Category: Overlapping Illnesses

Evaluation of Post–COVID-19 Cognitive Dysfunction: Recommendations for Researchers

Opinion:

SARS-CoV-2 infection is associated with increased rates of postillness cognitive dysfunction, colloquially referred to as “brain fog,”1 that may portend significant consequences for patient functioning and quality of life. Post–COVID-19 cognitive dysfunction is 1 of approximately 200 symptoms of post–COVID-19 condition (PCC), defined by the World Health Organization as developing within 3 months of an initial SARS-CoV-2 infection, lasting at least 2 months, and cannot be explained by an alternative diagnosis. A pooled analysis of 54 studies and 1.2 million individuals found that 3.2% of patients’ self-reported cognitive problems 3 months after symptomatic infection,1 while other studies have shown objective evidence of cognitive dysfunction in approximately 24% of patients nearly 1 year later.2 Accumulating evidence also supports the hypothesis that COVID-19 may increase risk for later neurodegeneration3 and exacerbate preexisting cognitive dysfunction.4 As one of the most common symptoms of PCC and one for which affected individuals may seek accommodations and disability benefits in accordance with the Americans With Disabilities Act, it is imperative that we use more rigorous studies of cognitive outcomes. Accordingly, the following recommendations have been generated by members of the NeuroCOVID International Neuropsychology Taskforce based on initial guidelines.5

Source: Jaqueline H. Becker, PhD; Tracy D. Vannorsdall, PhD; Sara L. Weisenbach, PhD. JAMA Psychiatry. Published online August 16, 2023. doi:10.1001/jamapsychiatry.2023.2820 https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2808155

Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome

Highlights:

  • Plasmalogens (Pls) are lipids containing a vinyl-ether bond in their glycerol backbone.
  • Pls have antioxidant properties and are important for curved membrane assemblies.
  • Post-COVID-19 symptoms are highly prevalent and share several features with ME/CFS.
  • Pls depletion is a shared biological hallmark of ME/CFS and acute COVID-19 syndrome.
  • Pls replacement is a promising tool against neuroinflammation in these two conditions.

Abstract:

After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties (“brain fog”), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions.

Of great interest, recent evidence revealed a significant reduction of plasmalogen contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms.

Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.

Source: Adriano Maia Chaves-Filho, Olivia Braniff, Angelina Angelova, Yuru Deng, Marie-Ève Tremblay. Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome. Brain Research Bulletin, Volume 201, September 2023, 110702. https://www.sciencedirect.com/science/article/pii/S0361923023001272 (Full text)

Long COVID, POTS, CFS and MTHFR: Linked by Biochemistry and Nutrition

Abstract:

The recent pandemic has energized research spotlighting chronic fatigue disorders. The similarities between Long COVID (LC) and Chronic Fatigue Syndrome (CFS), often accompanied by postural orthostatic tachycardia syndrome (POTS) are striking.

Furthermore, the majority afflicted with LC and CFS may be those with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, present in the majority of Americans and characterized by hypomethylation. Elevated homocysteine (Hcy) and depressed B9 and B12 may be links. Speculation about an association between these laboratory analytes and MTHFR abnormalities has been previously reported (Regland et al., 2015).

The absence of a blood-brain barrier (BBB) in CNS circumventricular organs (CVOs) that control autonomic and neuroendocrine functions, problematic in LC, CFS, POTS, and MTHFR, is provocative. Diffusion of CNS Hcy is associated with brain fog, cognitive impairment, and dementia. This provides a distinct link between MTHFR variants and the fog of LC, CFS, and POTS.

Small intestine bacterial overgrowth (SIBO), present in about 17% of Americans, is linked to POTS, mast cell activation syndrome (MCAS), and Ehlers Danlos syndrome (EDS). All exhibit histamine intolerance and female predominance. This may be due to hypomethylation and/or intestinal diamine oxidase (DAO) deficiency.

Metabolism of monoamines and histamine requires methylation. Specific CNS nuclei in CVOs may also provide insight to the POTS paradox. The similar gut microbiomes of LC/CFS (and vitamin D deficiency) may via CVOs trigger an imbalance in glutamate/GABA neurotransmission that translates to neuroendocrine and baroreflex dysfunction. Homozygosity for the MTHFR 677T allele can facilitate hypermethylation via an alternative “rescue” riboflavin pathway triggered by significant Hcy increase.

Hypermethylation predominates in Long Covid. The primary problem in these syndromes is compromised mitochondrial function due to oxidative stress induced by an antioxidant shortfall.

Victims are also frequently deficient in 25(OH)D3 (the storage form of vitamin D), magnesium, and B vitamins, consumed by the persistent chronic inflammatory state. Estrogen increases histamine, norepinephrine, and bradykinin (BKN), which may in part explain the brain fog and its predilection for females.

Source: Patrick W Chambers. Long COVID, POTS, CFS and MTHFR: Linked by Biochemistry and Nutrition. Journal of Orthomolecular Medicine. 38. https://www.researchgate.net/publication/373073968_Long_Covid_POTS_CFS_and_MTHFR_Linked_by_Biochemistry_and_Nutrition#fullTextFileContent (Full text)

Postacute sequelae of COVID-19 at 2 years

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection.

The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively.

Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6-89.6) and 642.8 (95% CI: 596.9-689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9-31.0%) and 21.3% (18.2-24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year.

In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.

Source: Bowe B, Xie Y, Al-Aly Z. Postacute sequelae of COVID-19 at 2 years. Nat Med. 2023 Aug 21. doi: 10.1038/s41591-023-02521-2. Epub ahead of print. PMID: 37605079. https://www.nature.com/articles/s41591-023-02521-2 (Full text)

Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19

Abstract:

The coronavirus disease 2019 (COVID-19) remains an epidemic worldwide. Most patients suffer residual symptoms, the so-called “Long COVID,” which includes respiratory and neuropsychiatric symptoms. Brain Fog, one of the symptoms of Long COVID, is a major public health issue because it can impair patients’ quality of life even after recovery from the disease. However, neither the pathogenesis nor the treatment of this condition remains unknown.

We focused on serum ferritin levels in this study and collected information on the onset of Brain Fog through questionnaires and found that high ferritin levels during hospitalization were associated with the occurrence of Brain Fog. In addition, we excluded confounders as far as possible using propensity score analyses and found that ferritin was independently associated with Brain Fog in most of the models. We conducted phase analysis and evaluated the interaction of each phase with ferritin levels and Brain Fog.

We found a positive correlation between serum ferritin levels during hospitalization and Brain Fog after COVID-19. High ferritin levels in patients with Brain Fog may reflect the contribution of chronic inflammation in the development of Brain Fog. This study provides a novel insight into the pathogenic mechanism of Brain Fog after COVID-19.

Source: Ishikura T, Nakano T, Kitano T, Tokuda T, Sumi-Akamaru H, Naka T. Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19. Sci Rep. 2023 Aug 11;13(1):13095. doi: 10.1038/s41598-023-40011-0. PMID: 37567939; PMCID: PMC10421912. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421912/ (Full text)

Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort

Summary:

Background: Post-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear.

Methods: In this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3–8, 9–16, and 17–20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers.

Findings: Patients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS.

Interpretation: Our findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity.

Source: Franziska Legler, Lil Meyer-Arndt, Lukas Mödl, Claudia Kedor, Helma Freitag, Elisa Stein, Uta Hoppmann, Rebekka Rust, Kirsten Wittke, Nadja Siebert, Janina Behrens, Andreas Thiel, Frank Konietschke, Friedemann Paul, Carmen Scheibenbogen, Judith Bellmann-Strobl,
Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort, eClinicalMedicine, Volume 63, 2023, 102146, ISSN 2589-5370, https://doi.org/10.1016/j.eclinm.2023.102146. https://www.sciencedirect.com/science/article/pii/S2589537023003231 (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)

Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study

Summary:

Background: Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association.

Methods: A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs.

Findings: The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12–2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03–1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09–1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33–1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13–1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83–3.11)]; Graves’ disease [aHR: 1.30 (95% CI: 1.10–1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47–3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82–2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17–6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04–2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves’ disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis.

Interpretation: Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings.

Source: Kuan Peng, Xue Li, Deliang Yang, Shirley C.W. Chan, Jiayi Zhou, Eric Y.F. Wan, et al. Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study. The Lancet, VOLUME 63, 102154, SEPTEMBER 2023 https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00331-0/fulltext (Full text)

Influence of Prior SARS-CoV-2 Infection on COVID-19 Severity: Evidence from the National COVID Cohort Collaborative

Abstract:

Background As SARS-CoV-2 has transitioned from a pandemic to endemic disease, the majority of new infections have been among previously infected individuals. To manage the risks and benefits of ongoing COVID-19 policies, it is important to understand whether prior infection modifies the severity of subsequent infections.

Methods We used data from first and second COVID-19 episodes in the National COVID Cohort Collaborative (N3C), a collection of health systems who provide de-identified electronic health records for research purposes. Our analysis was a sequential series of nested trial emulations. In the first of two analytic stages, we created a month-specific model of the probability of prior infection for each individual. In the second stage, we used an ordinal logistic regression with inverse probability weights calculated in the first stage to simulate a series of monthly trials comparing severity between the cohorts of first and second infections. In addition to cohort-wide effect estimates, we also conducted analyses among race/ethnicity, sex, and age subgroups.

Results From an initial cohort of 7,446,481 combined first and second infections, we identified a cohort of 2,227,484 infections, among which 7.6% were second infections. Ninety-four percent of patients with two recorded infections experienced mild disease for both. The overall odds ratio (OR) for more severe disease with prior infection was 1.06 (95% confidence interval [CI]: 1.03 – 1.10). Monthly point estimates of the OR ranged from 0.56 (95% CI: 0.37 – 0.84) in October 2020 to 1.64 (95% CI: 1.33 – 2.00) in February 2023. In most subgroups, the effect of prior infection was significant. In 8 out of 10 subgroups, the maximum monthly OR occurred after the minimum monthly OR, suggesting that protection has waned throughout the pandemic.

Conclusion Overall, prior infection was associated with a significant slightly elevated risk of severe disease. This effect varied month to month. As the pandemic proceeded, the effect of prior infection tended to evolve from generally protective during the pre-Omicron era to unprotective during the Omicron era. This points to the need for continued strategies to avert and minimize the harms of COVID-19, rather than relying upon immunity acquired through previous infection.

Question Does prior infection with SARS-CoV-2 affect the severity of subsequent COVID-19 episodes?

Findings We observed a mild protective effect of prior infection during the early and mid-stages of the pandemic that waned after the rise of the Omicron variants, ultimately resulting in loss of protection or a tendency toward more severe second infections.

Meaning Prior infection alone is likely not enough to avert the worst public health harms of endemic SARS-CoV-2. Interventions to avoid infection and reduce the severity of COVID-19 will still be important in the post-pandemic era.

Source: Nathaniel Hendrix, Hythem Sidky, David K. Sahner, The N3C Consortium. Influence of Prior SARS-CoV-2 Infection on COVID-19 Severity: Evidence from the National COVID Cohort Collaborative. medRxiv 2023.08.03.23293612; doi: https://doi.org/10.1101/2023.08.03.23293612 https://www.medrxiv.org/content/10.1101/2023.08.03.23293612v1.full-text (Full text)

Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study

Abstract:

A significant proportion of patients after SARS-CoV-2 infection suffer from long-lasting symptoms. Although many different symptoms are described, the majority of patients complains about neuropsychological symptoms. Additionally, a subgroup of patients fulfills diagnostic criteria for ME/CFS. We analyzed a registry of all patients presenting in the out-patients clinic at a German university center. For patients with more than one visit, changes in reported symptoms from first to second visit were analyzed.

A total of 1022 patients were included in the study, 411 of them had more than one visit. 95.5% of the patients reported a polysymptomatic disease. At the first visit 31.3% of the patients fulfilled ME/CFS criteria after a median time of 255 days post infection and and at the second visit after a median of 402 days, 19.4% still suffered from ME/CFS. Self-reported fatigue (83.7-72.7%) and concentration impairment (66.2-57.9%) decreased from first to second visit contrasting non-significant changes in the structured screening.

A significant proportion of SARS-CoV-2 survivors presenting with ongoing symptoms present with ME/CFS. Although the proportion of subjective reported symptoms and their severity reduce over time, a significant proportion of patients suffer from long-lasting symptoms necessitating new therapeutic concepts.

Source: Reuken PA, Besteher B, Finke K, Fischer A, Holl A, Katzer K, Lehmann-Pohl K, Lemhöfer C, Nowka M, Puta C, Walter M, Weißenborn C, Stallmach A. Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study. Eur Arch Psychiatry Clin Neurosci. 2023 Aug 16. doi: 10.1007/s00406-023-01661-3. Epub ahead of print. PMID: 37587244. https://link.springer.com/article/10.1007/s00406-023-01661-3 (Full text)