The risks of autoimmune- and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the US, and Korea

ABSTRACT

Objectives We aimed to assess the risk of autoimmune- and inflammatory post-acute COVID-19 conditions.

Design Descriptive network cohort study.

Setting Electronic health records from UK and Dutch primary care, Norwegian linked health registry, hospital records of specialist centres in Spain, France, and Korea, and healthcare claims from Estonia and the US.

Participants We followed individuals between September 2020 and the latest available data from the day they fulfilled at least 365 days of prior observation (general population), additionally from day 91 after a SARS-Cov-2 negative test (comparator) or a COVID-19 record (exposed patients).

Main outcome measures We assessed postural orthostatic tachycardia syndrome (POTS) diagnoses/symptoms, myalgic encephalomyelitis / chronic fatigues syndrome (ME/CFS) diagnoses/symptoms, multi-inflammatory syndrome (MIS), and several autoimmune diseases. For contextualisation, we assessed any diabetes mellitus (DM).

Meta-analysed crude incidence rate ratios (IRR) of outcomes measures after COVID-19 versus negative testing yield the ratios of absolute risks. Furthermore, incidence rates (IR) of the outcomes in the general population describe the total disease burden.

Results We included 34’549’575 individuals of whom 2’521’812 had COVID-19, and 4’233’145 a first negative test. After COVID-19 compared to test negative patients, we observed IRRs of 1.24 (1.23-1.25), 1.22 (1.21-1.23), and 1.12 (1.04-1.21) for POTS symptoms, ME/CFS symptoms and diagnoses, respectively. In contrast, autoimmune diseases and DM did not yield higher rates after COVID-19. In individual general database populations, IRs of POTS and ME/CFS diagnoses were 17-1’477/100’000 person-years (pys) and 2-473/100’000 pys, respectively. IRs of MIS were lowest with IRs 0.4-16/100’000 pys, those of DM as a benchmark 8-86/100’000 pys. IRs largely depended on the care setting.

Conclusion In our unmatched comparison, we observed that, following COVID-19, POTS and ME/CFS yielded higher rates than after negative testing. In absolute terms, we observed POTS and ME/CFS diagnoses to have a similar disease burden as DM.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Observational research suggested positive associations between COVID-19 and so called post-acute COVID-19 conditions, whose spectrum is yet to be established

  • Basic research suggested pathways that link COVID-19 with autoimmune- and inflammatory diseases such as postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis / chronic fatigues syndrome (ME/CFS), multiple inflammatory syndrome (MIS), and autoimmune diseases

WHAT THIS STUDY ADDS

  • After COVID-19, the rates of POTS symptoms and ME/CFS symptoms/diagnoses was higher than those after negative testing

  • After COVID-19 versus negative testing, rates of ME/CFS diagnoses were increased in the working age group and rates of symptoms of POTS and ME/CFS were increased in children and elderly

  • Disease burdens of POTS and ME/CFS diagnoses in the general population were higher among women than among men and overall similar to that of diabetes mellitus

Source: Theresa Burkard, Kim López-Güell, Martí Català, Edward Burn, Antonella Delmestri, Sara Khalid, Annika M Joedicke, Daniel Dedman, Jessie O Oyinlola, Alicia Abellan, Laura Pérez-Crespo, Núria Mercadé-Besora, Talita Duarte-Salles, Daniel Prieto-Alhambra, Johnmary T Arinze, Mees Mosseveld, Raivo Kolde, Jaime Meléndez-Cardiel, Raúl López-Blasco, Álvaro Martínez, Bernardo Valdivieso, Dominique Delseny, Gregoire Mercier, Chungsoo Kim, Ji-woo Kim, Kristin Kostka, Juan Manuel Ramírez-Anguita, Miguel A Mayer, Nhung TH Trinh, Hedvig ME Nordeng, Roger Paredes, Anneli Uusküla, Akihiko Nishimura, Cora Loste, Lourdes Mateu, Junqing Xie. The risks of autoimmune- and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the US, and Korea. (Full text)

Unequal access to diagnosis of myalgic encephalomyelitis in England

Abstract:

Background People with Myalgic Encephalomyelitis (ME/CFS; sometimes referred to as chronic fatigue syndrome) experience very poor health-related quality of life and only rarely recover. ME/CFS has no curative treatment and no single diagnostic test. Public health and policy decisions relevant to ME/CFS require knowledge of its prevalence and barriers to diagnosis. However, people with ME/CFS report lengthy diagnostic delays and widespread misunderstanding of their symptoms. Published prevalence estimates vary greatly by country, gender, age and ethnicity.

Methods Hospital Episode Statistics data is routinely collected by the NHS in England together with patient age, gender and ethnicity. This data, downloaded from the Feasibility Self-Service of NHS DigiTrials, was used to stratify individuals with the ICD-10 code that best reflects ME/CFS symptoms (G93.3; “Postviral fatigue syndrome”) according to their age, self-reported gender and ethnicity, General Practice and NHS England Integrated Care Board (ICB).

Results In all, 100,055 people in England had been diagnosed with ME/CFS (ICD-10:G93.3) between April 1 1989 and October 7 2023, 0.16% of all registered patients. Of these, 79,445 were females and 20,590 males, a female-to-male ratio of 3.88:1. Female relative to male prevalence peaked at about 6-to-1 in individuals’ fourth and fifth decades of life. Prevalence varied widely across the 42 ICBs: 0.086%-0.82% for females and 0.024%-0.21% for males. White individuals were approximately 5-fold more likely to be diagnosed with ME/CFS than others; black, Asian or Chinese ethnicities are associated with particularly low rates of ME/CFS diagnoses. This ethnicity bias is stronger than for other common diseases. Among active English GP practices, 176 (3%) had no registered ME/CFS patients. Eight ICBs (19%) each contained fewer than 8 other-than-white individuals with a G93.3 code despite their registers containing a total of 293,770 other-than-white patients.

Conclusion Those who are disproportionately undiagnosed with ME/CFS are other-than-white ethnic groups, older females (>60y), older males (>80y), and people living in areas of multiple deprivation. The lifetime prevalence of ME/CFS for English females and males may be as high as 0.92% and 0.25%, respectively, or approximately 390,000 UK individuals overall. This improved estimate of ME/CFS prevalence allows more accurate assessment of the socioeconomic and disease burden imposed by ME/CFS.

Source: Gemma L. Samms, Chris P. Ponting. Unequal access to diagnosis of myalgic encephalomyelitis in England. medRxiv 2024.01.31.24302070; doi: https://doi.org/10.1101/2024.01.31.24302070 https://www.medrxiv.org/content/10.1101/2024.01.31.24302070v1.full-text (Full text)

Long COVID Disability Burden in US Adults: YLDs and NIH Funding Relative to Other Conditions

Abstract:

Background Long COVID (LC) is novel, debilitating and likely chronic. Yet, scant data exist about its disability burden to guide scientific research and public health planning. We estimated Long COVID’s non-fatal disease burden in US adults and its FY2024 actual: burden-commensurate research funding from the National Institutes of Health (NIH) relative to other conditions, and biological sex.

Methods We present YLDs/100,000 for 70 NIH Research, Condition, and Disease Categories (RCDCs). Prevalence of disabling Long COVID was obtained from cross sectional surveys of representative samples of US adults, from September 2022 to August 2023. Disabling Long COVID was defined as incident symptoms persisting more than 3 months post-COVID, that significantly compromise daily activities. We calculated burden-commensurate funding for the top YLD conditions and for female vs. male dominant conditions.

Findings Disabling Long COVID was reported by 1.5% (n= 10,401) of n=757,580 respondents: Compared to the overall sample, those with disabling LC disproportionately identify as female (64.4% vs. 51.4%) and experiencing disability (80.8% vs. 52.9%) anxiety (57.5% vs. 23.8%) and depression (51.3% vs.18.5%). It ranked in the top 25% of YLDs at 320/100,000, between Alzheimer’s (279.4/100,000) and asthma (355.7/100,000) but received just 10% of its actual: YLD-commensurate funding. Only 5 conditions received less actual: burden: commensurate funding, including Myalgic Encephalitis/Chronic Fatigue Syndrome (<1%), another post-viral, female-dominant condition.

Interpretation LC has debilitated 3.8 million (weighted frequency) US adults. Research funding for it, like other female dominant conditions, lags behind its disability burden.

Research in Context Evidence before this study – We analyzed Long-COVID’s (LC) non-fatal disease burden in the US–represented by YLD (years lived with disability= prevalence x disability weight) — and National Institutes of Health (NIH) research 2024 funding relative to other conditions. We searched PubMed through 11/28/2023 for Long COVID prevalence (US), and Long COVID disability and disease burden (not US-specific). The keywords “years lived with disability” + “COVID” yielded n= 38 articles (11/29/23); but most referenced “disability-adjusted life years” (DALYs) in other countries. Similarly, “disease burden” + Long COVID yielded 23 papers, but no US YLD data. See Supplement 1 for meta-analyses, systematic reviews and US studies of Long COVID prevalence and impact.

We instead sourced YLD data from the US Census Bureau’s Household Pulse Survey (HPS) and the Institute for Health Metrics and Evaluation (IHME) /Global Burden of Disease (GBD) Long COVID Study Group. The HPS queries adults about Long COVID-related symptoms and their impact on daily activities. We applied the IHME/GBD’s estimated Long COVID disability weight of 0.21 and harmonized it with our LC case definition from the HPS data in consultation with IHME/GBD researchers. To harmonize IHME/GBD disability weights for non-LC diseases/conditions with the NIH’s terminology, we consulted with NIH staff. LC definition and measurement affects prevalence and burden estimates; our use of high-quality data sources and transparency in reporting how they were applied reduces the risk of biased assumptions.

Added value of this study- Long COVID is a chronic debilitating condition. While there is ample research on COVID’s acute illness and loss of life, there are no population-based data on its disability burden. We provide that data. To guide scientific research and public health planning, we report YLDs associated with disabling Long COVID (i.e., symptoms significantly limit activity), and; compare it to other conditions’ YLDs, NIH funding, and female-vs. male-dominance. It ranked in the top 25% of YLDs at 320/100,000, between Alzheimer’s (279.4/100,000) and asthma (355.7/100,000) but received just 10% of its YLD-commensurate funding. Only 5 conditions received less burden-commensurate funding; 3/5 were female-dominant, including Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) at <1%, another post-viral condition that shares significant overlap with Long COVID. Overall, median funding/YLD was >= 5 times greater for male-vs. female-dominant conditions.

Implications of all the available evidence-Nearly 4 million US adults (weighted frequency) live with disabling Long COVID. They disproportionately identify as female and as having a disability, anxiety and depression. Yet NIH funding for diagnostic and treatment research for Long COVID hasn’t kept pace with its disability burden.

Source: Karen BonuckQi GaoSeth CongdonRyung Kim. Long COVID Disability Burden in US Adults: YLDs and NIH Funding Relative to Other Conditions.

The health impact of long COVID: a cross-sectional examination of health-related quality of life, disability, and health status among individuals with self-reported post-acute sequelae of SARS CoV-2 infection at various points of recovery

Abstract:

Objective: The novel Coronavirus (COVID-19) has continued to present a significant burden to global public health efforts. The purpose of this study was to estimate the health-related quality of life, disability, and health status of individuals with self-reported long COVID at various lengths of recovery.

Methods: We conducted a cross-sectional online survey of individuals with self-reported long COVID. Participants were asked to complete the five-item EuroQOL EQ-5D-5L and EQ visual analog scale, the 12-item World Health Organization Disability Assessment Schedule (WHODAS) 2.0 and the 10-item Patient Reported Outcome Measurement Information System (PROMIS) Global Health v1.2 short form. Descriptive and inferential statistics were used to characterize the responses and differences across groups.

Results: Eighty-two participants from 13 countries completed the EQ-5D-5L, 73 completed the WHODAS 2.0 and 80 participants completed the PROMIS. The mean EQ-5D-5L utility score was 0.51. The mean WHODAS score was 49.0. In the previous 30 days, participants reported their symptoms affected them for a mean of 24 days, they were totally unable to carry out usual activities for 15 days, and they cut back or reduced activities for 26 days. The mean PROMIS physical health and mental health scores were 10.7 and 8.6, respectively, corresponding to below-average health. No significant differences were detected across time or according to severity of acute infection.

Conclusions: Long COVID presents a significant chronic health burden to adults in the US and abroad. This health burden may persist for many months post-acute infection.

Source: Tak CR. The health impact of long COVID: a cross-sectional examination of health-related quality of life, disability, and health status among individuals with self-reported post-acute sequelae of SARS CoV-2 infection at various points of recovery. J Patient Rep Outcomes. 2023 Mar 21;7(1):31. doi: 10.1186/s41687-023-00572-0. PMID: 36943643; PMCID: PMC10029785. https://jpro.springeropen.com/articles/10.1186/s41687-023-00572-0 (Full text)

Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis

Abstract

Importance: Neurological and neuropsychiatric symptoms that persist or develop three months after the onset of COVID-19 pose a significant threat to the global healthcare system. These symptoms are yet to be synthesized and quantified via meta-analysis.

Objective: To determine the prevalence of neurological and neuropsychiatric symptoms reported 12 weeks (3 months) or more after acute COVID-19 onset in adults.

Data sources: A systematic search of PubMed, EMBASE, Web of Science, Google Scholar and Scopus was conducted for studies published between January 1st, 2020 and August 1st, 2021. The systematic review was guided by Preferred Reporting Items for Systematic Review and Meta-Analyses.

Study selection: Studies were included if the length of follow-up satisfied the National Institute for Healthcare Excellence (NICE) definition of post-COVID-19 syndrome (symptoms that develop or persist ≥3 months after the onset of COVID-19). Additional criteria included the reporting of neurological or neuropsychiatric symptoms in individuals with COVID-19.

Data extraction and synthesis: Two authors independently extracted data on patient characteristics, hospital and/or ICU admission, acute-phase COVID-19 symptoms, length of follow-up, and neurological and neuropsychiatric symptoms.

Main outcome(s) and measure(s): The primary outcome was the prevalence of neurological and neuropsychiatric symptoms reported ≥3 months post onset of COVID-19. We also compared post-COVID-19 syndrome in hospitalised vs. non-hospitalised patients, with vs. without ICU admission during the acute phase of infection, and with mid-term (3 to 6 months) and long-term (>6 months) follow-up.

Results: Of 1458 articles, 19 studies, encompassing a total of 11,324 patients, were analysed. Overall prevalence for neurological post-COVID-19 symptoms were: fatigue (37%, 95% CI: 24%-50%), brain fog (32%, 9%-55%), memory issues (27%, 18%-36%), attention disorder (22%, 10%-34%), myalgia (18%, 4%-32%), anosmia (12%, 7%-17%), dysgeusia (11%, 4%-17%) and headache (10%, 1%-21%). Neuropsychiatric conditions included sleep disturbances (31%, 18%-43%), anxiety (23%, 13%-33%) and depression (12%, 7%-21%). Neuropsychiatric symptoms substantially increased in prevalence between mid- and long-term follow-up. Compared to non-hospitalised patients, patients hospitalised for acute COVID-19 had reduced frequency of anosmia, anxiety, depression, dysgeusia, fatigue, headache, myalgia, and sleep disturbance at three (or more) months post-infection. Conversely, hospital admission was associated with higher frequency of memory issues (OR: 1.9, 95% CI: 1.4-2.3). Cohorts with >20% of patients admitted to the ICU during acute COVID-19 experienced higher prevalence of fatigue, anxiety, depression, and sleep disturbances than cohorts with <20% of ICU admission.

Conclusions and relevance: Fatigue, cognitive dysfunction (brain fog, memory issues, attention disorder) and sleep disturbances appear to be key features of post-COVID-19 syndrome. Psychiatric manifestations (sleep disturbances, anxiety, and depression) are common and increase significantly in prevalence over time. Randomised controlled trials are necessary to develop intervention strategy to reduce disease burden.

Source: Premraj L, Kannapadi NV, Briggs J, Seal SM, Battaglini D, Fanning J, Suen J, Robba C, Fraser J, Cho SM. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J Neurol Sci. 2022 Jan 29;434:120162. doi: 10.1016/j.jns.2022.120162. Epub ahead of print. PMID: 35121209; PMCID: PMC8798975. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8798975/ (Full text)

Research Update: The Relation Between ME/CFS Disease Burden and Research Funding in the USA

Abstract:

Background: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is a debilitating, chronic, multisystem disease that affects an estimated 1 to 2.5 million Americans. It has no widely accepted biomarkers and no FDA-approved treatment. ME/CFS has traditionally been one of the lowest funded diseases by the United States National Institutes of Health (NIH).

Objectives: We provide here an update to our 2016 article, which estimated the disease burden of ME/CFS in the United States in 2013 and its relation to NIH’s 2015 analysis of research funding and disease burden. This update incorporates more recent burden data from 2015 and funding data from 2017.

Methods: We perform a regression analysis on funding versus disease burden to determine 2017 funding levels that would be commensurate with burden. Burden figures for 2017 are estimated using population-based extrapolations of earlier data.

Results: We find the disease burden of ME/CFS is double that of HIV/AIDS and over half that of breast cancer. We also find that ME/CFS is more underfunded with respect to burden than any disease in NIH’s analysis of funding and disease burden, with ME/CFS receiving roughly 7% of that commensurate with disease burden.

Conclusions: To be commensurate with disease burden, NIH funding would need to increase roughly 14-fold.

Source: Mirin AA, Dimmock ME, Jason LA. Research update: The relation between ME/CFS disease burden and research funding in the USA [published online ahead of print, 2020 Jun 16]. Work. 2020;10.3233/WOR-203173. doi:10.3233/WOR-203173 https://pubmed.ncbi.nlm.nih.gov/32568148/