Category: Overlapping Illnesses

Red Blood Cell Morphology Is Associated with Altered Hemorheological Properties and Fatigue in Patients with Long COVID

Simple Summary:
SARS-CoV-2 alters the properties of oxygen-carrying red blood cells (RBCs) through a possible deterioration of hemorheological properties, such as aggregation and deformability. However, long-term changes in these properties and a possible association with morphological abnormalities remain unknown. Therefore, this study aims to investigate changes in the above-mentioned RBC properties in Long-COVID (LC). Venous blood was collected from n = 30 diagnosed LC and n = 30 non-Long-COVID controls (non-LC). Hematological parameters were measured, as well as the aggregation, deformability, and morphology of the RBCs and the mechanical sensitivity index (MS), which reflects the functional capacity of RBCs to deform. The results indicate that hematological parameters were not altered in LC. However, LC showed higher overall aggregation parameters. RBC deformability was higher in LC compared to non-LC; however, MS was limited in this group. LC showed a higher percentage of RBCs with abnormal shapes, which was related to MS and to fatigue, which is considered the leading symptom of LC. It is concluded that the symptoms of LC and changes in the blood flow determining the properties of RBCs are related to the morphological changes in RBCs. Future studies should investigate the underlying causes in order to develop appropriate therapies for this relatively new disease.
Abstract:

Background: SARS-CoV-2 infection adversely affects rheological parameters, particularly red blood cell (RBC) aggregation and deformability, but whether these changes persist in patients suffering from Long-COVID (LC) and whether these changes are related to RBC morphology remain unknown.
Methods: Venous blood was collected from n = 30 diagnosed LC patients and n = 30 non-LC controls and RBC deformability, RBC aggregation, and hematological parameters were measured. In addition, RBCs were examined microscopically for morphological abnormalities. The mechanical sensitivity index (MS) was assessed in n = 15 LC and n = 15 non-LC samples.
Results: Hematological parameters did not differ between the groups. However, LC showed higher aggregation-related parameters. Although RBC deformability was higher in LC, MS, reflecting the functional capacity to deform, was limited in this group. RBCs from LC showed significantly more morphological abnormalities. The extent of morphological abnormalities correlated with MS and the FACIT-Fatigue score of the LC patients.
Conclusion: RBCs from LC show a high degree of morphological abnormalities, which might limit the blood flow determining RBC properties and also be related to fatigue symptomatology in LC. Approaches are now needed to understand the underlying cause of these alterations and to ameliorate these permanent changes.
Source: Grau M, Presche A, Krüger A-L, Bloch W, Haiduk B. Red Blood Cell Morphology Is Associated with Altered Hemorheological Properties and Fatigue in Patients with Long COVID. Biology. 2024; 13(11):948. https://doi.org/10.3390/biology13110948 https://www.mdpi.com/2079-7737/13/11/948 (Full text)

Cognitive impact and brain structural changes in long COVID patients: a cross-sectional MRI study two years post infection in a cohort from Argentina

Abstract:

Objective: Long COVID is a condition characterised by persistent symptoms after a SARS-CoV-2 infection, with neurological manifestations being particularly frequent. Existing research suggests that long COVID patients not only report cognitive symptoms but also exhibit measurable cognitive impairment. Neuroimaging studies have identified structural alterations in brain regions linked to cognitive functions. However, most of these studies have focused on patients within months of their initial infection. This study aims to explore the longer-term cognitive effects and brain structural changes in long COVID patients, approximately two years post-infection, in a cohort from San Martín, Buenos Aires, Argentina.

Methods: We conducted a cross-sectional study involving 137 participants: 109 with long COVID symptoms and 28 healthy controls. The participants underwent an initial clinical assessment, completed a structured questionnaire and standardised scales, underwent a cognitive assessment, and had a brain MRI scan. Structural MRI images were processed via FreeSurfer and FSL to obtain volumetric measures for subcortical and cortical regions, along with regional cortical thickness. Differences between groups for these variables were analysed using ANCOVA, with permutation tests applied to correct for multiple comparisons.

Results: Long COVID patients reported persistent cognitive symptoms such as memory problems and brain fog, with higher levels of fatigue and reduced quality of life compared to controls. Despite subjective cognitive complaints, cognitive tests did not reveal significant differences between groups, except for the TMT-A (p = 0.05). MRI analysis revealed decreased volume in the cerebellum (p = 0.03), lingual gyrus (p = 0.04), and inferior parietal regions (p = 0.03), and reduced cortical thickness in several areas, including the left and right postcentral gyri (p = 0.02, p = 0.03) and precuneus (p = 0.01, p = 0.02).

Conclusions: This study highlights the enduring impact of long COVID on quality of life and physical activity, with specific brain structural changes identified two years post-infection. Although cognitive tests did not show clear impairment, the observed brain atrophy and significant reduction in quality of life emphasize the need for comprehensive interventions and further longitudinal studies to understand the long-term effects of long COVID on cognition and brain health.

Source: Cataldo SA, Micciulli A, Margulis L, Cibeyra M, Defeo S, Horovitz SG, Martino A, Melano R, Mena M, Parisi F, Santoro D, Sarmiento F, Belzunce MA. Cognitive impact and brain structural changes in long COVID patients: a cross-sectional MRI study two years post infection in a cohort from Argentina. BMC Neurol. 2024 Nov 18;24(1):450. doi: 10.1186/s12883-024-03959-8. PMID: 39558250; PMCID: PMC11572126. https://pmc.ncbi.nlm.nih.gov/articles/PMC11572126/ (Full text)

Postural orthostatic tachycardia syndrome and other common autonomic disorders are not functional neurologic disorders

Introduction:

In the past 4 years of COVID-19 and Long COVID, a renewed interest in postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders brought to light a common misconception that these disorders are based in or are associated with functional neurologic disorder (FND). Recently, one narrative review attempted to link autonomic disorders and autonomic nervous system dysfunction with symptoms of FND (1). Others have similarly suggested that Long COVID may be based in functional or somatic etiology (2–5). As medical professionals with expertise in autonomic disorders, we would like to emphasize the distinction between autonomic disorders, autonomic symptoms and FND in order to ensure that appropriate diagnostic and therapeutic pathways are implemented by clinicians.

Source: Blitshteyn S, Treisman GJ, Ruhoy IS, Saperstein DS, Schofield JR, Goodman BP, Davenport TE, Cutchins AC and Grubb BP (2024) Postural orthostatic tachycardia syndrome and other common autonomic disorders are not functional neurologic disorders. Front. Neurol. 15:1490744. doi: 10.3389/fneur.2024.1490744 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1490744/full (Full text)

On the Prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome after a SARS-CoV-2 infection

Introduction:

There is an increasing body of evidence connecting the post-acute SARS-CoV-2 condition (PASC, commonly known as long COVID) to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disease of unknown cause characterized by persistent and unexplained fatigue, post-exertional malaise (PEM), among other symptoms. This connection implies that, in the clinic, some PASC cases comply with the official case definitions of ME/CFS. As such, there is a necessity to quantify the burden of ME/CFS among the PASC population in order to delineate effective healthcare interventions for the benefit of these patients who are often neglected or, in some extreme cases, stigmatized by medical staff and society.
To answer this urgent research question, Dehlia and Guthridge performed a systematic review and meta-analysis of recent data on PASC adults and reported an ME/CFS prevalence estimate of 51% (95% CI, 42%-60%); this systematic review and meta-analysis will be referred to as PASC-ME/CFS study. In the present Letter to Editor, we aimed to discuss the reliability of this estimate using the research protocol from the European Network on ME/CFS (EUROMENE) for systematic reviews and meta-analysis on the epidemiology burden of ME/CFS in Europe.

Source: Sepúlveda N, Westermeier F. On the Prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome after a SARS-CoV-2 infection. J Infect. 2024 Nov 16:106353. doi: 10.1016/j.jinf.2024.106353. Epub ahead of print. PMID: 39557089. Sepúlveda N, Westermeier F. On the Prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome after a SARS-CoV-2 infection. J Infect. 2024 Nov 16:106353. doi: 10.1016/j.jinf.2024.106353. Epub ahead of print. PMID: 39557089. https://www.journalofinfection.com/article/S0163-4453(24)00288-3/fulltext (Full text)

Initiating Long Covid RECOVERy

Introduction:

The coronavirus disease 2019 (COVID-19) pandemic paralyzed the United States, rendering thousands critically ill and ultimately killing more than 1 million Americans. Many survivors, particularly those with adult respiratory distress syndrome, required prolonged rehabilitation. Many more people, including those who did not require hospitalization for their acute illness, presented with a host of other persistent, disabling symptoms. The latter condition was termed “Long Covid” and turned out to be the most prevalent postacute sequelae of the COVID-19 pandemic.

The symptom complex that characterizes Long Covid resembles that seen in other infection-associated chronic conditions, notably overlapping with those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overlapping symptoms include fatigue, unrefreshing sleep, neurocognitive dysfunction characterized by impaired executive function, exercise intolerance, fluctuating heart rate and sense of dizziness particularly in the upright position, and postexertional malaise, a signature symptom of ME/CFS. The drivers of these conditions remain unknown, and no treatments have proven effective. Data suggest that many individuals with Long Covid may return to health months or years after onset, but debilitating symptoms and unknown long-term outcomes remain in too many people. Of greatest concern is that, for some individuals, Long Covid may last a lifetime.

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Source: Marrazzo J, Gibbons GH, Koroshetz W. Initiating Long Covid RECOVERy. Sci Transl Med. 2024 Nov 13;16(773):eadr9971. doi: 10.1126/scitranslmed.adr9971. Epub 2024 Nov 13. PMID: 39536123. https://www.science.org/doi/10.1126/scitranslmed.adr9971 (Full text)

Trajectories of functional limitations, health-related quality of life and societal costs in individuals with long COVID: a population-based longitudinal cohort study

Abstract:

Objectives: To examine trajectories of functional limitations, fatigue, health-related quality of life (HRQL) and societal costs of patients referred to long COVID clinics.

Design: A population-based longitudinal cohort study using real-time user data.

Setting: 35 specialised long COVID clinics in the UK.

Participants: 4087 adults diagnosed with long COVID in primary or secondary care deemed suitable for rehabilitation and registered in the Living With Covid Recovery (LWCR) programme between 4 August 2020 and 5 August 2022.

Main outcome measures: Generalised linear mixed models were fitted to estimate trajectories of functional limitations, using the Work and Social Adjustment Scale (WSAS); scores of ≥20 indicate moderately severe limitations. Other outcomes included fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) reversed score (scores of ≥22 indicate impairment), HRQL using the EQ-5D-5L, and long COVID-related societal costs, encompassing healthcare costs and productivity losses.

Results: The mean WSAS score at 6 months after registration in the LWCR was 19.1 (95% CI 18.6, 19.6), with 46% of the participants (95% CI 40.3%, 52.4%) reporting a WSAS score above 20 (moderately severe or worse impairment). The mean change in the WSAS score over the 6-month period was -0.86 (95% CI -1.32, -0.41). The mean reversed FACIT-F score at 6 months was 29.1 (95% CI 22.7, 35.5) compared with 32.0 (95% CI 31.7, 32.3) at baseline. The mean EQ-5D-5L score remained relatively constant between baseline (0.63, 95% CI 0.62, 0.64) and 6 months (0.64, 95% CI 0.59, 0.69). The monthly societal cost per patient related to long COVID at 6 months was £931, mostly driven by the costs associated with working days lost.

Conclusions: Individuals referred to long COVID clinics in the UK reported small improvements in functional limitations, fatigue, HRQL and ability to work within 6 months of registering in the LWCR programme.

Source: Wang J, Goodfellow H, Walker S, Blandford A, Pfeffer P, Hurst JR, Sunkersing D, Bradbury K, Robson C, Henley W, Gomes M. Trajectories of functional limitations, health-related quality of life and societal costs in individuals with long COVID: a population-based longitudinal cohort study. BMJ Open. 2024 Nov 13;14(11):e088538. doi: 10.1136/bmjopen-2024-088538. PMID: 39537389. https://bmjopen.bmj.com/content/14/11/e088538 (Full text)

Overlapping conditions in Long COVID at a multisite academic center

Abstract:

Background: Many patients experience persistent symptoms after COVID-19, a syndrome referred to as Long COVID (LC). The goal of this study was to identify novel new or worsening comorbidities self-reported in patients with LC.

Methods: Patients diagnosed with LC (n = 732) at the Mayo Long COVID Care Clinic in Rochester, Minnesota and Jacksonville, Florida were sent questionnaires to assess the development of new or worsening comorbidities following COVID-19 compared to patients with SARS-CoV-2 that did not develop LC (controls). Both groups were also asked questions screening for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), generalized joint hypermobility (GJH) and orthostatic intolerance. 247 people with LC (33.7%) and 40 controls (50%) responded to the surveys.

Results: In this study LC patients averaged 53 years of age and were predominantly White (95%) women (75%). The greatest prevalence of new or worsening comorbidities following SARS-CoV-2 infection in patients with LC vs. controls reported in this study were pain (94.4% vs. 0%, p < 0.001), neurological (92.4% vs. 15.4%, p < 0.001), sleep (82.8% vs. 5.3%, p < 0.001), skin (69.8% vs. 0%, p < 0.001), and genitourinary (60.6% vs. 25.0%, p = 0.029) issues. 58% of LC patients screened positive for ME/CFS vs. 0% of controls (p < 0.001), 27% positive for GJH compared to 10% of controls (p = 0.026), and a positive average score of 4.0 on orthostatic intolerance vs. 0 (p < 0.001). The majority of LC patients with ME/CFS were women (77%).

Conclusion: We found that comorbidities across 12 surveyed categories were increased in patients following SARS-CoV-2 infection. Our data also support the overlap of LC with ME/CFS, GJH, and orthostatic intolerance. We discuss the pathophysiologic, research, and clinical implications of identifying these conditions with LC.

Source: Grach SL, Dudenkov DV, Pollack B, Fairweather D, Aakre CA, Munipalli B, Croghan IT, Mueller MR, Overgaard JD, Bruno KA, Collins NM, Li Z, Hurt RT, Tal MC, Ganesh R, Knight DTR. Overlapping conditions in Long COVID at a multisite academic center. Front Neurol. 2024 Oct 25;15:1482917. doi: 10.3389/fneur.2024.1482917. PMID: 39524912; PMCID: PMC11543549. https://pmc.ncbi.nlm.nih.gov/articles/PMC11543549/ (Full text)

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

Stroop task and practice effects demonstrate cognitive dysfunction in long COVID and myalgic encephalomyelitis / chronic fatigue syndrome

Abstract:

Background: The Stroop task was used to investigate differences in cognitive function between Long COVID (LC), Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and healthy control subjects.

Methods: Subjects viewed four color words or neutral (XXXX) stimuli with the same (congruent) or different color ink (incongruent). Cognitive conflict was inferred from response times for pairings of prestimuli and subsequent stimuli. Overall effects were assessed by univariate analysis with time courses determined for binned response times.

Results: LC and ME/CFS had significantly longer response times than controls indicating cognitive dysfunction. Initial response times were ranked LC > ME > HC, and decreased according to power functions. At the end of the task (900s), times were ranked LC = ME > HC. Response times were significantly slower for stimuli following an incongruent prestimulus. Time series for Stroop effect, facilitation, interference, surprise index and practice power law parameters were generally similar in LC, ME/CFS and HC suggesting comparable patterns for recruitment of cognitive resources. The prestimulus data were analyzed and generated positive Stroop and interference effects that were distinct from stimulus effects.

Conclusion: LC and ME/CFS have global slowing of response times that cannot be overcome by practice suggesting impaired communications between network nodes during problem solving. Analysis of matched prestimulus – stimulus effects adds a new dimension for understanding cognitive conflict.

Brief summary: Cognitive dysfunction in Long COVID and ME/CFS was demonstrated using the Stroop task which found global slowing of response times and limitations of practice effects.

Source: Baraniuk JN, Thapaliya K, Inderyas M, Shan ZY, Barnden LR. Stroop task and practice effects demonstrate cognitive dysfunction in long COVID and myalgic encephalomyelitis / chronic fatigue syndrome. Sci Rep. 2024 Nov 5;14(1):26796. doi: 10.1038/s41598-024-75651-3. PMID: 39500939; PMCID: PMC11538523. https://pmc.ncbi.nlm.nih.gov/articles/PMC11538523/ (Full text)

Web-based telemedicine approach for treatment of post-COVID-19 in Thuringia (WATCH)

Abstract:

Objective: After infection with SARS-CoV-2, a substantial proportion of patients develop long-lasting sequelae. These sequelae include fatigue (potentially as severe as that seen in ME/CFS cases), cognitive dysfunction, and psychiatric symptoms. Because the pathophysiology of these sequelae remains unclear, existing therapeutic concepts address the symptoms through pacing strategies, cognitive training, and psychological therapy.

Methods: Here, we present a protocol for a digital multimodal structured intervention addressing common symptoms through three intervention modules: BRAIN, BODY, and SOUL. This intervention includes an assessment conducted via a mobile “post-COVID-19 bus” near the patient’s home, as well as the use of wearable devices and mobile applications to support pacing strategies and collection of data, including ecological momentary assessment.

Results: We will focus on physical component subscore of the SF36 as Quality of Life parameter as the primary outcome parameter for WATCH to take into account the holistic approach that is necessary for care of post-COVID patients.

Conclusion: In the current project, we present a protocol for a holistic and multimodal structured therapeutic concept which is easily accessible, and scalable for post-COVID patients.

Source: Reuken PA, Besteher B, Bleidorn J, Brockmann D, Finke K, Freytag A, Lehmann-Pohl K, Lemhöfer C, Mikolajczyk R, Puta C, Scherag A, Wiedermann M, Zippel-Schultz B, Stallmach A. Web-based telemedicine approach for treatment of post-COVID-19 in Thuringia (WATCH). Digit Health. 2024 Oct 14;10:20552076241291748. doi: 10.1177/20552076241291748. PMID: 39493638; PMCID: PMC11528766. https://pmc.ncbi.nlm.nih.gov/articles/PMC11528766/ (Full text)