Tag: 2023

Senolytic drugs: from discovery to translation

Abstract:

Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis-driven approach.

SC accumulate with ageing and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP.

Because SC take weeks to reaccumulate, senolytics can be administered intermittently – a ‘hit-and-run’ approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment.

As anticipated for agents targeting the fundamental ageing mechanisms that are ‘root cause’ contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans.

Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer’s disease, COVID-19, osteoarthritis, osteoporosis, eye diseases and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.

Source: Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020 Nov;288(5):518-536. doi: 10.1111/joim.13141. Epub 2020 Aug 4. PMID: 32686219; PMCID: PMC7405395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/ (Full text)

Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: To examine ocular symptoms and signs of veterans with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diagnosis, ME/CFS symptoms, and controls.

Methods: This was a prospective, cross-sectional study of 124 South Florida veterans in active duty during the Gulf War era. Participants were recruited at an ophthalmology clinic at the Miami Veterans Affairs Hospital and evaluated for a diagnosis of ME/CFS, or symptoms of ME/CFS (intermediate fatigue, IF) using the Canadian Consensus criteria. Ocular symptoms were assessed via standardised questionnaires and signs via comprehensive slit lamp examination. Inflammatory blood markers were analysed and compared across groups.

Results: Mean age was 55.1 ± 4.7 years, 88.7% identified as male, 58.1% as White, and 39.5% as Hispanic. Ocular symptoms were more severe in the ME/CFS (n = 32) and IF (n = 48) groups compared to controls (n = 44) across dry eye (DE; Ocular Surface Disease Index [OSDI]: 48.9 ± 22.3 vs. 38.8 ± 23.3 vs. 19.1 ± 17.8, p < 0.001; 5 item Dry Eye Questionnaire [DEQ-5]: 10.8 ± 3.9 vs. 10.0 ± 4.6 vs. 6.6 ± 4.2, p < 0.001) and pain-specific questionnaires (Numerical Rating Scale 1-10 [NRS] right now: 2.4 ± 2.8 vs. 2.4 ± 2.9 vs 0.9 ± 1.5; p = 0.007; Neuropathic Pain Symptom Inventory modified for the Eye [NPSI-E]: 23.0 ± 18.6 vs. 19.8 ± 19.1 vs. 6.5 ± 9.0, p < 0.001). Ocular surface parameters and blood markers of inflammation were generally similar across groups.

Conclusion: Individuals with ME/CFS report increased ocular pain but similar DE signs, suggesting that mechanisms beyond the ocular surface contribute to symptoms.

Source: Victor Sanchez BS, Colin K. Kim BS, Elyana V. T. Locatelli BS, Adam K. Cohen, Kimberly Cabrera MS, Kristina Aenlle PhD, Nancy G. Klimas MD, Robert O’Brien PhD, Anat Galor MD, MSPH. Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis/chronic fatigue syndrome. First published: 12 November 2023 https://doi.org/10.1111/ceo.14313 https://onlinelibrary.wiley.com/doi/10.1111/ceo.14313 (Full text)

Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization

Abstract:

Introduction: A chronic post-vaccination syndrome (PVS) after covid-19 vaccination has been reported but has yet to be well characterized.

Methods: We included 241 individuals aged 18 and older who self-reported PVS after covid-19 vaccination and who joined the online Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study from May 2022 to July 2023. We summarized their demographics, health status, symptoms, treatments tried, and overall experience.

Results: The median age of participants was 46 years (interquartile range [IQR]: 38 to 56), with 192 (80%) identifying as female, 209 (87%) as non-Hispanic White, and 211 (88%) from the United States. Among these participants with PVS, 127 (55%) had received the BNT162b2 [Pfizer-BioNTech] vaccine, and 86 (37%) received the mRNA-1273 [Moderna] vaccine. The median time from the day of index vaccination to symptom onset was three days (IQR: 1 day to 8 days). The time from vaccination to symptom survey completion was 595 days (IQR: 417 to 661 days). The median Euro-QoL visual analogue scale score was 50 (IQR: 39 to 70). The five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%). In the week before survey completion, participants reported feeling unease (93%), fearfulness (82%), and overwhelmed by worries (81%), as well as feelings of helplessness (80%), anxiety (76%), depression (76%), hopelessness (72%), and worthlessness (49%) at least once. Participants reported a median of 20 (IQR: 13 to 30) interventions to treat their condition.

Conclusions: In this study, individuals who reported PVS after covid-19 vaccination had low health status, high symptom burden, and high psychosocial stress despite trying many treatments. There is a need for continued investigation to understand and treat this condition.

Source: Harlan M Krumholz, Yilun Wu, Mitsuaki Sawano, Rishi Shah, Tianna Zhou, Adith S Arun, Pavan Khosla, Shayaan Kaleem, Anushree Vashist, Bornali Bhattacharjee, Qinglan Ding, Yuan Lu, Cesar Caraballo, Frederick Warner, Chenxi Huang, Jeph Herrin, David Putrino, Danice Hertz, Brianne Dressen, Akiko Iwasaki. Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization. medRxiv 2023.11.09.23298266; doi: https://doi.org/10.1101/2023.11.09.23298266 https://www.medrxiv.org/content/10.1101/2023.11.09.23298266v1 (Full text available as PDF file)

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)

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses

Abstract:

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs.

In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM).

These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected.

Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43.

This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an ‘original antigenic sin’ (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease.

Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

Source: Spatola M, Nziza N, Jung W, Deng Y, Yuan D, Dinoto A, Bozzetti S, Chiodega V, Ferrari S, Lauffenburger DA, Mariotto S, Alter G. Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses. Brain. 2023 Oct 3;146(10):4292-4305. doi: 10.1093/brain/awad155. PMID: 37161609. https://academic.oup.com/brain/article/146/10/4292/7158783 (Full text)

Sequential multi-omics analysis identifies clinical phenotypes and predictive biomarkers for long COVID

Abstract:

The post-acute sequelae of COVID-19 (PASC), also known as long COVID, is often associated with debilitating symptoms and adverse multisystem consequences. We obtain plasma samples from 117 individuals during and 6 months following their acute phase of infection to comprehensively profile and assess changes in cytokines, proteome, and metabolome.

Network analysis reveals sustained inflammatory response, platelet degranulation, and cellular activation during convalescence accompanied by dysregulation in arginine biosynthesis, methionine metabolism, taurine metabolism, and tricarboxylic acid (TCA) cycle processes.

Furthermore, we develop a prognostic model composed of 20 molecules involved in regulating T cell exhaustion and energy metabolism that can reliably predict adverse clinical outcomes following discharge from acute infection with 83% accuracy and an area under the curve (AUC) of 0.96.

Our study reveals pertinent biological processes during convalescence that differ from acute infection, and it supports the development of specific therapies and biomarkers for patients suffering from long COVID.

Source: Wang K, Khoramjoo M, Srinivasan K, Gordon PMK, Mandal R, Jackson D, Sligl W, Grant MB, Penninger JM, Borchers CH, Wishart DS, Prasad V, Oudit GY. Sequential multi-omics analysis identifies clinical phenotypes and predictive biomarkers for long COVID. Cell Rep Med. 2023 Oct 18:101254. doi: 10.1016/j.xcrm.2023.101254. Epub ahead of print. PMID: 37890487. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00431-7 (Full text)

“It was almost like it’s set up for people to fail” A qualitative analysis of experiences and unmet supportive needs of people with Long COVID

Abstract:

Background: Almost twenty percent of adults with COVID-19 develop Long COVID, leading to prolonged symptoms and disability. Understanding the supportive needs of people with Long COVID is vital to enacting effective models of care and policies.

Design/methods: This qualitative sub-study explored the experiences of people with Long COVID and their unmet needs. Participants enrolled in a larger study to evaluate the post-acute cardiovascular impacts of COVID-19 were invited to participate in subsequent in-depth interviews. Participants were enrolled purposively until saturation at 24 participants. Data were analyzed using thematic content analysis.

Results: Participants focused on adaptations to life with Long COVID and their unmet needs in different life spheres. Three domains, 1) occupational and financial; 2) healthcare-related; and 3) social and emotional support, emerged as areas affecting quality of life. Although participants were motivated to return to work for financial and personal reasons, Long COVID symptoms often resulted in the inability to perform tasks required by their existing jobs, and unemployment. Those who maintained employment through employer accommodations still needed additional support. Participants encountered diagnostic challenges, challenges in accessing specialty appointments, insurance loopholes, high healthcare costs, and medical skepticism. Existing social networks provided support for completing daily tasks; however, those with Long COVID typically turned to others with similar lived experiences for emotional support. Participants found government support programs inadequate and difficult to access in all three domains.

Discussion: We propose a five-pronged policy approach to support persons with Long COVID. These overarching recommendations are (1) improve public awareness of Long COVID; (2) improve clinical care quality and access; (3) implement additional school and workplace accommodations; (4) strengthen socioeconomic benefits and social services; and (5) improve research on Long COVID.

Source: McNabb, K.C., Bergman, A.J., Smith-Wright, R. et al. “It was almost like it’s set up for people to fail” A qualitative analysis of experiences and unmet supportive needs of people with Long COVID. BMC Public Health 23, 2131 (2023). https://doi.org/10.1186/s12889-023-17033-4 https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-023-17033-4 (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Me/Cfs): The Biology of a Neglected Disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic disease with debilitating symptoms that impact all aspects of life. The diverse symptom presentation indicates that ME/CFS is likely to have a multifactorial origin. However, it is an extremely understudied disease with no standardised diagnostic criteria or proven treatment avenues. It is hypothesised that environmental insults (such as acute infection, mainly viral) or stress in genetically susceptible individuals may trigger the development of ME/CFS.

These insults result in acute inflammatory responses, along with aberrant immune activation. A spiralling disruption of homeostasis promotes subsequent patho-mechanisms including gut dysbiosis and systemic inflammation, and eventually a pathological clotting system, chronic endothelialitis, vasoconstriction, and hypoxia. Additionally, dysfunctional energy metabolism including oxidative stress is also present in the development of ME/CFS. Since the exact pathophysiology of ME/CFS remains unclear, additional research is required to reveal further insight into this “neglected” disease.

Source: Arron, Hayley and Marsh, Benamin and Khan, M. Asad and Jaeger, Beate and Kell, Douglas and Pretorius, Etheresia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Me/Cfs): The Biology of a Neglected Disease. Available at SSRN: https://ssrn.com/abstract=4622074 or http://dx.doi.org/10.2139/ssrn.4622074 (Full text available as PDF file)

Prevalence and Predictive Factors of Small Intestinal Bacterial Overgrowth in Patients With Chronic Fatigue Syndrome

Introduction: Chronic fatigue syndrome (CFS) is a poorly understood illness, characterized by fatigue and related symptoms including cognitive dysfunction, headaches, joint pains, and gastrointestinal distress. Irritable bowel syndrome (IBS) is common and present in approximately 60% patients with CFS while the prevalence of small intestinal bacterial overgrowth (SIBO) in IBS is approximately 40%. Our study aimed to 1) Determine the prevalence of SIBO in patients with CFS with and without IBS symptoms 2) Identify factors associated with increased risk of SIBO.

Methods: A retrospective chart review of 479 patients with CFS referred for hydrogen/methane breath testing. Clinical documentation was reviewed to identify positive breath test result diagnosing SIBO. Statistical analysis was conducted with 2-proportions z test and logistic regression analysis to identify predictive variables of SIBO diagnosis.

Results: 479 patients with CFS referred for glucose or lactulose breath testing were identified. Three hundred sixty-seven of those patients completed a breath test with available result: 152(41%) SIBO+ (mean age (SD) 50 (17)), 164(45%) SIBO- (mean age SD 46 (15)), and 78(21%) equivocal results. In CFS patients with conclusive breath test result, 48% tested positive for SIBO, and the diagnosis of IBS was present in 186/316 (59%). There was no difference in the prevalence of IBS between the SIBO+ vs SIBO-group [98/152 (64%) vs 88/164 (53%), P < 0.05]. Using multiple logistic regression analysis, age, unknown race, and IBS diagnosis all significantly predicted increased odds of having a positive breath test (Table 1). Conversely, PPI use was associated with decreased odds of a positive breath test. Due to the high prevalence of IBS in our cohort and the association between IBS and SIBO, an analysis was performed excluding patients with IBS diagnosis. When excluding patients with IBS, unknown race and TCA use were associated with increased odds of positive breath test, while diarrhea, hypothyroidism, PPI, and naltrexone use were associated with decreased odds (P< 0.05).

Conclusion: SIBO is highly prevalent in patients with CFS referred for breath testing. Older age and comorbid IBS diagnosis predict increased odds of positive breath test. Surprisingly, PPI use predicted decreased odds despite its prior implication as a possible risk factor for SIBO. Further studies are needed to explore the underlying mechanism causing the overlap between CFS, IBS and SIBO which may provide insights into potential therapies for CFS.

Source: Karhu, Elisa MD, MS; Neshatian, Leila MD, MS; Fass, Ofer MD; Sonu, Irene MD; Nguyen, Linda Anh MD. S1821 Prevalence and Predictive Factors of Small Intestinal Bacterial Overgrowth in Patients With Chronic Fatigue Syndrome. The American Journal of Gastroenterology 118(10S):p S1351-S1352, October 2023. | DOI: 10.14309/01.ajg.0000956924.26236.c4 https://journals.lww.com/ajg/fulltext/2023/10001/s1821_prevalence_and_predictive_factors_of_small.2162.aspx

The economic burden of myalgic encephalomyelitis/chronic fatigue syndrome in Australia

Abstract:

Objective Estimate costs of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to patients, government, and Australian society.

Methods Australian ME/CFS patients and their carers were recruited using convenience sampling. Patients completed an online retrospective cost diary, providing ME/CFS-related direct medical, non-medical and indirect costs. Informal care costs were collected directly from carers. Data from the Pharmaceutical Benefits Scheme and Medicare Benefits Schedule were linked to participant survey data. Annual per/patient and total societal costs were estimated, and broken down by category, and presented in 2021AUD. Factors associated with higher costs were investigated using generalized linear models.

Results 175 patients (mean/SD age of 49/14 years, 79.4% female) completed the cost diary. Estimated total annual societal costs of ME/CFS in Australia ranged between $1.38 and $10.09billion, with average annual total costs of $63,400/patient. Three-quarters of these costs were due to indirect costs ($46,731). Disability severity was the key factor associated with higher costs, particularly for indirect costs (being 2.27-fold higher for severe disability than no/mild disability).

Conclusions ME/CFS poses a significant economic burden in Australia, owing mainly to high indirect and informal care costs.

Source: Ting Zhao, Ingrid Cox, Hasnat Ahmed, Julie Campbell, Martin Hensher, Andrew Palmer, Ryan Kelly, Melissa Rogerson, Karen Wills, Barbara de Graaff. The economic burden of myalgic encephalomyelitis/chronic fatigue syndrome in Australia. Australian Health Review. AH23106 Accepted 07 November 2023 https://www.publish.csiro.au/AH/justaccepted/AH23106