Tag: long covid symptoms

Longitudinal Progression of Patients with Long COVID Treated in a Post-COVID Clinic: A Cross-Sectional Survey

Abstract:

Background: In addition to the morbidity and mortality associated with acute infection, COVID-19 has been associated with persistent symptoms (>30 days), often referred to as Long COVID (LC). LC symptoms often cluster into phenotypes, resembling conditions such as fibromyalgia, postural orthostatic tachycardiac syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). LC clinics have been established to best address the needs of LC patients and continuity of care. We developed a cross-sectional survey to assess treatment response through our LC Clinic (LCC).

Methods: A 25-question survey (1-10 Likert scale) was expert- and content-validated by LCC clinicians, patients, and patient advocates. The survey assessed LC symptoms and the helpfulness of different interventions, including medications and supplements. A total of 852 LCC patients were asked to complete the survey, with 536 (62.9%) responding.

Results: The mean time from associated COVID-19 infection to survey completion was 23.2 ± 6.4 months. The mean age of responders was 52.3 ± 14.1 (63% females). Self-reported symptoms were all significantly improved (P < .001) from the initial visit to the LCC (baseline) to the time of the follow-up survey. However, only 4.5% (24/536) of patients rated all symptoms low (1-2) at the time of the survey, indicating low levels of full recovery in our cohort. The patients rated numerous interventions as being helpful, including low-dose naltrexone (45/77; 58%), vagal nerve stimulation (18/34; 53%), and fisetin (28/44; 64%).

Conclusions: Patients report general improvements in symptoms following the initial LCC visit, but complete recovery rates remain low at 23.2 ± 6.4 months.

Source: Hurt RT, Yadav S, Schroeder DR, Croghan IT, Mueller MR, Grach SL, Aakre CA, Gilman EA, Stephenson CR, Overgaard J, Collins NM, Lawson DK, Thompson AM, Natividad LT, Mohamed Elfadil O, Ganesh R. Longitudinal Progression of Patients with Long COVID Treated in a Post-COVID Clinic: A Cross-Sectional Survey. J Prim Care Community Health. 2024 Jan-Dec;15:21501319241258671. doi: 10.1177/21501319241258671. PMID: 38813984. https://journals.sagepub.com/doi/10.1177/21501319241258671 (Full text)

Examining well-being and cognitive function in people with long Covid and ME/CFS, and age-matched healthy controls: A Case-Case-Control Study

Abstract:

Purpose: Well-being and cognitive function had not previously been compared between people with long COVID and people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Therefore, this study examined well-being and cognitive function in people with long COVID (∼16 months illness duration; n= 17) and ME/CFS (∼16 years illness duration; n=24), versus age-matched healthy controls (n=16).

Methods: Well-being was examined using several questionnaires, namely the Health Visual Analogue Scale (VAS), Fatigue Severity Scale (FSS), Post-exertional malaise (PEM), Pittsburgh Sleep Quality Index (PSQI), European Quality of Life-5 Domains (EQ-5D), MRC Dyspnoea, Self-Efficacy (SELTC), The Edinburgh Neurosymptoms Questionnaire (ENS), General Anxiety Disorder 7 (GAD-7), and Patient Health Questionnaire 9 (PHQ-9). Cognitive function was examined using Single Digit Modalities Test (SDMT), Stroop test, and Trails A and B. These were delivered via a mobile application (app) built specifically for this remote data collection.

Results: The main findings of the present investigation were that people with ME/CFS and people with long COVID were generally comparable on all well-being and cognitive function measures, but self-reported worse values for pain, fatigue, Post-exertional malaise, sleep quality, general well-being in relation to mobility, usual activities, self-care, breathlessness, neurological symptoms, self-efficacy, and other well-being such as anxiety and depression, compared to controls. There was no effect of group for cognitive function measures.

Conclusions: These data suggest that both people with long COVID and people with ME/CFS have similar impairment on well-being measures examined herein. Therefore, interventions that target well-being of people with ME/CFS and long COVID are required.

Source: Sanal-Hayes NEM, Mclaughlin M, Hayes LD, Berry ECJ, Sculthorpe NF. Examining well-being and cognitive function in people with long Covid and ME/CFS, and age-matched healthy controls: A Case-Case-Control Study. Am J Med. 2024 May 13:S0002-9343(24)00273-0. doi: 10.1016/j.amjmed.2024.04.041. Epub ahead of print. PMID: 38750713. https://www.amjmed.com/article/S0002-9343(24)00273-0/fulltext (Full text)

Persistence of SARS-CoV-2 in Platelets and Megakaryocytes in Long COVID

Abstract:

Background: We have shown that acute COVID-19 pathophysiology is profoundly altered by infection of lung megakaryocytes (MKs) and platelets by SARS‑CoV‑2 (Zhu et al, 2022). A significant proportion of COVID-19 patients have symptoms persisting for > 3 months after initial infection with SARS-CoV-2, referred to as Long COVID or Post-acute Sequelae of SARS-CoV-2 (PASC) patients. Persistent or re-emerging symptoms are varied, with a predominance of asthenia, neuro-cognitive impairment and cardio-vascular symptoms. The pathophysiology underlying long-onset COVID remains poorly understood.

Methods: Blood was collected from patients with Long COVID with symptoms duration > 3 months (LC) (n=30), previously infected by SARS-CoV-2 but without persistent symptoms (resolved COVID-19 (CR), n=10), or healthy donor (n=20). MK frequency in blood was quantified by flow cytometry. Platelets and blood MKs were analysed for microclots, the presence of Spike protein and SARS-CoV-2 RNA by in situ hybridization and immunodetection visualized by confocal microscopy. Spike and serotonin were quantified in plasma.

Results: The frequency of CD41+ MKs in peripheral blood mononucleated cells (PBMCs) was significantly higher than healthy donors (0.28±0.05 versus 0.03±0.02) as a sign of MK infection, as we previously shown in acutely infected individuals with SARS-CoV-2 in platelets. Accordingly, in all samples analyzed, circulating MK in Long COVID sheltered both Spike and SARS-CoV-2 ssRNA, but also dsRNA suggestive of viral replication. These infected MKs produced blood platelets that contain also P Spike and SARS-CoV-2 ssRNA. Platelets microclots were detected in all tested Long COVID patients. Spike protein was detected at the pg level in 30 % of analyzed plasma from Long COVID but not CR individuals. The level of serotonin in platelet and of tryptophan hydroxylase-1 (TPH-1), the enzyme that regulates serotonin synthesis decreased significantly (p<0.0001) in blood of Long COVID patients compared to CR individuals.

Conclusions: In patients developing Long COVID, SARS-CoV-2 persists and replicates in MKs producing virus-containing platelets. The presence of spike in plasma might be an additional sign of viral persistence that could be used as a Long COVID biomarker. The presence of the virus could lead to abnormal platelet activation and the formation of microclots, which would contribute to the various symptoms and to deregulation of serotonin uptake, contributing to the neurocognitive symptoms observed in long-onset COVID.

Source: Feifan He, Boxin Huang, Andrea Cottignies-Calamarte, Wiem Bouchneb, Agathe Goubard, Faroudy Boufassa, Jacques Callebert, Dominique Salmon, Morgane Bomsel. Persistence of SARS-CoV-2 in Platelets and Megakaryocytes in Long COVID. The Conference on Retroviruses and Opportunistic Infections (CROI), March 3-6, 2024 | Denver, Colorado. https://www.croiconference.org/abstract/persistence-of-sars-cov-2-in-platelets-and-megakaryocytes-in-long-covid/ 

Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy

Abstract:

Post-COVID condition (PCC) and multiple sclerosis (MS) share some clinical and demographic features, including cognitive symptoms and fatigue. Some pathophysiological mechanisms well-known in MS, such as autoimmunity, neuroinflammation and myelin damage, have also been implicated in PCC. In this study, we aimed to compare the cognitive phenotypes of two large cohorts of patients with PCC and MS, and to evaluate the relationship between fatigue and cognitive performance.

Cross-sectional study including 218 patients with PCC and 218 with MS matched by age, sex, and years of education. Patients were evaluated with a comprehensive neuropsychological protocol and were categorized according to the International Classification of Cognitive Disorders system. Fatigue and depression were also assessed.

Cognitive profiles of PCC and MS largely overlapped, with a greater impairment in episodic memory in MS, but with small effect sizes. The most salient deficits in both disorders were in attention and processing speed. The severity of fatigue was greater in patients with PCC. Still, the correlations between fatigue severity and neuropsychological tests were more prominent in the case of MS. There were no differences in the severity of depression among groups. Our study found similar cognitive profiles in PCC and MS. Fatigue was more severe in PCC, but was more associated with cognitive performance in MS. Further comparative studies addressing the mechanisms related to cognitive dysfunction and fatigue may be of interest to advance the knowledge of these disorders and develop new therapies.

Source: Delgado-Alonso C, Delgado-Alvarez A, Díez-Cirarda M, Oliver-Mas S, Cuevas C, Montero-Escribano P, Ramos-Leví AM, Gil-Moreno MJ, López-Carbonero JI, Hermann BP, Matias-Guiu J, Matias-Guiu JA. Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy. Sci Rep. 2024 Apr 29;14(1):9806. doi: 10.1038/s41598-024-60368-0. PMID: 38684843; PMCID: PMC11059260. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11059260/ (Full text)

PASC (Post Acute Sequelae of COVID-19) is associated with decreased neutralizing antibody titers in both biological sexes and increased ANG-2 and GM-CSF in females

Abstract:

Post-acute sequelae of COVID-19 (PASC) or the continuation of COVID-19 (Coronavirus disease 2019) symptoms past 12 weeks may affect as many as 30% of people recovering from a SARS-CoV-2 (severe acute respiratory coronavirus 2) infection. The mechanisms regulating the development of PASC are currently not known; however, hypotheses include virus reservoirs, pre-existing conditions, microblood clots, immune dysregulation, as well as poor antibody responses. Importantly, virus neutralizing antibodies are essential for COVID-19 recovery and protection from reinfection but there is currently limited information on these immune regulators and associated cytokines in PASC patients. Understanding the key drivers of general and specific symptoms associated with Long COVID and the presence of virus neutralizing antibodies in PASC will aid in the development of therapeutics, diagnostics, and vaccines which currently do not exist.

We designed a cross-sectional study to investigate systemic antibody and cytokine responses during COVID-19 recovery and PASC. In total, 195 participants were recruited in one of four groups: (1) Those who never had COVID-19 (No COVID); (2) Those in acute COVID-19 recovery (Acute Recovery) (4–12 weeks post infection); (3) Those who recovered from COVID-19 (Recovered) (+ 12 weeks from infection); and (4) those who had PASC (PASC) (+ 12 weeks from infection). Participants completed a questionnaire on health history, sex, gender, demographics, experiences with COVID-19 acute and COVID-19 recovery/continuing symptoms. Serum samples collected were evaluated for antibody binding to viral proteins, virus neutralizing antibody titers, and serum cytokine levels using Ella SimplePlex Immunoassay™ panels.

We found participants with PASC reported more pre-existing conditions (e.g. such as hypertension, asthma, and obesity), and PASC symptoms (e.g. fatigue, brain fog, headaches, and shortness of breath) following COVID-19 than COVID-19 Recovered individuals. Importantly, we found PASC individuals to have significantly decreased levels of neutralizing antibodies toward both SARS-CoV-2 and the Omicron BA.1 variant. Sex analysis indicated that female PASC study participants had sustained antibody levels as well as levels of the inflammatory cytokines GM-CSF and ANG-2 over time following COVID-19.

Our study reports people experiencing PASC had lower levels of virus neutralizing antibodies; however, the results are limited by the collection time post-COVID-19 and post-vaccination. Moreover, we found females experiencing PASC had sustained levels of GM-CSF and ANG-2. With lower levels of virus neutralizing antibodies, this data suggests that PASC individuals not only have had a suboptimal antibody response during acute SARS-CoV-2 infection but may also have increased susceptibility to subsequent infections which may exacerbate or prolong current PASC illnesses. We also provide evidence suggesting GM-CSF and ANG-2 to play a role in the sex-bias of PASC. Taken together, our findings maybe important for understanding immune molecular drivers of PASC and PASC subgroups.

Source: Jansen EB, Ostadgavahi AT, Hewins B, Buchanan R, Thivierge BM, Sganzerla Martinez G, Goncin U, Francis ME, Swan CL, Scruten E, Bell J, Darbellay J, Facciuolo A, Falzarano D, Gerdts V, Fenton ME, Hedlin P, Kelvin DJ, Kelvin AA. PASC (Post Acute Sequelae of COVID-19) is associated with decreased neutralizing antibody titers in both biological sexes and increased ANG-2 and GM-CSF in females. Sci Rep. 2024 Apr 29;14(1):9854. doi: 10.1038/s41598-024-60089-4. PMID: 38684819; PMCID: PMC11058778. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11058778/ (Full text)

Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition

Abstract:

With an estimated 65 million individuals affected by post-COVID-19 condition (also known as long COVID), non-invasive biomarkers are direly needed to guide clinical management. To address this pressing need, we used blood transcriptomics in a general practice-based case-control study. Individuals with long COVID were diagnosed according to WHO criteria, and validated clinical scales were used to quantify patient-reported outcomes.

Whole blood samples were collected from 48 individuals with long COVID and 12 control individuals matched for age, sex, time since acute COVID-19, severity, vaccination status, and comorbidities (appendix 1 p 2). Digital transcriptomic analysis was performed using the nCounter (Nanostring Technologies, Seattle, WA, USA) platform, as described for critical COVID-19.

Consequently, 212 genes were identified to be differentially expressed between individuals with long COVID and controls (figure A), of which 70 remained significant after adjustment for false discovery rate correction (appendix 1). Several viral RNAs were upregulated: nucleocapsid, ORF7a, ORF3a, Mpro (a nirmatrelvir plus ritonavir [Paxlovid] target), and antisense ORF1ab RNA. Specifically, the upregulation of antisense ORF1ab RNA suggests ongoing viral replication. SARS-CoV-2-related host RNAs (ACE2/TMPRSS2 receptors, DPP4/FURIN proteases) and RNAs prototypical for memory B-cells and platelets were also upregulated (figure A).

Multivariable logistic regression identified antisense SARS-CoV-2 and FYN RNA concentrations as independent predictors of long COVID (corrected for age and sex; appendix 1 p 2). Receiver operating characteristic curve analysis showed significant discrimination (area under curve [AUC] 0·94, 95% CI 0·86–1·00) between individuals with long COVID (n=48) and controls (n=12), with 93·8% sensitivity and 91·7% specificity (figure B).

Single biomarkers antisense SARS-CoV-2 (AUC 0·78, 0·65–0·90) and FYN RNA (AUC 0·89, 0·79–0·99) were significant predictors with lower sensitivity (52·1% and 72·9%, respectively) but similar specificity (91·7% and 100%, respectively; figure B). Upon summarising transcriptomic results into biological pathways, we found significantly decreased immunometabolism in individuals with long COVID, which was negatively correlated with the blood viral load (appendix 1 p 3).

A qualitative analysis of individual SARS-CoV-2 transcript positivity revealed significant differences between individuals with long COVID and controls for antisense (65% vs 25%), ORF7a (60% vs 25%), and nucleocapsid (50% vs 8%) RNAs (figure C). Similarly, the SARS-CoV-2 transcript positivity with respect to the total blood viral load was also significantly different (60% vs 8%).

By use of multivariable logistic regression, we found that age and sex were not associated with the distinction between a low and high viral RNA load status. Conversely, the number of comorbidities (odds ratio [OR] 1·61, 95% CI 1·14–2·49) and COVID vaccine doses (OR 0·36, 0·14–0·79) emerged as independent predictors of distinguishing between low and high viral RNA load status (appendix 2).

We found that viral and immune parameters, such as the antisense Orf1ab RNA concentrations and immunometabolism score, were also linked to the patient-reported anxiety or depression score. Individuals classified as having severe anxiety or depression (with a score of 4 and 5) displayed significantly higher antisense RNA concentrations and lower immunometabolism scores (p<0·05) than those categorised as mild (with scores of 1–3; figure D).

In conclusion, the associations among persistent viral RNA, immunometabolism, and patient-reported outcomes provide mechanistic insights for addressing the challenges posed by long COVID.

Source: Menezes SM, Jamoulle M, Carletto MP, Moens L, Meyts I, Maes P, Van Weyenbergh J. Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition. Lancet Microbe. 2024 Apr 24:S2666-5247(24)00055-7. doi: 10.1016/S2666-5247(24)00055-7. Epub ahead of print. PMID: 38677304. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00055-7/fulltext (Full text)

Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study

Abstract:

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear.

Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Source: Maffitt NJ, Germann M, Baker AME, Baker MR, Baker SN, Soteropoulos DS. Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study. Sci Rep. 2024 Apr 17;14(1):8874. doi: 10.1038/s41598-024-59232-y. PMID: 38632415; PMCID: PMC11024107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024107/ (Full text)

Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19

Abstract:

Objectives: To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment.

Methods: A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention.

Results: Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02).

Discussion: Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN.

Classification of evidence: This study provides Class III evidence. It is a retrospective cohort study.

Source: McAlpine L, Zubair AS, Joseph P, Spudich S. Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200244. doi: 10.1212/NXI.0000000000200244. Epub 2024 Apr 17. PMID: 38630952. https://www.neurology.org/doi/10.1212/NXI.0000000000200244 (Full text)

Exploring Cognitive Dysfunction in Long COVID Patients: Eye Movement Abnormalities and Frontal-Subcortical Circuits Implications via Eye-Tracking and Machine Learning

Abstract:

Background: Cognitive dysfunction is regarded as one of the most severe aftereffects following coronavirus disease 2019 (COVID-19). Eye movements, controlled by various brain regions, including the dorsolateral prefrontal cortex and frontal-thalamic circuits, offer a potential metric for evaluating cognitive dysfunction. We aimed to examine the utility of eye movement measurements in identifying cognitive impairments in long COVID patients.

Methods: We recruited 40 long COVID patients experiencing subjective cognitive complaints and 40 healthy controls and used a certified eye-tracking medical device to record saccades and antisaccades. Machine learning was applied to enhance the analysis of eye movement data.

Results: Patients did not differ from the healthy controls regarding age, sex, and years of education. However, the patients’ Montreal Cognitive Assessment total score was significantly lower than healthy controls. Most eye movement parameters were significantly worse in patients: the latencies, gain, and velocity of visually and memory-guided saccades, the number of correct memory saccades, the latencies and duration of reflexive saccades, and the number of errors in the antisaccade test. Machine learning permitted distinguishing between long COVID patients experiencing subjective cognitive complaints and healthy controls.

Conclusion: Our findings suggest impairments in frontal subcortical circuits in long COVID patients experiencing subjective cognitive complaints. Eye-tracking, combined with machine learning, offers a novel, efficient way to assess and monitor long COVID patients’ cognitive dysfunctions, suggesting its utility in clinical settings for early detection and personalized treatment strategies. Further research is needed to determine the long-term implications of these findings and the reversibility of cognitive dysfunctions.

Source: Benito-León J, Lapeña J, García-Vasco L, Cuevas C, Viloria-Porto J, Calvo-Córdoba A, Arrieta-Ortubay E, Ruiz-Ruigómez M, Sánchez-Sánchez C, García-Cena C. Exploring Cognitive Dysfunction in Long COVID Patients: Eye Movement Abnormalities and Frontal-Subcortical Circuits Implications via Eye-Tracking and Machine Learning. Am J Med. 2024 Apr 5:S0002-9343(24)00217-1. doi: 10.1016/j.amjmed.2024.04.004. Epub ahead of print. PMID: 38583751. https://pubmed.ncbi.nlm.nih.gov/38583751/

Cluster analysis of long COVID symptoms for deciphering a syndrome and its long-term consequence

Abstract:

The long-term symptoms of COVID-19 are the subject of public and scientific discussions. Understanding how those long COVID symptoms co-occur in clusters of syndromes may indicate the pathogenic mechanisms of long COVID. Our study objective was to cluster the different long COVID symptoms. We included persons who had a COVID-19 and assessed long-term symptoms (at least 4 weeks after first symptoms). Hierarchical clustering was applied to the symptoms as well as to the participants based on the Euclidean distance h of the log-values of the answers on symptom severity. The distribution of clusters within our cohort is shown in a heat map.

From September 2021 to November 2023, 2371 persons with persisting long COVID symptoms participated in the study. Self-assessed long COVID symptoms were assigned to three symptom clusters. Cluster A unites rheumatological and neurological symptoms, cluster B includes neuro-psychological symptoms together with cardiorespiratory symptoms, and a third cluster C shows an association of general infection signs, dermatological and otology symptoms. A high proportion of the participants (n = 1424) showed symptoms of all three clusters.

Clustering of long COVID symptoms reveals similarities to the symptomatology of already described syndromes such as the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or rheumatological autoinflammatory diseases. Further research may identify serological parameters or clinical risk factors associated with the shown clusters and might improve our understanding of long COVID as a systemic disease. Furthermore, multimodal treatments can be developed and scaled for symptom clusters and associated impairments.

Source: Niewolik J, Mikuteit M, Klawitter S, Schröder D, Stölting A, Vahldiek K, Heinemann S, Müller F, Behrens G, Klawonn F, Dopfer-Jablonka A, Steffens S. Cluster analysis of long COVID symptoms for deciphering a syndrome and its long-term consequence. Immunol Res. 2024 Apr 16. doi: 10.1007/s12026-024-09465-w. Epub ahead of print. PMID: 38627327. https://link.springer.com/article/10.1007/s12026-024-09465-w (Full text)