Tag: complement system

Probing long COVID through a proteomic lens: a comprehensive two-year longitudinal cohort study of hospitalised survivors

Abstract:

Background: As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not clearly understood, and underlying biomarkers that can affect the long-term consequences of COVID-19 are paramount to be identified.

Methods: Participants for the current study were from a cohort study of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. We profiled the proteomic of plasma samples from hospitalised COVID-19 survivors at 6-month, 1-year, and 2-year after symptom onset and age and sex matched healthy controls. Fold-change of >2 or <0.5, and false-discovery rate adjusted P value of 0.05 were used to filter differentially expressed proteins (DEPs). In-genuity pathway analysis was performed to explore the down-stream effects in the dataset of significantly up- or down-regulated proteins. Proteins were integrated with long-term consequences of COVID-19 survivors to explore potential biomarkers of long COVID.

Findings: The proteomic of 709 plasma samples from 181 COVID-19 survivors and 181 matched healthy controls was profiled. In both COVID-19 and control group, 114 (63%) were male. The results indicated four major recovery modes of biological processes. Pathways related to cell-matrix interactions and cytoskeletal remodeling and hypertrophic cardiomyopathy and dilated cardiomyopathy pathways recovered relatively earlier which was before 1-year after infection. Majority of immune response pathways, complement and coagulation cascade, and cholesterol metabolism returned to similar status of matched healthy controls later but before 2-year after infection. Fc receptor signaling pathway still did not return to status similar to healthy controls at 2-year follow-up. Pathways related to neuron generation and differentiation showed persistent suppression across 2-year after infection. Among 98 DEPs from the above pathways, evidence was found for association of 11 proteins with lung function recovery, with the associations consistent at two consecutive or all three follow-ups. These proteins were mainly enriched in complement and coagulation (COMP, PLG, SERPINE1, SRGN, COL1A1, FLNA, and APOE) and hypertrophic/dilated cardiomyopathy (TPM2, TPM1, and AGT) pathways. Two DEPs (APOA4 and LRP1) involved in both neuron and cholesterol pathways showed associations with smell disorder.

Interpretation: The study findings provided molecular insights into potential mechanism of long COVID, and put forward biomarkers for more precise intervention to reduce burden of long COVID.

Source: Gu X, Wang S, Zhang W, Li C, Guo L, Wang Z, Li H, Zhang H, Zhou Y, Liang W, Li H, Liu Y, Wang Y, Huang L, Dong T, Zhang D, Wong CCL, Cao B. Probing long COVID through a proteomic lens: a comprehensive two-year longitudinal cohort study of hospitalised survivors. EBioMedicine. 2023 Nov 2;98:104851. doi: 10.1016/j.ebiom.2023.104851. Epub ahead of print. PMID: 37924708. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00417-6/fulltext (Full text)

Relevance of complement immunity with brain fog in patients with long COVID

Abstract:

Introduction: This study aimed to elucidate the prevalence and clinical characteristics of patients with long COVID (coronavirus disease 2019), especially focusing on 50% hemolytic complement activity (CH50).

Methods: This retrospective observational study focused on patients who visited Okayama University Hospital (Japan) for the treatment of long COVID between February 2021 and March 2023. CH50 levels were measured using liposome immunometric assay (Autokit CH50 Assay, FUJIFILM Wako Pure Chemical Corporation, Japan); high CH50 was defined as ≥59 U/mL. Univariate analyses assessed differences in the clinical background, long COVID symptoms, inflammatory markers, and clinical scores of patients with normal and high CH50. Logistic regression model investigated the association between high CH50 levels and these factors.

Results: Of 659 patients who visited our hospital, 478 patients were included. Of these, 284 (59.4%) patients had high CH50 levels. Poor concentration was significantly more frequent in the high CH50 group (7.2% vs. 13.7%), whereas no differences were observed in other subjective symptoms (fatigue, headache, insomnia, dyspnea, tiredness, and brain fog). Multivariate analysis was performed on factors that could be associated with poor concentration, suggesting a significant relationship to high CH50 levels (adjusted odds ratio [aOR], 2.70; 95% confidence interval [CI], 1.33–5.49). Also, high CH50 was significantly associated with brain fog (aOR, 1.66; 95% CI, 1.04–2.66).

Conclusions: High CH50 levels were frequently reported in individuals with long COVID, indicating a relationship with brain fog. Future in-depth research should examine the pathological role and causal link between complement immunity and the development of long COVID.

Source: Hagiya H, Tokumasu K, Otsuka Y, Sunada N, Nakano Y, Honda H, Furukawa M, Otsuka F. Relevance of complement immunity with brain fog in patients with long COVID. J Infect Chemother. 2023 Oct 20:S1341-321X(23)00261-1. doi: 10.1016/j.jiac.2023.10.016. Epub ahead of print. PMID: 37866620. https://www.sciencedirect.com/science/article/abs/pii/S1341321X23002611

Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms

Abstract:

Persistence of COVID-19 symptoms may follow SARS-CoV-2 infection. The incidence of long COVID increases with the severity of acute disease, but even mild disease can be associated with sequelae. The symptoms vary widely with fatigue, shortness of breath, and cognitive dysfunction being the most common. Abnormalities of multiple organs have been documented and histopathology has revealed widespread microthrombi. Elevated levels of complement are present in acute COVID-19 patients and may persist at lower levels in long COVID. Evidence supports complement activation with endotheliopathy associated disease as the molecular mechanism causing both acute and long COVID.

Section snippets

Prevalence and Definition: A review and meta-analysis of published results of long COVID studies suggest a global prevalence of the post COVID-19 condition of approximately 43% with a wide range of 9-81%.1 Using a population-representative survey epidemiologists have estimated the prevalence of long COVID in the United States to be 7.3%.2 In an effort to standardize the definition of long COVID the World Health Organization (WHO) established a Clinical Case Definition Working Group on the Post-COVID-19 Condition.3

Symptoms: The symptoms of long COVID are similar to those observed in patients following chronic critical illness and hospitalization in intensive care units.4 In the United Kingdom a retrospective matched cohort study was undertaken to determine symptoms beyond 12 weeks in non-hospitalized SARS-CoV-2 infected patients compared with uninfected patients.5 A cohort of 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection was compared to 1,944,580 propensity score-matched adults with no record

Evaluation and Testing: The previously referenced study of COVID patients 6 months after discharge from hospital in Wuhan, China enrolled patients in radiographic, pulmonary function, and blood testing.7 High resolution computerized tomography (HRCT) was performed on 390 patients and was abnormal in 52% not requiring supplemental oxygen and 54% of patients requiring supplemental oxygen. Lung diffusion impairment was noted in 22% of patients not requiring oxygen and up to 56% of patients requiring supplemental oxygen

Pathology and Histopathology: Autopsy data has contributed considerable information to our understanding of SARS-CoV-2 infection. A review of the histopathological findings in coronavirus disease 2019 reported diffuse alveolar damage (DAD), multiple organ microvasculitis, and lymphocytic infiltration with changes in immune organs and emphasized the observance of microthrombosis in numerous studies.18 An autopsy study from New York Presbyterian Hospital revealed macroscopic and/or microscopic thrombi in 84% patients.19

Complement, von Willebrand factor, and Endotheliopathy: A prospective study in the Netherlands was conducted to examine the role of complement as a component of the innate immune response to SARS-CoV-2 infection.29 Investigators found that complement factors C3a, C3c, and the terminal complement complex or membrane attack complex (MAC) were increased in COVID-19 patients compared to healthy controls. Furthermore, these complement factors were more increased in patients who were admitted to intensive care units, died, or experienced thromboembolic

Discussion: Long COVID or post acute sequelae of COVID-19 (PASC) is a frequent occurrence in patients recovering from acute SARS-CoV-2 infection. Estimates of the incidence vary widely with the more recent estimates trending below 10% in the United States. Changes in definition, increasing population immunity, treatment with antivirals and monoclonal antibodies, and newer variants may all play a role in the downward trend. The symptoms of long COVID are numerous and reflect the multi-organ nature of both…

Conclusion: The pathology and histopathology of COVID-19 patients has demonstrated the presence of widespread multi-organ microthrombi as a central feature of SARS-CoV-2 infection. Elevated levels of complement factors and von Willebrand factor have been found in COVID-19 patients and the degree of increases are directly related to the severity of disease and persistent high levels correlate with long COVID symptoms.39 Persisting symptoms following acute COVID-19 occur more often and are more debilitating

Source: Hawley HB. Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms. Am J Med. 2023 Sep 11:S0002-9343(23)00539-9. doi: 10.1016/j.amjmed.2023.08.008. Epub ahead of print. PMID: 37704072. https://www.sciencedirect.com/science/article/abs/pii/S0002934323005399

Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome

Abstract:

We studied the role of cytotoxic components (DAMPs) formed in the body of patients with COVID-19 in ensuring the long-term preservation of post-COVID-19 manifestations and the possibility of creating an experimental model by transferring DAMPs to rats. In patients with post-COVID-19 syndrome (PCS) 2 months after SARS-CoV-2 infection we determined the presence of cytotoxic components in the blood serum (Terasaki test, Dunaliella viridis test and content of DAMPs).

In post-COVID-19 syndrome patients with a high content of serum cytotoxic oligopeptide fraction (selective group, n = 16) we determined the number of leukocytes, lymphocytes, neutrophil granulocytes and monocytes in the blood, the content of C-reactive protein (CRP), the concentration of C3 and C4 complement components and circulating immune complexes, the serum content of IL-6, IL -10, IL-18, TNF-α, phagocytic activity of neutrophils, presence of neutrophil traps and autoantibodies ANA.

It has been shown that in patients with PCS, there are components with cytotoxicity in the blood serum, form specific immunopathological patterns, which are characterized by: an increased content of CRP, complement system components C3 and C4 and cytokines (TNF-α, IL-6, IL-10, IL-18) activation, the formation of a wide range of autoantibodies ANA, the low efficiency of endocytosis in oxygen-independent phagocytosis; their phagocytic activity reaches its functional limit, and against this background, activation of neutrophil traps occurs, which can contribute to further induction of DAMPs. This self-sustaining cell-killing activation provided long-term preservation of PCS symptoms.

The transfer of blood serum components from selective group patients with PCS to rats was accompanied by the appearance of cytotoxic components in them which induced sensitization and immunopathological reactions. Preventive administration of a biologically active substance with polyfunctional properties MF to experimental animals “corrected” the initial functional state of the body’s immune-metabolic system and eliminated or facilitated immuno-inflammatory reactions.

Source: Klimova EM, Bozhkov AI, Lavinska OV, Drozdova LA, Kurhuzova NI. Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome. Immunobiology. 2023 Jan;228(1):152316. doi: 10.1016/j.imbio.2022.152316. Epub 2022 Dec 20. PMID: 36565610; PMCID: PMC9764760. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9764760/ (Full text)

Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping

Abstract:

Background: Routine blood analytics are systematically used in the clinic to diagnose disease or confirm individuals’ healthy status. For myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disease relying exclusively on clinical symptoms for its diagnosis, blood analytics only serve to rule out underlying conditions leading to exerting fatigue. However, studies evaluating complete and large blood datasets by combinatorial approaches to evidence ME/CFS condition or detect/identify case subgroups are still scarce.

Methods: This study used unbiased hierarchical cluster analysis of a large cohort of 250 carefully phenotyped female ME/CFS cases toward exploring this possibility.

Results: The results show three symptom-based clusters, classified as severe, moderate, and mild, presenting significant differences (p < 0.05) in five blood parameters. Unexpectedly the study also revealed high levels of circulating complement factor C1q in 107/250 (43%) of the participants, placing C1q as a key molecule to identify an ME/CFS subtype/subgroup with more apparent pain symptoms.

Conclusions: The results obtained have important implications for the research of ME/CFS etiology and, most likely, for the implementation of future diagnosis methods and treatments of ME/CFS in the clinic.

Source: Castro-Marrero J, Zacares M, Almenar-Pérez E, Alegre-Martín J, Oltra E. Complement Component C1q as a Potential Diagnostic Tool for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subtyping. J Clin Med. 2021 Sep 15;10(18):4171. doi: 10.3390/jcm10184171. PMID: 34575280. https://pubmed.ncbi.nlm.nih.gov/34575280/

Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – a secondary analysis of experimental comparative studies

Abstract:

Background and aims: The interaction between the immune system and pain has been thoroughly explored in the recent decades. The release of inflammatory mediators from immune cells has the capability of activating neurons and glial cells, in turn sensitizing the nervous system. Both immune system alterations and pain modulation dysfunctions have been shown in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) following exercise. However, no studies tried to explore whether these two phenomena are linked and can explain exercise-induced symptoms worsening in people with ME/CFS. We hypothesized that exercise-induced changes in descending pain modulation is associated to changes in immune system functions. We used complement system product C4a and elastase activity as indicators of immune system activity.

Methods: The study design was a secondary analysis of controlled experimental studies. Twenty-two patients with ME/CFS and 22 healthy sedentary controls were enrolled. In experiment 1, subjects performed an aerobic submaximal exercise test; in experiment 2 they underwent a self-paced exercise test. One week of rest period were set between the two exercise tests. Before and after each experiment, subjects underwent clinical assessment, pain thresholds (PPTs) measurement, and blood sampling. Immune system function was assessed measuring complement system C4a products and elastase activity.

Results: Changes in elastase activity were not associated to changes in PPTs. Associations were observed in the ME/CFS group between changes in PPTs and C4a products, following both types of exercise. After submaximal exercise, the change in C4a products was associated with the change in PPT at the thumb in patients (r=0.669, p=0.001). Similarly, after self-paced exercise the change in C4a products was associated witht the change in PPT at the calf in patients (r=0.429, p=0.047). No such correlations were found in healthy controls. Regression analysis showed that C4a changes after the submaximal exercise significantly predicted the change in PPTs (R2=0.236; p=0.02).

Conclusions: Moderate associations between exercise-induced changes in PPTs and immune system activity were found only in ME/CFS. The change in the complement system following submaximal exercise might be able to explain part of the change in patient’s pain thresholds, providing evidence for a potential link between immune system alteration and dysfunctional endogenous pain modulation. These results have to be taken with caution, as only one out of three measures of PPTs was found associated with C4a changes. We cannot reject the hypothesis that C4a might therefore be a confounding factor, and changes during exercise might be mediated by other mechanism. Implications Immune system changes following exercise might contribute to exercise-induced symptoms worsening in patients with ME/CFS. However, the role of the complement system is questionable.

Source: Polli A, Van Oosterwijck J, Meeus M, Lambrecht L, Nijs J, Ickmans K. Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – a secondary analysis of experimental comparative studies. Scand J Pain. 2018 Oct 16. pii: /j/sjpain.ahead-of-print/sjpain-2018-0075/sjpain-2018-0075.xml. doi: 10.1515/sjpain-2018-0075. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/30325737

Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta

Abstract:

OBJECTIVES: Too vigorous exercise or activity increase frequently triggers postexertional malaise in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a primary characteristic evident in up to 95% of people with ME/CFS. The present study aimed at examining whether two different types of exercise results in changes in health status, circulating elastase activity, interleukin (IL)-1beta and complement C4a levels.

DESIGN: Comparative experimental design.

SETTING: University.

SUBJECTS: Twenty-two women with ME/CFS and 22 healthy sedentary controls.

INTERVENTIONS: participants were subjected to a submaximal exercise (day 8) and a self-paced, physiologically limited exercise (day 16). Each bout of exercise was preceded and followed by blood sampling, actigraphy and assessment of their health status.

RESULTS: Both submaximal exercise and self-paced, physiologically limited exercise resulted in postexertional malaise in people with ME/CFS. However, neither exercise bout altered elastase activity, IL-1beta or complement C4a split product levels in people with ME/CFS or healthy sedentary control subjects (P > 0.05). Postexercise complement C4a level was identified as a clinically important biomarker for postexertional malaise in people with ME/CFS.

CONCLUSIONS: Submaximal exercise as well as self-paced, physiologically limited exercise triggers postexertional malaise in people with ME/CFS, but neither types of exercise alter acute circulating levels of IL-1beta, complement C4a split product or elastase activity. Further studying of immune alterations in relation to postexertional malaise in people with ME/CFS using multiple measurement points postexercise is required.

 

Source: Nijs J, Van Oosterwijck J, Meeus M, Lambrecht L, Metzger K, Frémont M, Paul L. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. J Intern Med. 2010 Apr;267(4):418-35. doi: 10.1111/j.1365-2796.2009.02178.x. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2009.02178.x/full (Full article)

 

Frequency of deviant immunological test values in chronic fatigue syndrome patients

Abstract:

Of 11 immunological tests done on chronic fatigue syndrome patients and on fatigued controls, 3 tests (protein A binding, Raji cell, or C3 or C4 [deviant values in either complement component were counted as positive]) with deviant results discriminated best among the groups. Other tests, including immunoglobulin G subclasses, complement component CH50, interleukin-2, and anticardiolipin antibodies, did not discriminate well among the groups.

 

Source: Natelson BH, Ellis SP, Braonáin PJ, DeLuca J, Tapp WN. Frequency of deviant immunological test values in chronic fatigue syndrome patients. Clin Diagn Lab Immunol. 1995 Mar;2(2):238-40. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC170136/

You can read the full article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC170136/pdf/020238.pdf

 

Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes

Abstract:

375 patients with chronic fatigue syndrome (CFS) were examined using a standardized questionnaire and subsequent interview on 11 risk factors and 45 symptoms. Additionally immunologic, serologic, toxicologic, neuroradiologic, neurophysiologic and cardiologic investigations were performed.

Immunologic tests showed cellular immunodeficiences particularly in functional regard (pathological lymphocyte stimulation in 50% of the patients, disorders of granulocyte function in 44%). Furthermore variable deviations were found in the lymphocyte subpopulations (CD3, CD4, CD8, CD19, DR, Leu 11 + 19).

In the humoral part tendencies to low IgG-3- and IgG-1-subclass-levels occurred (59% respectively 11% of the patients) also as decreases in complement system (CH50, C3, C4, C1-esterase-inhibitor). In the group of activation markers and cytokines 42% of the investigated patients had circulating immune complexes (CIC), 47% increases of tumor-necrosis-factor (TNF-a) and 21% increases of soluble interleukin-2-receptor (IL-2-R).

The increased occurrence of autoantibodies in the CFS-patients (specially antinuclear anti-bodies [ANA], microsomal thyroid antibodies) suggest, that CFS is associated with or the beginning of manifest autoimmune disease.

Under the pathogens 78% of the patients had a striking serological constellation of Epstein-Barr-Virus (EBV-EA positive, low EBNA-titers), in the HHV-6-Virus 47% showed increased antibody-titers. Tests on further herpes viruses and on Borreliae, Chlamydiae, Candida and Amoebae were positive in 8 to 36% of the examined patients. Furthermore there were found variable deficits of vitamins and trace elements also as hormonal disturbances.

In 26% of the patients there were hints of pollutants (e.g. wood preservatives), in 32 patients blood-levels of pentachlorphenol (PCP) and gamma-hexachlorcyclohexan (γ-HCH, lindan) were measured, which showed vanable increases.

178 (83%) of 225 investigated patients showed disturbances of perfusion in cerebral SPECT imaging, 65 (29%) of 218 patients cerebral punctuate signal changes in cranial magnetic resonance imaging (MRI).

Neurophysiologic measurements (motor evoked potentials, MEP) showed in about 50% of 112 patients prolonged central motor conduction times. 62 patients were additionally investigated by myocardial SPECT-imaging, which was abnormal under exercise in 73%. Our data confirm the concept, that CFS must be considered as a complex psycho-neuro-immunological disorder.

 

Source: Hilgers A, Frank J. Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med Wochenschr. 1994;144(16):399-406.[Article in German] http://www.scopus.com/record/display.uri?eid=2-s2.0-0027940724&origin=inward&txGid=0

and http://www.ncbi.nlm.nih.gov/pubmed/7856214