusions (e.g., unmasking/hastening of neurodegeneration vs. (para-) infectious parkinsonism). 3. Several case reports and few systematic studies addressed focal symptoms and lesions, most notably hyposmia. Results are variable, although some studies found regional hypometabolism of regions related to olfaction (e.g., orbitofrontal and mesiotemporal). 4. A case series and systematic studies in inpatients with COVID-19-related encephalopathy (acute to subacute stage) consistently found a frontoparietal-dominant neocortical dysfunction (on imaging and clinically) that proved to be grossly reversible in the majority of cases until 6 months. 5. Studies in "Post-COVID-19 syndrome" provided controversial results. In patients with a high level of self-reported complaints (e.g., fatigue, memory impairment, hyposmia, dyspnea) some authors found extensive areas of limbic and subcortical hypometabolism, while others found no metabolic alterations on PET and only minor cognitive impairments (if any) on neuropsychological assessment.
Link to study : Molecular imaging findings on acute and long-term effects of COVID-19 on the brain: A systematic review
Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study
Maamar M, Artime A, Pariente E, Fierro P, Ruiz Y, Gutiérrez S, Tobalina M, Díaz-Salazar S, Ramos C, Olmos JM, Hernández JL. Curr Med Res Opin. 2022 Feb 15:1-26. doi: 10.1080/03007995.2022.2042991. Epub ahead of print. PMID: 35166141.
Authors analysed 121 mild COVID-19 cases (mean age =45.7 years, 56.2% women). Among the acute symptoms, women presented a higher frequency of fatigue (54.4% vs 30.2%; p= 0.008). Post-COVID syndrome (PCS) affected 35.8% of women and 20.8% of men (p = 0.07), and the most reported symptoms were fatigue (42.8%), anosmia (40%), ageusia (22.8%), dyspnea (17.1%) and myalgia (11.4%). Neutrophil count, NLR, CRP and fibrinogen showed the best correlations with PCS, and were selected to develop the indices. In women PCS+, C1, C3 and C4 indices were more frequently met, while in men PCS+, C2, C5 and CRP in range of LGI. Anosmia, ageusia and fatigue were related to higher neutrophil counts, with sex differences. Fibrinogen levels were higher in persistent myalgia (510 ± 82 mg/dL vs 394 ± 87;p = 0.013). In multivariable analysis, a woman with a neutrophil count above the median, or with fibrinogen level or NLR in the highest tertile, had a 4- to 5-fold increased risk of prevalent PCS. A man with CRP in range of LGI, or fibrinogen level or a neutrophil count in the highest tertile, had a 10- to 17-fold increased risk of prevalent PCS. The data obtained in the present cross-sectional study seems to demonstrate a consistent association between PCS and upper ranges of the neutrophil count, NLR, fibrinogen, and CRP in the LGI range. Furthermore, composite indices appear useful in detecting relationships between slight elevations of biomarkers and PCS, and our study identifies relevant sex differences in symptoms and markers regarding the PCS.
Link to study: Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: a cross-sectional study
Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVID-19 respiratory disease
Vijayakumar B, Boustani K, Ogger PP, Papadaki A, Tonkin J, Orton CM, Ghai P, Suveizdyte K, Hewitt RJ, Desai SR, Devaraj A, Snelgrove RJ, Molyneaux PL, Garner JL, Peters JE, Shah PL, Lloyd CM, Harker JA. Immunity. 2022 Jan 26:S1074-7613(22)00046-2. doi: 10.1016/j.immuni.2022.01.017. Epub ahead of print. PMID: 35151371; PMCID: PMC8789571.
Authors evaluated 38 patients undergoing bronchoscopy for the investigation of persistent respiratory abnormalities 3–6 months following acute SARS-CoV-2 infection and delineated the immune-proteomic landscape in the airways and peripheral blood 3 to 6 months after hospital discharge compared to 29 healthy volunteers recruited prior to the COVID-19 pandemic as controls. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with an elevated concentration of proteins associated with apoptosis, tissue repair, and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. A one-year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to the ongoing activation of cytotoxic T cells.
Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations
Vestad B, Ueland T, Lerum TV, Dahl TB, Holm K, Barratt-Due A, Kåsine T, Dyrhol-Riise AM, Stiksrud B, Tonby K, Hoel H, Olsen IC, Henriksen KN, Tveita A, Manotheepan R, Haugli M, Eiken R, Berg Å, Halvorsen B, Lekva T, Ranheim T, Michelsen AE, Kildal AB, Johannessen A, Thoresen L, Skudal H, Kittang BR, Olsen RB, Ystrøm CM, Skei NV, Hannula R, Aballi S, Kvåle R, Skjønsberg OH, Aukrust P, Hov JR, Trøseid M. J Intern Med. 2022 Feb 25. doi: 10.1111/joim.13458. Epub ahead of print. PMID: 35212063.
In Norway, plasma was collected during hospital admission and after three months from the NOR-Solidarity trial (n = 181) and analysed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analysed by sequencing the 16S rRNA gene.Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal three months after hospitalisation. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalisation, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 -(P/F ratio) < 26.6 kPa. LBP levels remained elevated during and after hospitalisation and were associated with low-grade inflammation and respiratory dysfunction after three months. Respiratory dysfunction after COVID-19 is associated with altered gut microbiota and persistently elevated LBP levels.
Link to study: Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations
Autoimmunity is a hallmark of post-COVID syndrome
Rojas M, Rodríguez Y, Acosta-Ampudia Y, Monsalve DM, Zhu C, Li QZ, Ramírez-Santana C, Anaya JM. J Transl Med. 2022 Mar 16;20(1):129. doi: 10.1186/s12967-022-03328-4. PMID: 35296346; PMCID: PMC8924736.
Lien vers l'article scientifique : Autoimmunity is a hallmark of post-COVID syndrome
