Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem neuroimmune disease characterized by neurological, immunological, gastrointestinal, and mitochondrial disorders. The criteria include a “substantial impairment or decrease in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities” for at least 6 months, accompanied by a profound fatigue that is not alleviated by rest, along with postexertional malaise, unrefreshing sleep, cognitive impairment, dysautonomia, especially postural orthostatic tachycardia syndrome (POTS), and altered pain and sensory perception. Since many recent studies have addressed the overlapping presentations between ME/CFS and long COVID, the Japanese authors examined the clinical and laboratory features of patients with long COVID who subsequently developed a clinical diagnosis of ME/CFS based on internationally standardized criteria. In their previous study, the same team of researchers found that the prevalence of ME/CFS following COVID-19 is 16.8%, significantly higher than the general population’s rate of less than 1%.
The pathogenesis of ME/CFS has not been fully elucidated. Immune dysfunction is a key feature of ME/CFS, and many symptoms suggest chronic immune activation. Biomedical findings in ME/CFS patients include T-cell abnormalities, diminished function of natural killer cells, mitochondrial dysfunction, and vascular and endothelial abnormalities. Other findings include intolerance to exercise, reduced oxygen consumption, reduced anaerobic threshold, and abnormal metabolic profiles.
Ferritin is the major intracellular protein that stores iron in a soluble and nontoxic state in prokaryotes and eukaryotes. Hyperferritinemia is caused by inflammation, infectious diseases, hematological and malignant diseases, and liver and renal dysfunctions. Ferritin is composed of light-chain ferritin (L-ferritin), required for the long-term storage of iron, and heavy-chain ferritin (H-ferritin), with ferroxidase activity. The variation in subunit composition may affect the rates of iron uptake and release in different tissues. Defects in the light chain ferritin gene are associated with hyperferritinemia-cataract syndrome and neurodegeneration caused by brain iron accumulation. Neuronal loss and gliosis were found in the cerebral cortex, thalamus, substantia nigra, caudate, putamen, globus pallidus, and cerebellum. Intranuclear and intracytoplasmic inclusion bodies stained positively for iron were observed in neurons, glia, and endothelial cells. Their greatest density was detected in the putamen. Autoantibodies specific to ferritin light-chain polypeptide are frequently detected in patients with immune-related pancytopenia. Interestingly, the computational study of Yapici-Eser et al. (2021) found a mimicry of SARS-CoV-2 proteins (spike protein, NSP7, and papain-like protease, which is responsible for viral replication) with ferritin light chain protein. (Yapici-Eser et al. Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins’ Mimicry of Human Protein. Front Hum Neurosci 2021 15:656313.) https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2021.656313/full
light-chain ferritin structure
About the study
This retrospective observational study enrolled patients treated at the long COVID clinic at Okayama University Hospital, with persistent symptoms for more than 4 weeks after COVID-19 onset and without pre-existing hyperferritinemia. The participants were categorized into three groups: (1) patients with a clinical diagnosis of ME/CFS (ME/CFS group), based on all of the three internationally standardized criteria, such as the Fukuda, the Canadian Consensus, and the Institute of Medicine (IOM) criteria, (2) individuals who experienced fatigue but did not meet the ME/CFS criteria (non-ME/CFS group), and (3) participants with no fatigue (no-fatigue group).
Data on gender, age, body mass index, acute-phase severity, and time from COVID-19 onset to the first visit to the long COVID clinic were collected from the medical records. At the first visit to the clinic, the symptom severity was measured by the Fatigue Assessment Scale (FAS), EuroQol 5 Dimensions 5 Levels (EQ-5D-5L), the Self-Rating Depression Scale (SDS), and the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG). Laboratory analysis included blood cell count, biochemistry, and endocrine parameters (serum adrenocorticotropin (ACTH), cortisol, free thyroxin (FT4), thyrotropin (TSH), growth hormone (GH) and insulin-like growth factor (IGF)-I).
Results
The authors analyzed data from 234 patients, followed up for at least six months from the disease onset. 59% (139 patients) complained of general fatigue, while 41% (95 patients) did not. Of 139 patients with fatigue, 50 patients (40%) met all of the three sets of diagnostic criteria for ME/CFS (Fukuda criteria, CCC, and IOM criteria). These patients were included in the ME/CFS group, whereas the remaining 89 patients who experienced fatigue but did not meet diagnostic criteria for ME/CFS, were included in the non-ME/CFS group. There was no significant difference in gender, age, BMI, and acute-phase treatment between the three groups.
The scores for all self-rating scales (FAS, FAS physical, FAS mental, EQ-5D-5L, EQ-5D VAS, and SDS) were more severe in the ME/CFS group than in the other two groups.
Laboratory Data
The levels of hemoglobin, and inflammatory or coagulation markers did not differ among the three groups.
Serum ferritin levels were about two times higher in patients with long COVID who subsequently developed ME/CFS (193.0 μg/L) than in patients with long COVID who did not meet the ME/CFS criteria (98.2 μg/L) and participants with no fatigue (86.7 μg/L).
Serum ferritin levels were significantly higher in men (223.0 μg/L) than in women (50.3 μg/L). However, women with long COVID and clinical diagnosis of ME/CFS had higher serum ferritin levels (68.9 μg/L) than women in the non-ME/CFS group (43.8 μg/L). This difference was not observed in men.
The authors emphasized that women are more likely to suffer from iron deficiency and have lower serum ferritin levels than men, but, in this study, women who developed ME/CFS had higher serum ferritin levels than women with long COVID who did not meet the ME/CFS criteria.
Serum ferritin levels correlated negatively with IGF-I levels in the ME/CFS group. This correlation was stronger in women.
The HPA axis function did not differ between the groups, according to similar serum FT4, cortisol, and ACTH levels, and ACTH/cortisol ratios. However, patients with long COVID and ME/CFS had higher serum TSH levels and lower FT4/TSH ratios than participants from the non-ME/CFS group. Also, in the ME/CFS group, serum GH levels were lower than in participants with no fatigue (0.22 ng/mL versus 0.37 ng/mL).
Conclusion
This study found that patients with long COVID who developed ME/CFS based on all three internationally standardized criteria had elevated serum ferritin levels, identifying serum ferritin as a possible biomarker for detecting the transition to ME/CFS, especially in female patients. Endocrine workup further showed that long COVID patients who developed ME/CFS had higher serum TSH levels but lower growth hormone levels and that insulin-like growth factor-I levels correlated inversely with ferritin levels.
Overall, there is a possible link between the inflammatory process, serum ferritin levels, and the occurrence of ME/CFS in long COVID syndrome. It was suggested that a moderate increase of serum ferritin levels observed in long COVID syndrome could contribute to ME/CFS occurrence, enhancing the pro-inflammatory burden in disease pathogenesis or inducing oxidative DNA damage. However, as hyperferritinemia was not accompanied by an increase in other inflammatory markers in this study, the authors concluded that persistent inflammation cannot explain the phenomenon of hyperferritinemia in long COVID.
Since a pathophysiological mechanism of hyperferritinemia in patients with long COVID who have developed ME/CFS remains hypothetical, the authors concluded that further studies are needed to understand ferritin metabolism in this patient group.
This study was published in the Journal of Clinical Medicine.
Journal Reference
Yamamoto, Y.; Otsuka, Y.;Tokumasu, K, et al. Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID. J. Clin.Med. 2023, 12, 4737. https://doi.org/10.3390/jcm12144737
