Tag: post-infectious sequelae

Infection-associated chronic conditions: Why Long Covid is our best chance to untangle Osler’s web

Abstract:

The recognition of Long Covid has renewed efforts to understand other infection-associated chronic conditions (IACCs). Here, we describe how studies of Long Covid and other IACCs might inform one another. We argue for the importance of a coordinated research agenda addressing these debilitating illnesses.

INTRODUCTION

For nearly a century, individuals with medically unexplained chronic conditions, particularly those thought to be attributable to presumably transient infectious pathogens, have faced bewilderment, skepticism, or outright dismissal from the medical establishment. Debilitating symptoms lasting for years have been reported after acute infections with viruses [enterovirus, Epstein-Barr virus (EBV), influenza virus, Ebola virus, dengue virus, chikungunya virus, West Nile virus, and severe acute respiratory syndrome coronavirus 1 (SARS-CoV)], bacteria (Borrelia and Anaplasma), and protozoa (Giardia) (1). Myalgic encephalomyelitis (ME), sometimes referred to as chronic fatigue syndrome (CFS), is perhaps the best example of a disabling syndrome that many experts believe follows an acute, often undiagnosed viral infection. Several names have been applied to these syndromes, including post-acute infection syndromes (PAIS), infection-associated chronic illnesses, and infection-associated chronic conditions (IACCs). Here, we will use IACCs.
Despite consistent reports regarding these conditions dating back nearly 100 years (2–4), the biomedical establishment has made limited progress in defining the epidemiology, natural history, and pathogenesis of most IACCs. No diagnostic tests are available, no widely accepted treatments exist, and industry engagement on finding a cure has been limited. In her 1996 book Osler’s Web, investigative journalist Hillary Johnson catalogued the challenges facing ME/CFS research (5), which can be applied to many IACCs. Barriers to progress included the inability to fit ME/CFS into existing disease paradigms, variability and inconsistency in case ascertainment, skepticism on the part of many clinicians and scientists, and intense stigma that kept many of those affected from seeking medical care. William Osler, the “father of modern medicine,” emphasized the importance of listening to patients to discern important features of their condition. However, contemporary medical practice relies heavily on diagnostic tests, which are currently inadequate to confirm the presence of an IACC. This results in people being neglected or misdiagnosed and prevents them from receiving appropriate care and support.
The year 2020 has the potential to be a turning point in this story. Shortly after the COVID-19 pandemic began, reports of individuals with prolonged COVID-attributed symptoms emerged, a condition now often referred to as Long Covid. The synchronicity of the inciting infection, universality of the exposure, and visibility, aided by social, popular, and scientific media (6), resulted in the ideal environment for a coordinated effort to understand this new IACC. Substantial investment in scientific effort is starting to pay off, with real progress in defining the epidemiology, natural history, and biology of Long Covid now emerging. After a Congressional appropriation, the US National Institutes of Health rapidly launched the Researching COVID to Enhance Recovery (RECOVER) initiative, which is the first large-scale program aimed at tackling an IACC. The progress to date has been hard-won, however, in part because there is no widely accepted clinical definition, biomarker, or diagnostic test for Long Covid. However, clinical trials, slow to start, are now being pursued in earnest. Although there is no guarantee that this momentum will be sustained without dedicated scientific and financial commitments (7), there is reason to believe that efforts to understand Long Covid have the potential to draw attention to, reframe, and revitalize the efforts to study other IACCs.
High-quality academic reviews of Long Covid are multiplying rapidly (8–12). Our goal in this Viewpoint is not to provide a comprehensive overview of the field but rather to place efforts to study Long Covid in the context of other IACCs. In doing so, we hope to outline several areas that we believe will require consideration as the field attempts to make progress in navigating what has been described as a “labyrinth” (5).
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Source: Michael J. Peluso et al. Infection-associated chronic conditions: Why Long Covid is our best chance to untangle Osler’s web. Sci. Transl. Med.16,eado2101(2024). DOI:10.1126/scitranslmed.ado2101

Increased risk of chronic fatigue syndrome following pneumonia: A population-based Cohort study

Abstract:

Background: Chronic fatigue syndrome (CFS) has been linked to several conditions, including infections, immune system changes, or emotional stress. Our study aimed to assess the risk of CFS after a pneumonia diagnosis using data from National Health Insurance Research Database of Taiwan.

Methods: In this nested case-control study, we identified 2,000,000 adult patients from a nationwide population-based health insurance claims database spanning from January 1, 2000, to December 31, 2017. Each case diagnosed with a pathogenic infection was matched with a corresponding control using propensity scores. We excluded individuals under 20 years of age, those with a history of pathogenic infections before the index date, or those with more than one potential pathogen. To estimate hazard ratios (HR) and the adjusted hazard ratio (aHR) with their respective 95 % confidence intervals (CI), we applied univariable and multivariable Cox proportional hazard models. The multivariable analysis incorporated adjustments for age, sex, and comorbidity-related confounders.

Results: The relationship between infection and the subsequent risk of CFS was assessed using Cox proportional hazards regression analysis. The incidence density rates were 6.13 and 8.70 per 1000 person-years among the non-pulmonary infection and pulmonary infection populations, respectively (adjusted hazard ratio [HR] = 1.4, 95 % confidence interval [CI] 1.32-1.5). Patients infected with Pseudomonas, Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, and influenza virus exhibited a significantly higher risk of CFS than those without these pathogens (p < 0.05). Additionally, patients with pneumonia had a significantly increased risk of thromboembolism compare with control group (p < 0.05).

Source: Hsu HJ, Chang H, Lin CL, Yao WC, Hung CL, Pang SP, Kuo CF, Tsai SY. Increased risk of chronic fatigue syndrome following pneumonia: A population-based Cohort study. J Infect Public Health. 2024 Jul 14;17(8):102495. doi: 10.1016/j.jiph.2024.102495. Epub ahead of print. PMID: 39018725. https://www.sciencedirect.com/science/article/pii/S1876034124002296 (Full text)

How Patient Input Helped Create Culturally Sensitive Multinational Instruments Assessing Post Viral Symptoms

Our study involves collaboration/participation in order to develop culturally sensitive multinational tools for assessing post viral symptoms.

We discuss the creation of questionnaires using patient participation, and the translation of these questionnaires using international collaboration.

Patient engagement in collaboration on the creation and use of these types of instruments is of particular importance for patients who historically have not been true partners in collaborative efforts to understand diseases.

This has occurred for those with the post-viral illness called Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which has generated considerable resentment and estrangement among the patient community.

Our article reviews:

1) why participation of diverse groups/patients is important in the development of instruments to measure key symptoms of ME/CFS,

2) why the ME/CFS group of patients needs to be included specifically (as an example),

and

3) why structured health questionnaires are important/useful.

Our article also has an overall aim of demonstrating collaborative efforts with patients and others on creating multinational scales.

We provide examples of participatory processes used in developing and translating patient-driven instruments so that they can be used in non-English speaking countries.

Our article illustrates how patients and international researchers can be involved in efforts to develop and translate international assessment instruments to validly capture domains of unexplained illness like ME/CFS.

With the onset of another post-viral illness, Long COVID, there is a world-wide need to create valid and culturally sensitive assessment instruments to measure critical symptoms, many of which are similar to ME/CFS.

Source: Leonard A. Jason and Joseph A. Dorri. How Patient Input Helped Create Culturally Sensitive Multinational Instruments Assessing Post Viral Symptoms. The Australian Community Psychologist., Volume 32 No 1  https://psychology.org.au/getmedia/c300a432-c7fd-4f97-9322-ce16429067e4/ac-vol-32(1)-2023-final-draft.pdf#page=63 (Full text)

Muscle abnormalities worsen after post-exertional malaise in long COVID

Abstract:

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear.

With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

Source: Appelman, B., Charlton, B.T., Goulding, R.P. et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun 15, 17 (2024). https://doi.org/10.1038/s41467-023-44432-3 https://www.nature.com/articles/s41467-023-44432-3 (Full text)

Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions

Abstract:

Post-viral pain syndrome, also known as post-viral syndrome (PVS), is a complex condition characterized by persistent pain, fatigue, musculoskeletal pain, neuropathic pain, neurocognitive difficulties, and sleep disturbances1,2 that can occur after an individual has recovered from a viral infection. Much remains unknown regarding the pathophysiology of post-viral syndromes and few studies have provided a comprehensive summary of the condition, agents that cause it, and successful treatment modalities.

With the COVID-19 pandemic continuing to affect millions of people worldwide, the need for understanding the etiology of post-viral illness and how to help individuals cope with the sequalae is paramount.2 This narrative review provides a summary of the sequelae of post-viral syndromes, viral agents that cause it, the pathophysiology, treatment, and future considerations for research and targeted therapies.

Source: Caleb Tackey, P. Maxwell Slepian, Hance Clarke & Nimish Mittal (2023) Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions, Canadian Journal of Pain, DOI: 10.1080/24740527.2023.2272999 https://www.tandfonline.com/doi/full/10.1080/24740527.2023.2272999 (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)

The microbiome in post-acute infection syndrome (PAIS)

Abstract:

Post-Acute Infection Syndrome (PAIS) is a relatively new medical terminology that represents prolonged sequelae symptoms after acute infection by numerous pathogenic agents. Imposing a substantial public health burden worldwide, PASC (post-acute sequelae of COVID-19 infection) and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) are two of the most recognized and prevalent PAIS conditions. The presences of prior infections and similar symptom profiles in PAIS reflect a plausible common etiopathogenesis. The human microbiome is known to play an essential role in health and disease.

In this review, we reviewed and summarized available research on oral and gut microbiota alterations in patients with different infections or PAIS conditions. We discussed key theories about the associations between microbiome dysbiosis and PAIS disease development, aiming to explore the mechanistic roles and potential functions the microbiome may have in the process. Additionally, we discuss the areas of knowledge gaps and propose the potential clinical applications of the microbiome for prevention and treatment of PAIS conditions.

Source: Guo C, Yi B, Wu J, Lu J. The microbiome in post-acute infection syndrome (PAIS). Comput Struct Biotechnol J. 2023 Aug 5;21:3904-3911. doi: 10.1016/j.csbj.2023.08.002. PMID: 37602232; PMCID: PMC10432703. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432703/ (Full text)

Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases?

Abstract:

It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin that is amyloid in character; the resultant clots and microclots entrap many other molecules, stain with fluorogenic amyloid stains, are rather resistant to fibrinolysis, can block up microcapillaries, are implicated in a variety of diseases including Long COVID, and have been referred to as fibrinaloids. A necessary corollary of this anomalous polymerisation is the generation of novel epitopes in proteins that would normally be seen as ‘self’, and otherwise immunologically silent.

The precise conformation of the resulting fibrinaloid clots (that, as with prions and classical amyloid proteins, can adopt multiple, stable conformations) must depend on the existing small molecules and metal ions that the fibrinogen may (and is some cases is known to) have bound before polymerisation. Any such novel epitopes, however, are likely to lead to the generation of autoantibodies.

A convergent phenomenology, including distinct conformations and seeding of the anomalous form for initiation and propagation, is emerging to link knowledge in prions, prionoids, amyloids and now fibrinaloids. We here summarise the evidence for the above reasoning, which has substantial implications for our understanding of the genesis of autoimmunity (and the possible prevention thereof) based on the primary process of fibrinaloid formation.

Source: Kell DB, Pretorius E. Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? Biochem J. 2023 Aug 16;480(15):1217-1240. doi: 10.1042/BCJ20230241. PMID: 37584410. https://portlandpress.com/biochemj/article/480/15/1217/233389/Are-fibrinaloid-microclots-a-cause-of-autoimmunity (Full text)

Posttreatment Lyme disease syndrome and myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and comparison of pathogenesis

Abstract:

Lyme disease is the most common vector-borne illness in the United States and has been causing significant morbidity since its discovery in 1977. It is well-documented that about 10% of patients properly treated with antibiotics never fully recover, but instead go on to develop a chronic illness dubbed, posttreatment Lyme disease syndrome (PTLDS) characterized by severe fatigue, cognitive slowing, chronic pain, and sleep difficulties. This review includes 18 studies that detail the symptoms of patients with PTLDS and uses qualitative analysis to compare them to myalgic encephalitis/chronic fatigue syndrome (ME/CFS), a strikingly similar syndrome.

In the majority of the PTLDS studies, at least four of the six major symptoms of ME/CFS were also noted, including substantial impairment in activity level and fatigue for more than 6 months, post-exertional malaise, and unrefreshing sleep. In one of the included PTLDS articles, 26 of the 29 ME/CFS symptoms were noted. This study adds to the expanding literature on the post-active phase of infection syndromes, which suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Key points

  • This systematic review uses qualitative analysis to compare posttreatment Lyme disease syndrome to myalgic encephalitis/chronic fatigue syndrome, both of which are post-active phases of infection syndromes.
  • The result of this review suggests that chronic illnesses such as PTLDS and ME/CFS have similar pathogenesis despite different infectious origins.

Source: Bai, NA, Richardson, CS. Posttreatment Lyme disease syndrome and myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and comparison of pathogenesis. Chronic Dis Transl Med. 2023; 1– 8. doi:10.1002/cdt3.74 https://onlinelibrary.wiley.com/doi/full/10.1002/cdt3.74 (Full text)

Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study

Abstract:

Background: We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis.

Methods: We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus.

Findings: Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered. Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8+ T cells but impaired antigen presentation capacity of CD4+ T cells.

Interpretation: Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.

Funding: This study was funded by the Tianjin Haihe Hospital Science and Technology Fund (HHYY-202012) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-063B, TJYXZDXK-067C).

Source: Li K, Wu Q, Li H, Sun H, Xing Z, Li L, Chen H. Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study. EClinicalMedicine. 2023 Apr;58:101884. doi: 10.1016/j.eclinm.2023.101884. Epub 2023 Feb 27. PMID: 36873427; PMCID: PMC9969173.