Neuropathology and Neurological Manifestations in ME/CFS and Long COVID with focus on Post-Exertional Symptom Exacerbation: a Literature Review

Summary:

Many of the people that get infected with the Coronavirus develop long-lasting complaints and are diagnosed with Long COVID after the acute infection is gone. These complains can last several months or years and include fatigue, cognitive impairment, sleeping problems and post-exertional symptom exacerbation (PESE). Research shows that COVID-19 patients with an acute infection have abnormalities in their brain, which could potentially lead to long-lasting neurological problems and symptoms. However, although many researchers are trying to uncover the underlying mechanisms, Long COVID is still very new.
The underlying mechanisms causing and maintaining the disease are therefore unclear. A large group of Long COVID patients resembles patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in terms of symptoms and, in many cases, the viral trigger of the disease. A core symptom of ME/CFS is PESE, which is uncommon in other fatiguing illnesses, but frequently seen in Long COVID patients. PESE involves an abnormal worsening of symptoms and cognitive and physical functions after any type of normal activity. Because of the large symptom overlap and lack of knowledge regarding PESE, underlying brain-mechanisms associated with Long COVID and ME/CFS in general as well as after physical exertion were investigated.
The findings of this review indicate that ME/CFS is associated with several abnormalities in the brain which are also proposed to be present in Long COVID patients. Such abnormalities include inflammation of the brain, shrinkage of the brain and less blood flow to the brain. After physical exertion, these abnormalities might be exacerbated in ME/CFS patients. This results in a brain that needs to work harder than the healthy brain to complete a task. It is demonstrated by increased brain activity in several brain regions after physical exertion and general symptom exacerbation. Since the two diseases seem to have a large overlap in symptoms and underlying brain-mechanisms, this finding might apply to patients with long COVID as well. Importantly, Long COVID seems to consist of different subgroups of which a large part fulfills the criteria for ME/CFS.
Treatment and therapy for ME/CFS patients is therefore likely transferable to this subgroup of Long COVID patients, with explicit attention towards the PESE phenomenon. More research is needed to uncover the underlying mechanisms as well as correct treatment approach of these diseases. Future research should take subgroups of Long COVID into account.
Source: Rodenburg, Sanne. Neuropathology and Neurological Manifestations in ME/CFS and Long COVID with focus on Post-Exertional Symptom Exacerbation: a Literature Review. Master Thesis, Utrecht University. March 14, 2023. https://studenttheses.uu.nl/bitstream/handle/20.500.12932/43647/Rodenburg_7433050_Neuropathology%20and%20neurological%20manifestations%20in%20MECFS%20and%20Long%20COVID%20with%20focus%20on%20PESE.pdf (Full text)

Clinical and radiological outcomes of longCOVID: Is the post-COVID fibrosis common?

Abstract:

Introduction: COVID-19 survivors may take longer to regain full well-being. This study aimed to investigate clinical and functional evaluation and radiologic changes in the third month after COVID-19.

Materials and methods: A total of 126 patients were assessed in the third month for symptoms, pulmonary function, exercise capacity, radiologic imaging, and quality of life after being discharged following COVID-19 treatment. Two radiologists evaluated the initial and follow-up images.

Result: At the third month follow-up visit, the most common persisting symptoms were shortness of breath (32.5%), cough (12.7%), and muscle pain (12.7%). At the follow-up visit, oxygen saturations at rest and after a six min walking test were lower in patients with prior intensive care hospitalization compared to those without (p<0.001, p= 0.004). Computed tomography (CT) scans revealed persisting pulmonary pathologies in 64.6% of patients at the third month follow-up. The most common pathologies on follow-up thoracic CT were fibrotic-like changes in 44.2% and ground-glass opacities (GGO) in 33.3%. Regression analysis unveiled that age [95% confidence interval (CI), 1.01 to 1.15; p= 0.020], male sex (95% CI, 4.06 to 95.3, p<0.001), first CT severity score (95% CI, 1.02 to 1.41, p= 0.028), duration of hospitalization (95% CI, 1.02 to 1.18, p= 0.012), oxygen saturation (95% CI, 0.86 to 0.96, p<0.001) were independent predictors of fibrotic-like changes.

Conclusions: In the third month following COVID-19, the most common symptom was dyspnea, and the most common radiological findings were fibrotic-like changes and GGO. Longer follow-up studies of COVID-19 survivors are needed to observe lasting changes.

Source: Sarıoğlu N, Aksu GD, Çoban H, Bülbül E, Demirpolat G, Arslan AT, Erel F. Clinical and radiological outcomes of longCOVID: Is the post-COVID fibrosis common? Tuberk Toraks. 2023 Mar;71(1):48-57. English. doi: 10.5578/tt.20239907. PMID: 36912409. http://tuberktoraks.org/managete/fu_folder/2023-01/2023-71-1-48-57.pdf (Full text)

The Prevalence of Psychiatric Symptoms and their correlates as part of the Long-Covid Syndrome.

Abstract:

The Long COVID syndrome has now been documented clearly in the literature, but whether or not psychiatric symptoms are prominent is unclear. We performed a retrospective chart review of all patients receiving medical care during the pandemic in an outpatient Long-COVID specialty clinic that serves a large racial and ethnic minority population. As many as 44% of patients had symptoms that necessitated referrals to psychiatrists, predominantly depression or anxiety. Spanish speaking patients had greater COVID severity (48%) than did predominantly English speakers (15%). We conclude that the long COVID syndrome is predominantly a cluster of physical symptoms that are sequelae of the viral infection.

Source: Clifton Chow, Will Schleyer, Lynn E DeLisi. The Prevalence of Psychiatric Symptoms and their correlates as part of the Long-Covid Syndrome. Psychiatry Research, 2023, 115166, ISSN 0165-1781, https://doi.org/10.1016/j.psychres.2023.115166. https://www.sciencedirect.com/science/article/pii/S0165178123001178

Effect of laser acupuncture on immunomodulation and dyspnea in post-COVID-19 patients

Introduction: The post-COVID-19 syndrome is characterized by post-viral chronic fatigue syndrome as well as multi-organ complications. Its usual clinical symptoms are exhaustion, dyspnea, and chest pain. This study examines the effect of laser acupuncture (LA), which implies laser application on acupuncture points, on boosting immunity and reducing the inflammatory symptoms in post-COVID syndrome patients.

Material and methods: A total of 80 patients of both sexes with post-COVID symptoms were enrolled and randomly divided into the LA group (n = 40), which received LA three times/week for 12 weeks, and a placebo group (n = 40) which received sham LA. The following measures were taken for both groups before and after the study: Total lymphocyte count (TLC), Interleukin 6 (IL-6), dyspnea using the modified Medical Research Counseling Dyspnea Scale (mMRC), and fatigue using the Chalder Fatigue Scale (CFQ-11).

Results: LA group showed a significant elevation in TLC (p < 0.001) as well as a significant reduction in IL-6 levels, dyspnea, and fatigue scale (p < 0.001). On the other hand, the placebo group demonstrated a significant increase in TLC (p < 0.05).

Conclusions: The use of lasers at particular acupuncture points related to lung and immunity showed promising results in dealing with the typical main symptoms post-COVID, including chronic fatigue and dyspnea.

Source: Algitany SI, Fouad SA, Nassif AA, Guirguis SA. Effect of laser acupuncture on immunomodulation and dyspnea in post-COVID-19 patients. Advances in Rehabilitation / Postępy Rehabilitacji. 2023. doi:10.5114/areh.2023.125836. http://www.advrehab.org/Effect-of-laser-acupuncture-on-immunomodulation-and-dyspnea-in-post-COVID-19-patients,125,50340,0,1.html (Full text available as PDF file)

Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection

Abstract:

Background: Some months after the remission of acute COVID-19, some individuals show depressive symptoms, which are predicted by increased peak body temperature (PBT) and decreased blood oxygen saturation (SpO2). No data indicate whether Long COVID is associated with increased insulin resistance (IR) in association with neuroimmune and oxidative (NIO) processes.

Methods: This case control and retrospective cohort study used the homeostasis Model Assessment 2 (HOMA2) calculator© to compute β-cell function, insulin sensitivity and resistance (HOMA2-IR) and measured the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HAMD) in 86 Long COVID patients and 39 controls.

Results: Long COVID (3-4 months after the acute infection) is accompanied by increased HOMA2-IR, fasting blood glucose, and insulin levels; 33.7% of the patients versus 0% of the controls had HOMA2-IR values >1.8, suggesting IR. Increased IR was predicted by PBT during acute infection, and associated with depressive symptoms above and beyond the effects of NIO pathways (NLRP3 inflamasome, myeloperoxidase, protein oxidation). There were no significant associations between increased IR and the activated NIO pathways during Long COVID.

Conclusion: Long COVID is associated with new-onset IR which may contribute to the onset of depressive symptoms due to Long COVID by enhancing overall neurotoxicity.

Source: Al-Hakeim HK, Al-Rubaye HT, Jubran AS, Almulla AF, Moustafa SR, Maes M. Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection. Braz J Psychiatry. 2023 Mar 14. doi: 10.47626/1516-4446-2022-3002. Epub ahead of print. PMID: 36917827. https://pubmed.ncbi.nlm.nih.gov/36917827/ 

Comparison of Symptoms in Covid-19 Acute Infection and Long Covid-19

Abstract:

Background: Relatively little is known about the clinical course of covid-19 and the differences between the symptoms of covid-19 in acute phase of infection and the symptoms of long covid-19 in people with milder outpatient illnesses.

Objective: To compare clinical characteristics of covid-19 in acute infection with long covid-19 (presence of prolonged symptoms for at least 12 weeks, lasting at least 2 months, after acute covid-19 infection, and that are not explained by an alternative diagnosis).

Methodology: Comparison of secondary data among tow previous observational, longitudinal and prospective studies: 1) patients with post-acute covid-19 syndrome from March 15, 2020 to March 31, 2021; and 2) patients with Long covid-19 from March 15, 2020 to October 31, 2022, in the same population in general medicine.

Results: 33 covid-19 in acute phase, with 138 symptoms and 27 Long covid-19 cases with 44 symptoms were included. Respiratory symptoms predominated in both groups. Symptoms in Long covid-19 cases were significantly lower in general symptoms (X2= 5.9539. p= .014), and higher in Circulatory and Genitourinary system (Fisher exact test= 0.05).

Conclusion: Both in Long covid-19 and in covid-19 acute phase respiratory symptoms predominate. But they differ in that the symptoms of long covid-19 are less general than those of covid-19 acute phase, and present more symptoms of almost all organs and systems, those of the Circulatory and Genitourinary system being significant. The symptoms of Long covid-19 vs. acute phase are more debilitating and clinically heterogeneous.

Source: Turabian, Jose. (2023). Comparison of Symptoms in Covid-19 Acute Infection and Long Covid-19. 2694-5843. 10.36266/JCMHR/170.  https://www.researchgate.net/publication/369088222_Comparison_of_Symptoms_in_Covid-19_Acute_Infection_and_Long_Covid-19 (Full text)

Long COVID and children’s rights

Abstract:

This policy note calls for the recognition of long COVID as a children’s rights issue in the UK. While children have been affected by school closures and lockdown restrictions throughout the pandemic, the relatively low rates of COVID-related hospitalizations and deaths among children have led to their de-prioritization in efforts to reduce the spread of the SARS-CoV-2 virus. Yet infection rates are extremely high among children in the UK, particularly secondary school students, and early studies suggest that many are not recovering for up to a year after infection.

Prolonged illness following infection, ‘long COVID’, has implications for children’s rights to education, health, and a private and family life, among others. By extension, children have a right to have their best interests taken into consideration in policy-making processes relating to long COVID. The policy note thus argues that we must recognize the significance of long COVID in children and, upon this basis, call upon the State to address its human rights implications.

Source: Vivek Bhatt, Long COVID and children’s rights, Journal of Human Rights Practice, 2023;, huac047, https://doi.org/10.1093/jhuman/huac047 (Full text)

Long-COVID Inducement Mechanism Based on the Path Module Correlation Coefficient

Abstract:

As the number of COVID-19 cases increases, the long-COVID symptoms become the focus of clinical attention. Based on the statistical analysis of long-COVID symptoms in European and Chinese populations, this study proposes the path module correlation coefficient, which can estimate the correlation between two modules in a network, to evaluate the correlation between SARS-CoV-2 infection and long-COVID symptoms, providing a theoretical support for analyzing the frequency of long-COVID symptoms in European and Chinese populations.
The path module correlation coefficients between specific COVID-19-related genes in the European and Chinese populations and genes that may induce long-COVID symptoms were calculated. The results showed that the path module correlation coefficients were completely consistent with the frequency of long-COVID symptoms in the Chinese population, but slightly different in the European population. Furthermore, the cathepsin C (CTSC) gene was found to be a potential COVID-19-related gene by a path module correlation coefficient correction rate.
Our study can help to explore other long-COVID symptoms that have not yet been discovered and provide a new perspective to research this syndrome. Meanwhile, the path module correlation coefficient correction rate can help to find more species-specific genes related to COVID-19 in the future.
Source: Liu Z, Yin Z, Mi Z, Guo B. Long-COVID Inducement Mechanism Based on the Path Module Correlation Coefficient. Mathematics. 2023; 11(6):1368. https://doi.org/10.3390/math11061368 (Full text)

Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID?

Abstract:

The relationship between viral infections and the risk of developing cancer is well known. Multiple mechanisms participate in and determine this process. The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in the deaths of millions of people worldwide. Although the effects of COVID-19 are limited for most people, a large number of people continue to show symptoms for a long period of time (long COVID). Several studies have suggested that cancer could also be a potential long-term complication of the virus; however, the causes of this risk are not yet well understood. In this review, we investigated arguments that could support or reject this possibility.
Source: Amiama-Roig A, Pérez-Martínez L, Rodríguez Ledo P, Verdugo-Sivianes EM, Blanco J-R. Should We Expect an Increase in the Number of Cancer Cases in People with Long COVID? Microorganisms. 2023; 11(3):713. https://doi.org/10.3390/microorganisms11030713 (Full text)

Long COVID-six months of prospective follow-up of changes in symptom profiles of non-hospitalised children and young people after SARS-CoV-2 testing: A national matched cohort study (The CLoCk) study

Abstract:

Background: Little is known about the prevalence and natural trajectory of post-COVID symptoms in young people, despite very high numbers of young people having acute COVID. To date, there has been no prospective follow-up to establish the pattern of symptoms over a 6-month time period.

Methods: A non-hospitalised, national sample of 3,395 (1,737 SARS-COV-2 Negative;1,658 SARS-COV-2 Positive at baseline) children and young people (CYP) aged 11-17 completed questionnaires 3 and 6 months after PCR-confirmed SARS-CoV-2 infection between January and March 2021 and were compared with age, sex and geographically-matched test-negative CYP.

Results: Three months after a positive SARS-CoV-2 PCR test, 11 of the 21 most common symptoms reported by >10% of CYP had reduced. There was a further decline at 6 months. By 3 and 6 months the prevalence of chills, fever, myalgia, cough and sore throat of CYP who tested positive for SARS-CoV-2 reduced from 10-25% at testing to <3%. The prevalence of loss of smell declined from 21% to 5% at 3 months and 4% at 6 months. Prevalence of shortness of breath and tiredness also declined, but at a lower rate. Among test-negatives, the same common symptoms and trends were observed at lower prevalence’s. Importantly, in some instances (shortness of breath, tiredness) the overall prevalence of specific individual symptoms at 3 and 6 months was higher than at PCR-testing because these symptoms were reported in new cohorts of CYP who had not reported the specific individual symptom previously.

Conclusions: In CYP, the prevalence of specific symptoms reported at time of PCR-testing declined with time. Similar patterns were observed among test-positives and test-negatives and new symptoms were reported six months post-test for both groups suggesting that symptoms are unlikely to exclusively be a specific consequence of SARS-COV-2 infection. Many CYP experienced unwanted symptoms that warrant investigation and potential intervention.

Source: Stephenson T, Pinto Pereira SM, Nugawela MD, McOwat K, Simmons R, Chalder T, Ford T, Heyman I, Swann OV, Fox-Smith L, Rojas NK, Dalrymple E, Ladhani SN, Shafran R; CLoCk Consortium. Long COVID-six months of prospective follow-up of changes in symptom profiles of non-hospitalised children and young people after SARS-CoV-2 testing: A national matched cohort study (The CLoCk) study. PLoS One. 2023 Mar 6;18(3):e0277704. doi: 10.1371/journal.pone.0277704. PMID: 36877677; PMCID: PMC9987792. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9987792/ (Full text)