Tag: longitudinal study

Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents significant challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. To address these complexities, we employed a comprehensive approach, integrating longitudinal cytokine profiling with extensive clinical, health, textual, pharmaceutical, and nutraceutical data, and performed personalized analyses using AI.

Focusing on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) and marginal symptom improvements, our study highlights the dynamic nature of symptoms, severity, triggers, and modifying factors. As part of this study, we introduced an updated platform and two applications, ME-CFSTrackerApp, and LexiTime, facilitating real-time symptom tracking and enhancing physician-patient communication.

Our longitudinal cytokine profiling underscores the significance of Th2-type cytokines and synergistic activities between mast cells and eosinophils, leading to skewing of Th1 toward Th2 immune responses in ME/CFS pathogenesis, especially in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major comorbidities.

Additionally, our data reveal potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasize the importance of investigating low-dose drugs with partial agonist activity in ME/CFS treatment. Our analyses underscore the patient-centered care approach for better healthcare management.

Source: Fereshteh Jahanbani1, Justin C. Sing, Rajan D. Maynard, Shaghayegh Jahanbani, Janet Dafoe, Whitney Dafoe, Nathan Jones, Kelvin J. Wallace, Azuravesta Rastan, Hannes Rost, Holden Maecker, Michael P. Snyder, Ronald W. Davis. Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity. Front. Immunol. Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders. Volume 15 – 2024 | doi: 10.3389/fimmu.2024.1369295 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1369295/abstract

Examining the relationship between inflammatory biomarkers during COVID-19 hospitalization and subsequent long-COVID symptoms: A longitudinal and retrospective study

Abstract:

Introduction: Long-COVID is a heterogeneous condition with a litany of physical and neuropsychiatric presentations and its pathophysiology remains unclear. Little is known about the association between inflammatory biomarkers, such as interleukin-6 (IL-6) and C-reactive protein (CRP) in the acute phase, and persistent symptoms after hospitalization in COVID-19 patients.

Methods: IL-6, CRP, troponin-T, and ferritin were analyzed at admission for all patients with COVID-19 between September 1, 2020 to January 10, 2021. Survivors were followed up 3-months following hospital discharge and were asked to report persistent symptoms they experienced. Admission data were retrospectively collected. Independent t-tests and Mann-Whitney U tests were performed.

Results: In a sample of 144 patients (62.5% male, mean Age 62 years [SD = 13.6]) followed up 3 months after hospital discharge, the commonest symptoms reported were fatigue (54.2%), breathlessness (52.8%), and sleep disturbance (37.5%). In this sample, admission levels of IL-6, CRP and ferritin were elevated. However, those reporting myalgia, low mood, and anxiety at follow-up had lower admission levels of IL-6 (34.9 vs. 52.0 pg/mL, p = .043), CRP (83 vs. 105 mg/L, p = .048), and ferritin (357 vs. 568 ug/L, p = .01) respectively, compared with those who did not report these symptoms. Multivariate regression analysis showed that these associations were confounded by gender, as female patients had significantly lower levels of IL-6 and ferritin on admission (29.5 vs. 56.1, p = .03 and 421.5 vs. 589, p = .001, respectively) and were more likely to report myalgia, low mood and anxiety, when compared to males.

Conclusions: Our data demonstrate that female patients present more often with lower levels of inflammatory biomarkers on admission which are subsequently associated with long-term post-COVID symptoms, such as myalgia and anxiety, in those discharged from hospital with severe COVID-19. Further research is needed into the role of serum biomarkers in post-COVID prognostication.

Source: Sykes DL, Van der Feltz-Cornelis CM, Holdsworth L, Hart SP, O’Halloran J, Holding S, Crooks MG. Examining the relationship between inflammatory biomarkers during COVID-19 hospitalization and subsequent long-COVID symptoms: A longitudinal and retrospective study. Immun Inflamm Dis. 2023 Oct;11(10):e1052. doi: 10.1002/iid3.1052. PMID: 37904690; PMCID: PMC10614127. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614127/ (Full text)

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)

Children and Young People with Long COVID—Comparing Those Seen in Post-COVID Services with a Non-Hospitalised National Cohort: A Descriptive Study

Abstract:

Background: Post-COVID services have been set up in England to treat children with ongoing symptoms of Long COVID. To date, the characteristics of children seeking treatment from these services has not been described.
Purpose: (1) to describe the characteristics of children aged 11–17 referred to the Pan-London Post-COVID service and (2) to compare characteristics of these children with those taking part in the United Kingdom’s largest research study of Long COVID in children (CLoCk).
Design: Data from 95 children seeking treatment from the Post-COVID service between May 2021 and August 2022 were included in the study. Their demographic characteristics, symptom burden and the impact of infection are described and compared to children from CLoCk.
Results: A high proportion of children from the Post-COVID service and CLoCk reported experiencing health problems prior to the pandemic. Almost all Post-COVID service children met the research Delphi definition of Long COVID (94.6%), having multiple symptoms that impacted their lives. Symptoms were notably more severe than the participants in CLoCk.
Conclusions: This study describes the characteristics of children seeking treatment for Long COVID compared to those identified in the largest longitudinal observational study to date. Post-COVID service children have more symptoms and are more severely affected by their symptoms following infection with COVID-19 than children in the CLoCk study. Research to understand predisposing factors for severity and prognostic indicators is essential to prevent this debilitating condition. Evaluation of short- and long-term outcomes of interventions by clinical services can help direct future therapy for this group.
Source: Newlands F, Goddings A-L, Juste M, Boyd H, Nugawela MD, Pinto Pereira SM, Whelan E, Whittaker E, Stephenson T, Heyman I, et al. Children and Young People with Long COVID—Comparing Those Seen in Post-COVID Services with a Non-Hospitalised National Cohort: A Descriptive Study. Children. 2023; 10(11):1750. https://doi.org/10.3390/children10111750 https://www.mdpi.com/2227-9067/10/11/1750 (Full text)

Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study

Abstract:

Background: Previous serological studies have indicated an association between viruses and atypical pathogens and Chronic Fatigue Syndrome (CFS). This study aims to investigate the correlation between infections from common pathogens, including typical bacteria, and the subsequent risk of developing CFS. The analysis is based on data from Taiwan’s National Health Insurance Research Database.

Methods: From 2000 to 2017, we included a total of 395,811 cases aged 20 years or older newly diagnosed with infection. The cases were matched 1:1 with controls using a propensity score and were followed up until diagnoses of CFS were made.

Results: The Cox proportional hazards regression analysis was used to estimate the relationship between infection and the subsequent risk of CFS. The incidence density rates among non-infection and infection population were 3.67 and 5.40 per 1000 person-years, respectively (adjusted hazard ratio [HR] = 1.5, with a 95% confidence interval [CI] 1.47-1.54). Patients infected with Varicella-zoster virus, Mycobacterium tuberculosis, Escherichia coli, Candida, Salmonella, Staphylococcus aureus and influenza virus had a significantly higher risk of CFS than those without these pathogens (p < 0.05). Patients taking doxycycline, azithromycin, moxifloxacin, levofloxacin, or ciprofloxacin had a significantly lower risk of CFS than patients in the corresponding control group (p < 0.05).

Conclusion: Our population-based retrospective cohort study found that infection with common pathogens, including bacteria, viruses, is associated with an increased risk of developing CFS.

Source: Chang H, Kuo CF, Yu TS, Ke LY, Hung CL, Tsai SY. Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study. J Transl Med. 2023 Nov 11;21(1):804. doi: 10.1186/s12967-023-04636-z. PMID: 37951920. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04636-z (Full text)

Use of latent class analysis and patient reported outcome measures to identify distinct long COVID phenotypes: A longitudinal cohort study

Abstract:

Objectives: We sought to 1) identify long COVID phenotypes based on patient reported outcome measures (PROMs) and 2) determine whether the phenotypes were associated with quality of life (QoL) and/or lung function.

Methods: This was a longitudinal cohort study of hospitalized and non-hospitalized patients from March 2020 to January 2022 that was conducted across 4 Post-COVID Recovery Clinics in British Columbia, Canada. Latent class analysis was used to identify long COVID phenotypes using baseline PROMs (fatigue, dyspnea, cough, anxiety, depression, and post-traumatic stress disorder). We then explored the association between the phenotypes and QoL (using the EuroQoL 5 dimensions visual analogue scale [EQ5D VAS]) and lung function (using the diffusing capacity of the lung for carbon monoxide [DLCO]).

Results: There were 1,344 patients enrolled in the study (mean age 51 ±15 years; 780 [58%] were females; 769 (57%) were of a non-White race). Three distinct long COVID phenotypes were identified: Class 1) fatigue and dyspnea, Class 2) anxiety and depression, and Class 3) fatigue, dyspnea, anxiety, and depression. Class 3 had a significantly lower EQ5D VAS at 3 (50±19) and 6 months (54 ± 22) compared to Classes 1 and 2 (p<0.001). The EQ5D VAS significantly improved between 3 and 6 months for Class 1 (median difference of 6.0 [95% CI, 4.0 to 8.0]) and Class 3 (median difference of 5.0 [95% CI, 0 to 8.5]). There were no differences in DLCO between the classes.

Conclusions: There were 3 distinct long COVID phenotypes with different outcomes in QoL between 3 and 6 months after symptom onset. These phenotypes suggest that long COVID is a heterogeneous condition with distinct subpopulations who may have different outcomes and warrant tailored therapeutic approaches.

Source: Wong AW, Tran KC, Binka M, Janjua NZ, Sbihi H, Russell JA, Carlsten C, Levin A, Ryerson CJ. Use of latent class analysis and patient reported outcome measures to identify distinct long COVID phenotypes: A longitudinal cohort study. PLoS One. 2023 Jun 2;18(6):e0286588. doi: 10.1371/journal.pone.0286588. PMID: 37267379; PMCID: PMC10237387. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10237387/ (Full text)

Fatigue in Children and Adolescents: A Population-Based Longitudinal Study on Fatigue and Chronic Pain

Abstract:

Objective: There are limited data on the prevalence and stability of fatigue in pediatrics, particularly among youth with chronic pain. Little is known about longitudinal effects of fatigue on health outcomes such as sleep quality, psychological distress, Health-Related Quality of Life, and chronic pain.

Methods: A community-based sample of N = 1276 students (9-17 years; 52% female; 30.3% with chronic pain) from 3 schools was screened at 2 measurement points 3 months apart. Prevalence and stability of fatigue were examined. Longitudinal analyses regarding fatigue and health outcomes were run using repeated measures correlations. The impact of change in fatigue on pain progression was analyzed using multilevel linear models.

Results: In the total community sample, 4.4% reported severe fatigue symptoms. The prevalence of severe fatigue was significantly higher in students with chronic pain (11.4%) compared to those without (1.3%). Fatigue symptoms persisted for several months, worsening of symptoms was more common and improvement less common in children with chronic pain. Sleep, psychological distress, and Health-Related Quality of Life were significantly associated with fatigue across both measurement points (rs = |0.16-0.44|), with no significant differences in the strength of correlations between children with and without chronic pain (ps > .05). There was a significant interaction between change in fatigue and courses of pain intensity and functional impairment.

Conclusions: Fatigue is highly prevalent, particularly in youth with chronic pain. The negative association of fatigue with health outcomes, and its impact on the course of pain, require early identification and treatment of those affected to prevent negative long-term consequences.

Source: Sommer A, Grothus S, Claus BB, Stahlschmidt L, Wager J. Fatigue in Children and Adolescents: A Population-Based Longitudinal Study on Fatigue and Chronic Pain. J Pediatr Psychol. 2023 May 10:jsad026. doi: 10.1093/jpepsy/jsad026. Epub ahead of print. PMID: 37164626. https://pubmed.ncbi.nlm.nih.gov/37164626/

Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study

Abstract:

Importance Multi-organ impairment associated with Long COVID is a significant burden to individuals, populations and health systems, presenting challenges for diagnosis and care provision. Standardised assessment across multiple organs over time is lacking, particularly in non-hospitalised individuals.

Objective To determine the prevalence of organ impairment in Long COVID patients at 6 and at 12 months after initial symptoms and to explore links to clinical presentation.

Design This was a prospective, longitudinal study in individuals following recovery from acute COVID-19. We assessed symptoms, health status, and multi-organ tissue characterisation and function, using consensus definitions for single and multi-organ impairment. Physiological and biochemical investigations were performed at baseline on all individuals and those with organ impairment were reassessed, including multi-organ MRI, 6 months later.

Setting Two non-acute settings (Oxford and London).

Participants 536 individuals (mean 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post-COVID-19). 331 (62%) with organ impairment or incidental findings had follow up, with reduced symptom burden from baseline (median number of symptoms: 10 and 3, at 6 and 12 months).

Exposure SARS-CoV-2 infection 6 months prior to first assessment.

Main outcome Prevalence of single and multi-organ impairment at 6 and 12 months post-COVID-19.

Results Extreme breathlessness (36% and 30%), cognitive dysfunction (50% and 38%) and poor health-related quality of life (EQ-5D-5L<0.7; 55% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single organ impairment. At baseline, there was fibro-inflammation in the heart (9%), pancreas (9%), kidney (15%) and liver (11%); increased volume in liver (7%), spleen (8%) and kidney (9%); decreased capacity in lungs (2%); and excessive fat deposition in the liver (25%) and pancreas (15%). Single and multi-organ impairment were present in 59% and 23% at baseline, persisting in 59% and 27% at follow-up.

Conclusion and Relevance Organ impairment was present in 59% of individuals at 6 months post-COVID-19, persisting in 59% of those followed up at 1 year, with implications for symptoms, quality of life and longer-term health, signalling need for prevention and integrated care of Long COVID.

Source: Andrea Dennis, Daniel J Cuthbertson, Dan Wootton, Michael Crooks, Mark Gabbay, Nicole Eichert, Sofia Mouchti, Michele Pansini, Adriana Roca-Fernandez, Helena Thomaides-Brears, Matt Kelly, Matthew Robson, Lyth Hishmeh, Emily Attree, Melissa Heightman, Rajarshi Banerjee, Amitava Banerjee. Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study. medRxiv 2022.03.18.22272607; doi: https://doi.org/10.1101/2022.03.18.22272607  https://www.medrxiv.org/content/10.1101/2022.03.18.22272607v1.full.pdf (Full text)

Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease with variable severity throughout the ongoing illness. Patients experience relapses where symptoms increase in severity, leaving them with a marked reduction in quality of life. Previous work has investigated molecular differences between ME/CFS patients and healthy controls, but the dynamic changes specific to each individual patient are unknown. Precision medicine can determine how each patient responds individually during variations in their long-term illness. We apply precision medicine here to map genomic changes in two selected ME/CFS patients through a relapse recovery cycle.

Results: DNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) from two patients and a healthy age/gender matched control in a longitudinal study to capture a patient relapse. Reduced representation DNA methylation sequencing profiles were obtained from each time point spanning the relapse recovery cycle. Both patients throughout the time course showed a significantly larger methylome variability (10-20 fold) compared with the control. During the relapse changes in the methylome profiles of the two patients were detected in regulatory-active regions of the genome that were associated respectively with 157 and 127 downstream genes, indicating disturbed metabolic, immune and inflammatory functions occurring during the relapse.

Conclusions: Severe health relapses in ME/CFS patients result in functionally important changes in their DNA methylomes that, while differing among patients, lead to similar compromised physiology. DNA methylation that is a signature of disease variability in ongoing ME/CFS may have practical applications for strategies to decrease relapse frequency.

Source: Amber Helliwell, Peter Stockwell, Tina Edgar, Aniruddha Chatterjee, warren Perry Tate. Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
medRxiv 2022.02.24.22270912; doi: https://doi.org/10.1101/2022.02.24.22270912 (Full text)

Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study

Abstract:

(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multifaceted illness. The pathomechanism, severity and progression of this illness is still being investigated. Stressors have been implicated in symptom exacerbation for ME/CFS, however, there is limited information for an Australian ME/CFS cohort. The aim of this study was to assess the potential effect of life stressors including changes in work, income, or family scenario on symptom severity in an Australian ME/CFS cohort over five months;

(2) Methods: Australian residents with ME/CFS responded to questions relating to work, income, living arrangement, access to healthcare and support services as well as symptoms experienced;

(3) Results: thirty-six ME/CFS patients (age: 41.25 ± 12.14) completed all questionnaires (response rate 83.7%). Muscle pain and weakness, orthostatic intolerance and intolerance to extreme temperatures were experienced and fluctuated over time. Sleep disturbances were likely to present as severe. Work and household income were associated with worsened cognitive, gastrointestinal, body pain and sleep symptoms. Increased access to healthcare services was associated with improved symptom presentation;

(4) Conclusions: life stressors such as work and financial disruptions may significantly contribute to exacerbation of ME/CFS symptoms. Access to support services correlates with lower symptom scores.

Source: Balinas C, Eaton-Fitch N, Maksoud R, Staines D, Marshall-Gradisnik S. Impact of Life Stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms: An Australian Longitudinal Study. Int J Environ Res Public Health. 2021 Oct 11;18(20):10614. doi: 10.3390/ijerph182010614. PMID: 34682360; PMCID: PMC8535742.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535742/ (Full text)