Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys

Abstract:

Background Long COVID (LC) is a complex and multisystemic condition marked by a diverse range of symptoms, yet its associated risk factors remain poorly defined.

Methods Leveraging data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and National Health Interview Survey (NHIS), both representative of the United States population, this study aimed to identify demographic characteristics associated with LC. The sample was restricted to individuals aged 18 years and older who reported a positive COVID-19 test or doctor’s diagnosis. We performed a descriptive analysis comparing characteristics between participants with and without LC. Furthermore, we developed multivariate logistic regression models on demographic covariates that would have been valid at the time of the COVID-19 infection.

Results Among the 124,313 individuals in BRFSS and 10,131 in the NHIS reporting either a positive test or doctor’s diagnosis for COVID-19 (Table), 26,783 (21.5%) in BRFSS and 1,797 (17.1%) in NHIS reported LC. In the multivariate logistic regression model, we found middle age, female gender, Hispanic ethnicity, lack of a college degree, and residence in non-metropolitan areas associated with higher risk of LC. Notably, the initial severity of acute COVID-19 was strongly associated with LC risk. In contrast, significantly lower ORs were reported for Non-Hispanic Asian and Black Americans compared to Non-Hispanic White.

Conclusions In the United States, there is marked variation in the risk of LC by demographic factors and initial infection severity. Further research is needed to understand the underlying cause of these observations.

Source: Yixuan Wu, Mitsuaki Sawano, Yilun Wu, Rishi M. Shah, Pamela Bishop, Akiko Iwasaki, Harlan M. Krumholz. Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys. medRxiv 2024.01.12.24301170; doi: https://doi.org/10.1101/2024.01.12.24301170 https://www.medrxiv.org/content/10.1101/2024.01.12.24301170v1.full-text (Full text)

Explaining Long COVID: A Pioneer Cross-Sectional Study Supporting the Endocrine Hypothesis

Abstract:

Context: In some patients, symptoms may persist after COVID-19, defined as long COVID. Its pathogenesis is still debated and many hypotheses have been raised.

Objective: Our primary objective was to evaluate the corticotroph and somatotroph functions of patients previously infected with SARS-CoV-2 and experiencing post–COVID-19 syndrome to detect any deficiencies that may explain long COVID.

Methods: A cross-sectional study was conducted including patients who had previously contracted SARS-CoV-2 with a postinfection period of 3 months or less to 15 months, divided into 2 groups. The first group (G1) comprised fully recovered patients, while the second group (G2) included patients experiencing long COVID. The primary outcome was the comparison of corticotroph and somatotroph functions.

Results: A total of 64 patients were divided into 2 groups, each consisting of 32 patients. G2 exhibited more frequently anterior pituitary deficits compared to G1 (P = .045): for the corticotroph axis (G1: 6.3% vs G2: 28.1%) and for the somatotroph axis (G1: 31.3% vs G2: 59.4%). Baseline cortisol level was significantly lower in G2 (G1: 13.37 µg/dL vs G2: 11.59 µg/dL) (P = .045). The peak cortisol level was also lower in G2 (G1: 23.60 µg/dL vs G2: 19.14 µg/dL) (P = .01). For the somatotroph axis, the insulin growth factor-1 level was lower in G2 (G1: 146.03 ng/mL vs G2: 132.25 ng/mL) (P = .369). The peak growth hormone level was also lower in G2 (G1: 4.82 ng/mL vs G2: 2.89 ng/mL) (P = .041).

Conclusion: The results showed that long COVID patients in our cohort were more likely to have anterior pituitary deficiencies. The endocrine hypothesis involving anterior pituitary insufficiency can be considered to explain long COVID.

Source: Taieb Ach, Nassim Ben Haj Slama, Asma Gorchane, Asma Ben Abdelkrim, Meriem Garma, Nadia Ben Lasfar, Foued Bellazreg, Widéd Debbabi, Wissem Hachfi, Molka Chadli Chaieb, Monia Zaouali, Amel Letaief, Koussay Ach, Explaining Long COVID: A Pioneer Cross-Sectional Study Supporting the Endocrine Hypothesis, Journal of the Endocrine Society, Volume 8, Issue 3, March 2024, bvae003, https://doi.org/10.1210/jendso/bvae003 https://academic.oup.com/jes/advancearticle/doi/10.1210/jendso/bvae003/7517018 (Full text)

Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID

Abstract:

Background Long COVID contributes to the global burden of disease. Proposed root cause hypotheses include the persistence of SARS-CoV-2 viral reservoir, autoimmunity, and reactivation of latent herpesviruses. Patients have reported various changes in Long COVID symptoms after COVID-19 vaccinations, leaving uncertainty about whether vaccine-induced immune responses may alleviate or worsen disease pathology.

Methods In this prospective study, we evaluated changes in symptoms and immune responses after COVID-19 vaccination in 16 vaccine-naïve individuals with Long COVID. Surveys were administered before vaccination and then at 2, 6, and 12 weeks after receiving the first vaccine dose of the primary series. Simultaneously, SARS-CoV-2-reactive TCR enrichment, SARS-CoV-2-specific antibody responses, antibody responses to other viral and self-antigens, and circulating cytokines were quantified before vaccination and at 6 and 12 weeks after vaccination.

Results Self-report at 12 weeks post-vaccination indicated 10 out of 16 participants had improved health, 3 had no change, 1 had worse health, and 2 reported marginal changes. Significant elevation in SARS-CoV-2-specific TCRs and Spike protein-specific IgG were observed 6 and 12 weeks after vaccination. No changes in reactivities were observed against herpes viruses and self-antigens. Within this dataset, higher baseline sIL-6R was associated with symptom improvement, and the two top features associated with non-improvement were high IFN-β and CNTF, among soluble analytes.

Conclusions Our study showed that in this small sample, vaccination improved the health or resulted in no change to the health of most participants, though few experienced worsening. Vaccination was associated with increased SARS-CoV-2 Spike protein-specific IgG and T cell expansion in most individuals with Long COVID. Symptom improvement was observed in those with baseline elevated sIL-6R, while elevated interferon and neuropeptide levels were associated with a lack of improvement.

Plain language summary The impact of the COVID-19 vaccine on vaccine-naïve individuals suffering from Long COVID is uncertain. This study assessed the experience and immune signatures of 16 unvaccinated participants with Long COVID. A total of 10 participants had improved health status after vaccination, and one person reported only worsening health. As expected, vaccination increased immune cells and antibodies against the viral spike protein. Immune signatures may prove to be predictors of health status after vaccination. However, given the small number of participants, these initial findings need further validation.

Source: Connor B Grady, Bornali Bhattacharjee, Julio Silva, Jillian Jaycox, Lik Wee Lee, Valter Silva Monteiro, Mitsuaki Sawano, Daisy Massey, César Caraballo, Jeff R. Gehlhausen, Alexandra Tabachnikova, Tianyang Mao, Carolina Lucas, Mario A. Peña-Hernandez, Lan Xu, Tiffany J. Tzeng, Takehiro Takahashi, Jeph Herrin, Diana Berrent Güthe, Athena Akrami, Gina Assaf, Hannah Davis, Karen Harris, Lisa McCorkell, Wade L Schulz, Daniel Grffin, Hannah Wei, Aaron M Ring, Leying Guan, Charles Dela Cruz, Akiko Iwasaki, Harlan M Krumholz. Impact of COVID-19 vaccination on symptoms and immune phenotypes in vaccine-naïve individuals with Long COVID. medRxiv 2024.01.11.24300929; doi: https://doi.org/10.1101/2024.01.11.24300929. https://www.medrxiv.org/content/10.1101/2024.01.11.24300929v1.full-text (Full text)

Impact of sleep disruption on cognitive function in patients with post-acute sequelae of SARS-CoV-2 infection: Initial findings from a Neuro-COVID-19 clinic

Abstract:

Introduction: Fatigue, brain fog and sleep disturbance are among the most common symptoms of post-acute sequelae of SARS-CoV-2 infection (PASC). We sought to determine the impact of sleep disruption on cognition and quality-of-life in patients with neurologic manifestations of PASC (Neuro-PASC).

Methods: Thirty-nine patients were recruited from Neuro-COVID-19 clinic. Mean age was 48.1 years, 71.8% were female, and 82% were never hospitalized for COVID-19. Patients were evaluated via clinical assessment, quality-of-life measures in domains of cognitive function, fatigue, sleep disturbance, anxiety, and depression, NIH toolbox cognitive tests, and 7 days of wrist actigraphy.

Results: The median number of neurologic symptoms attributed to PASC was 6, with brain fog being the most common in 89.7%. Regarding non-neurologic symptoms, 94.9% complained of fatigue and 74.4% of insomnia. Patients reported significant impairment in all quality-of-life domains and performed worse in a task of attention compared to a normative US population. Actigraphy showed Neuro-PASC patients had lower sleep efficiency, longer sleep latency (both p<0.001) and later sleep midpoint (p=0.039) compared to 71 age-matched healthy controls with no PASC history. Self-reported cognitive symptoms correlated with severity of fatigue (p<0.001), anxiety (p=0.05), and depression (p<0.01). Objective evidence of sleep disruption measured by wakefulness after sleep onset, sleep efficiency and latency were associated with decreased performance in attention and processing speed.

Conclusion: Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep disruption on the cognitive function and quality of life of patients with PASC.

Source: Kathryn J Reid, Louis T Ingram, Millenia Jimenez, Zachary S Orban, Sabra M Abbott, Daniela Grimaldi, Kristen L Knutson, Phyllis C Zee, Igor J Koralnik, Mathew B Maas, Impact of sleep disruption on cognitive function in patients with post-acute sequelae of SARS-CoV-2 infection: Initial findings from a Neuro-COVID-19 clinic, SLEEP Advances, 2024;, zpae002, https://doi.org/10.1093/sleepadvances/zpae002 https://academic.oup.com/sleepadvances/advance-article/doi/10.1093/sleepadvances/zpae002/7517273 (Full text available as PDF file)

Randomised clinical trials with hyperbaric oxygen in COVID-19 and Long COVID : transcriptomic insights into benefits and harms

Abstract:

The flow from transcription of genes through translation and processing of proteins is a common basis for all life. Redox homeostasis is crucial for the defence against oxidative stress. We adapt through hormesis; non-lethal stress regulates redox-sensitive systems to maintain homeostasis. If the stress is chronic or acutely overwhelming, the cells can either go into apoptosis or into senescence to maintain homeostasis. Similar effects have been seen with HBOT as with intermittent oxygen deprivation. Hyperbaric oxygen therapy (HBOT) is delivered in a pressure chamber by breathing 100% oxygen intermittently, several times a week, in an ambient pressure equivalent to 10-20 meters of seawater. The aim of this thesis was to evaluate potential harms of HBOT for novel indications and to explore biomarkers in experimental and clinical trials in order to enable future precision medicine. We used methods evaluated on healthy volunteers in randomised clinical trials (RCTs) conducted in compliance with good clinical practice (ICH-GCP).

In Paper I, we evaluated Electron paramagnetic resonance (EPR) spectroscopy for measuring reactive oxygen species (ROS) in blood and RNA sequencing (RNAseq) of monocytes in peripheral blood (PBMC), and compared HBOT and HIIT in ten healthy volunteers. We could measure ROS in blood in the same physiological range in both interventions. We also discovered pathways involved in adaption to hypoxia and inflammation that were similar in both interventions. In Papers II and III, we evaluated harms and explored RNAseq in PBMC in an open label RCT where 31 patients with severe COVID- 19 were randomised to HBOT or best practice. We observed similar frequencies of adverse events (AEs) in the two groups and could not see any negative effect on vital signs or oxygenation. We discovered a unique transcriptomic signature in the subjects that had received HBOT. The differentially expressed genes were associated with the unfolded protein response, apoptosis, and immune response. In Paper IV, we evaluated harms and described health related quality of life (HRQoL)in an interim analysis of the first 20 subjects froma placebo controlled RCT where 80 patients with Long COIVD were randomised to HBOT or sham treatment. We reported more AEs than expected and severe physical and mental disabilities with a very poor HRQoL. Most AEs were mild, and all were transient.

We have shown that HBOT shares similarities in immune response with HIIT in healthy volunteers. HBOT has a favourable profile of harms and has a potent immunomodulatory effect that is associated with fast recovery for critical COVID-19 patients. HBOT has a favourable profile of harms for patients with post COVID-19 condition. The results provide a base for future clinical trials with HBOT.

Source: Kjellberg, Anders. Randomised clinical trials with hyperbaric oxygen in COVID-19 and Long COVID : transcriptomic insights into benefits and harms. Thesis: Karolinska Institute, Dept of Physiology and Pharmacology. https://openarchive.ki.se/xmlui/handle/10616/48928 (Full study available as PDF file)

A systematic scoping review of how people with ME/CFS use the internet

Abstract:

Purpose: Myalgic Encephalomyelitis (ME) is a chronic neurological illness also known as Chronic Fatigue Syndrome (CFS). Key symptoms are extreme fatigue, post-exertional malaise, cognitive problems and sleep disturbance. With reported higher levels of online activity for people with ME/CFS than other conditions, more knowledge of characteristics and experience of online use in everyday life is needed. This scoping review systematically identified, appraised and synthesised what is known on how people with ME/CFS use the internet.

Method: The following bibliographic databases were searched: Embase, Medline, PsychINFO, Cinahl, AMED, and ASSIA, plus Web of Science, ProQuest Dissertations & Theses Global, Scopus, and Google Scholar for grey literature. Two reviewers independently screened title-abstracts, and full text of studies against inclusion criteria. Remaining studies were quality-assessed using appropriate critical appraisal tools.

Results: Many people with ME/CFS go online daily to gain information and share experiences of their illness including difficulties with family, friends and doctors. Reciprocity of emotional and social support was found with a sense of in-group belonging and empowerment. Validation was sought online, and identity renegotiation took place. Some replacement of offline social support for online engagement was reported. Online lay expertise was seen to improve offline health professional relations but not replace them.

Conclusions: The internet is a valued source of support for people with ME/CFS in terms of sharing of experiences, legitimacy, empowerment, and integration into people’s everyday lives. The extent of interrelating of online and offline lives is not clear however and needs further investigation.

Source: Diane Shortland, Qulsom Fazil, Anna Lavis & Nutmeg Hallett (2024) A systematic scoping review of how people with ME/CFS use the internet, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2024.2303887  (Full text)

A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue

Abstract:

Many COVID-19 survivors experience lingering post-COVID-19 symptoms, notably chronic fatigue persisting for months after the acute phase. Despite its prevalence, limited research has explored effective treatments for post-COVID-19 fatigue. This randomized controlled clinical trial assessed the impact of Amantadine on patients with post-COVID-19 fatigue.

The intervention group received Amantadine for two weeks, while the control group received no treatment. Fatigue levels were assessed using the Visual Analog Fatigue Scale (VAFS) and Fatigue Severity Scale (FSS) questionnaires before and after the trial. At the study’s onset, VAFS mean scores were 7.90 ± 0.60 in the intervention group and 7.34 ± 0.58 in the control group (P-value = 0.087). After two weeks, intervention group scores dropped to 3.37 ± 0.44, significantly lower than the control group’s 5.97 ± 0.29 (P-value < 0.001). Similarly, FSS mean scores at the trial’s commencement were 53.10 ± 5.96 in the intervention group and 50.38 ± 4.88 in the control group (P-value = 0.053). At the trial’s end, intervention group scores decreased to 28.40 ± 2.42, markedly lower than the control group’s 42.59 ± 1.50 (P-value < 0.001).

In this study, we report the safety, tolerability, and substantial fatigue-relieving effects of Amantadine in post-COVID-19 fatigue. The intervention demonstrates a statistically significant reduction in fatigue levels, suggesting Amantadine’s potential as an effective treatment for this persistent condition.

Source: Harandi, A.A., Pakdaman, H., Medghalchi, A. et al. A randomized open-label clinical trial on the effect of Amantadine on post Covid 19 fatigue. Sci Rep 14, 1343 (2024). https://doi.org/10.1038/s41598-024-51904-z https://www.nature.com/articles/s41598-024-51904-z (Full text)

Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia

Abstract:

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease that affects various parts of the central nervous system. Fatigue, a common symptom, transient, prolonged, or chronic experienced by individuals with MS, can significantly impact daily functioning. It can be associated with underlying pathological processes or can have an idiopathic cause, such as chronic fatigue syndrome (CFS). The study aimed to assess the presence and etiology of fatigue in MS patients and its relationship with CFS.

MATERIALS AND METHODS: This cross-sectional study was conducted in the Eastern Province of Saudi Arabia. Data were collected using a questionnaire from a sample of 225 MS patients receiving care at our university hospital. The questionnaire included the Centers for Disease Control and Prevention (CDC) criteria for diagnosing CFS and the Expanded Disability Status Scale to evaluate fatigue in MS patients.

RESULTS: Of the total of 225 MS patients who participated in this study, 87.1% were diagnosed with relapsing-remitting MS, 6.7% with primary progressive MS, 3.6% with clinically isolated syndrome, and 2.7% with secondary progressive MS. About 53% had experienced fatigue that persisted for over 6 months. Analysis of CFS diagnosis revealed that 7.3% of patients met both CDC criteria and self-reported answers while 17.5% reported having CFS despite not meeting the CDC criteria. These findings highlight a significant lack of agreement between patient-reported diagnoses and established criteria, indicating poor agreement (P = 0.028).

CONCLUSION: The study found an association between CFS and MS, and a significant impact on daily functioning. The study revealed lack of agreement between patient-reported diagnoses and established criteria for CFS. This emphasizes the need for a standardized approach to diagnosis and evaluation of fatigue in MS patients.

Source: AlAmri, Abdullah S.; AlShamrani, Foziah J.; AlMohish, Noor M.; Zafar, Azra S.; Alnaaim, Saud A.1; Alazman, Hatem A.; Al-Ghanimi, Ibrahim A.2; AlNahdi, Abdullah A.; AlDawsari, Fahad A.; AlMatrafi, Shahad B.3; Alzahrani, Ghaida R.3; Alnamlah, Muna S.; Alkhalifa, Rawan A.. Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia. Journal of Family and Community Medicine 31(1):p 63-70, Jan–Mar 2024. | DOI: 10.4103/jfcm.jfcm_73_23 https://journals.lww.com/jfcm/fulltext/2024/31010/frequency_and_characteristics_of_chronic_fatigue.9.aspx (Full text)

Joint Flexibility and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After Mononucleosis

Abstract:

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease characterized by substantial fatigue, postexertional malaise, unrefreshing sleep, and orthostatic intolerance, among other symptoms. Specific risk factors for the development of ME/CFS have not been adequately characterized. It has been suggested that ME/CFS is a connective tissue disorder and that joint hyperflexibility is a risk factor for the development of ME/CFS.

Methods: The goal of this study was to examine whether joint hyperflexibility is a risk factor for the development of ME/CFS after infectious mononucleosis (IM). This study was part of a prospective cohort study. College students were studied for the development of IM and were followed up for the development of ME/CFS 6 months later. Participants in the cohort for the present study included 53 students who met criteria for ME/CFS 6 months after IM and 66 recovered control subjects who had modified Beighton scores (a measure of joint hyperflexibility) available.

Findings: No connection was found between joint hyperflexibility and the development of ME/CFS after IM. Differences in joint hyperflexibility (as measured by using the modified Beighton score) in the ME/CFS group and the control group were not statistically significant. Female subjects had significantly higher Beighton scores compared with male subjects.

Implication: After IM, no relationship was found between joint hyperflexibility and the development of ME/CFS.

Source: Poomkudy JT, Torres C, Jason LA, Fishbein J, Katz BZ. Joint Flexibility and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After Mononucleosis. Clin Ther. 2024 Jan 18:S0149-2918(24)00006-7. doi: 10.1016/j.clinthera.2023.12.011. Epub ahead of print. PMID: 38242746.

Persistent complement dysregulation with signs of thromboinflammation in active Long Covid

Abstract:

Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid.

Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte–platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.

Source: Carlo Cervia-Hasler et al. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science383,eadg7942(2024). DOI: 10.1126/science.adg7942 https://www.science.org/doi/10.1126/science.adg7942 (Full text)