Characteristics of long COVID and the impact of COVID-19 vaccination on long COVID 2 years following COVID-19 infection: prospective cohort study

Abstract:

This prospective cohort study aimed to identify characteristics of long COVID and any potential mitigating effects of COVID-19 vaccinations in patients 24 months following COVID-19 infection. Adult patients diagnosed with COVID-19 between February 17, 2020, and March 24, 2020, were scheduled to visit the study hospital four times (6, 12, 18, and 24 months after infection) to assess their symptoms, quality of life, and mental health. Among the 235 patients, 121 (51.5%) completed the study visits. Of these, 59.5% were female, with a median age of 52 years. Mild to moderate disease severity were identified in 101 (83.4%) patients.

A total of 75 participants (62.0%) were still experiencing long COVID symptoms 24 months after acute infection. Fatigue, amnesia, difficulty concentrating, and insomnia were the most common symptoms. The frequency of neuropsychiatric symptoms did not differ based on vaccination status or the number of doses received. Quality of life improved over time for the participants, but 32.2% of respondents still reported anxiety/depression at the end of the study. Overall, our cohort demonstrates that long COVID can persist up to 24 months after COVID-19 infection, affecting mental health and quality of life.

Source: Kim, Y., Bae, S., Chang, HH. et al. Characteristics of long COVID and the impact of COVID-19 vaccination on long COVID 2 years following COVID-19 infection: prospective cohort study. Sci Rep 14, 854 (2024). https://doi.org/10.1038/s41598-023-50024-4 https://www.nature.com/articles/s41598-023-50024-4 (Full text)

Exploring the central mechanism of mind-regulation electroacupuncture in treatment of chronic fatigue syndrome with anxiety and depression comorbidity based on functional magnetic resonance imaging

Abstract:

Objectives: To observe the changes in the regional homogeneity (ReHo) and functional brain network in treatment of chronic fatigue syndrome (CFS) with anxiety and depression comorbidity with the mind-regulation electroacupuncture (EA), using resting-state functional magnetic resonance imaging (rs-fMRI).

Methods: Thirty CFS patients with anxiety and depression comorbidity were enrolled from medical staffs as the observation group. The other 30 healthy subjects were recruited from medical university students as the control group, matching gender, age and education years with the observation group. No any acupuncture intervention was delivered in the control group, and EA for regulating the mind was operated in the observation group. Main points were the emotional area of Sun‘s scalp acupuncture, the regions 1 and 8 of Sun‘s abdominal acupuncture. Supplementary acupoints included Baihui (GV 20), Guanyuan (CV 4) and bilateral.

Results: The scores of the five domains in MFI-20 (i.e. general fatigue, physical fatigue, mental fatigue, reduced motivation and reduced activity), the total score of MFI-20, and the scores of SDS, SAS and PSQI in the observation group before treatment were higher than those of the control group (P<0.05). Except the score of reduced motivation in MFI-20, the scores of the other domains and the total score of MFI-20, as well as the scores of SDS, SAS and PSQI after treatment were lower than those before treatment in the observation group (P<0.05).

Compared with the values before treatment, ReHo value was increased in the the right precuneus and decreased in the left inferior temporal gyrus and the left angular gyrus of the brain in the observation group after treatment. In the observation group, when compared with the control group, ReHo values were increased in the left inferior cerebral lobe, the interhemispheric region, the right occipital lobe and the thalamus; and it was reduced in the left middle temporal gyrus, the right posterior central gyrus, the right middle temporal gyrus, the right orbital middle frontal gyrus, the paracentral lobule and the right fusiform gyrus before treatment.

In the observation group, the functional connectivity was decreased between the right thalamus and the left posterior central gyrus, the right hippocampus and the right fusiform gyrus before treatment, respectively; it was re-constructed after treatment between the right thalamus and the left posterior central gyrus, and the right fusiform gyrus.

Compared with the control group, the functional connectivity between the right thalamus and the left posterior central gyrus, the right hippocampus, and the right fusiform gyrus was reduced before treatment; while after treatment, the functional connectivity was reduced between the right thalamus and the hippocampus in the observation group. With Spearman correlation analysis between the differential brain regions and the scores of MFI-20, SAS, SDS and PSQI, it was found that the left middle temporal gyrus, the paracentral lobule, the right precuneus, and the left inferior temporal gyrus had a partial positive correlation with the above clinical scales; and the interhemispheric region, the thalamus, the right fusiform gyrus, and the right middle temporal gyrus showed a partial negative correlation.

Conclusions: There is the decrease of ReHo in many brain regions and the numbers of the local brain functional network connectivity in CFS patients with anxiety and depression comorbidity. The mind-regulation electroacupuncture therapy may relieve the clinical symptoms of the patients through adjusting the abnormal brain regions and activating emotion-related brain regions.

Source: Zeng X, Feng C, Zhang M, Cheng W, Sun Z, Yang T. Exploring the central mechanism of mind-regulation electroacupuncture in treatment of chronic fatigue syndrome with anxiety and depression comorbidity based on functional magnetic resonance imaging. Zhongguo Zhen Jiu. 2023 Jan 12;44(1):3-11. English, Chinese. doi: 10.13703/j.0255-2930.20230603-k0003. PMID: 38191152. https://pubmed.ncbi.nlm.nih.gov/38191152/

Links between Serotonin Levels and Stress: Cortisol, Candida A./Mycetes, Omega 3/6 Ratio and Dysbiosis (Skatole/Indoxyl Sulfate) Role in Chronic Fatigue Syndrome (CFS) and Depression

Abstract:

Intestinal microbiota attracts daily attention of a growing number of study which have attempted to link gut dysbiosIs with a variety of disease states: irritable bowel syndrome (IBS), inflamed bowel disease (IBD), Crohn’s disease (CD), leaky gut syndrome (LGS), food intolerance, diabetes, metabolic syndrome, cancer, etc.

In our study we analyzed how intestinal dysbiosis may be related to chronic fatigue syndrome (CFS) and depression through the exchange of information through the gut-brain axis (GBA).

We studied 33 subjects, 13 males and 20 females, who reported CFS or/and depression: we investigated their salivary cortisol levels, blood serotonin, omega 3/6 ratio, intestinal dysbiosis (calculated on the urinary levels of indoxyl sulfate and skatole), and we looked for the presence of Candida a. or mycetes in the stool; the data accumulated with this research show a correlation between the presence of Candida a./miceti, indoxyl sulfate urine values beyond the physiological and low serotonin levels.

In addition, data analysis showed that the EPA/DHA values also show pro-inflammatory levels in case of dysbiosis and low serotonina levels. The relationship, however, with cortisol levels requires further research although this study showed a statistically significant positive correlation between these values, measured at specific times, and serotonin levels.

Aims: We investigated the relationship between stress (evaluated through the measurement of salivary cortisol levels) and gastrointestinal efficiency measured as a function of intestinal fermentative and putrefactive dysbiosis, evaluating the levels of urinary indoxyl sulfate in the first case (a possible correlation with the presence of Candida spp or Mycetes in the subjects feces was investigated), urinary skatole levels in the second one, in patients with chronic fatigue syndrome (SFC) and depression.

In these patients we also have studied omega 3/6 ratio, and finally we have analized the impact that the alteration of these parameters can have on the serotonin levels.

This research attemps to highlight the contact points, in some cases not so obvious, among these topics, contact points that, although they give us interesting indications, show the need to be further deepened by analyzing a larger amount of data.

Source: Orlandoni, D.; Di Fede, G.; Mantovani, M.; Nava, C.R.; Tomasi, M.; Fusi, P. Links between Serotonin Levels and Stress: Cortisol, Candida A./Mycetes, Omega 3/6 Ratio and Dysbiosis (Skatole/Indoxyl Sulfate) Role in Chronic Fatigue Syndrome (CFS) and Depression. Preprints 2023, 2023090253. https://doi.org/10.20944/preprints202309.0253.v1 https://www.preprints.org/manuscript/202309.0253/v1 (Full text available as PDF file)

Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID

Abstract:

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.

In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3–10 months after remission of acute infection.

We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome.

Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19).

In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.

Source: Al-Hakeim HK, Khairi Abed A, Rouf Moustafa S, Almulla AF, Maes M. Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID. Front Mol Neurosci. 2023 Jun 2;16:1194769. doi: 10.3389/fnmol.2023.1194769. PMID: 37333619; PMCID: PMC10272345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272345/ (Full text)

Major Depressive Disorder and Chronic Fatigue Syndrome Show Characteristic Heart Rate Variability Profiles Reflecting Autonomic Dysregulations: Differentiation by Linear Discriminant Analysis

Abstract:

Major depressive disorder (MDD) and chronic fatigue syndrome (CFS) have overlapping symptoms, and differentiation is important to administer the proper treatment.

The present study aimed to assess the usefulness of heart rate variability (HRV) indices.

Frequency-domain HRV indices, including high-frequency (HF) and low-frequency (LF) components, their sum (LF+HF), and their ratio (LF/HF), were measured in a three-behavioral-state paradigm composed of initial rest (Rest), task load (Task), and post-task rest (After) periods to examine autonomic regulation.

It was found that HF was low at Rest in both disorders, but was lower in MDD than in CFS. LF and LF+HF at Rest were low only in MDD. Attenuated responses of LF, HF, LF+HF, and LF/HF to task load and an excessive increase in HF at After were found in both disorders.

The results indicate that an overall HRV reduction at Rest may support a diagnosis of MDD. HF reduction was found in CFS, but with a lesser severity.

Response disturbances of HRV to Task were observed in both disorders, and would suggest the presence of CFS when the baseline HRV has not been reduced.

Linear discriminant analysis using HRV indices was able to differentiate MDD from CFS, with a sensitivity and specificity of 91.8% and 100%, respectively. HRV indices in MDD and CFS show both common and different profiles, and can be useful for the differential diagnosis.

Source: Shinba T, Kuratsune D, Shinba S, Shinba Y, Sun G, Matsui T, Kuratsune H. Major Depressive Disorder and Chronic Fatigue Syndrome Show Characteristic Heart Rate Variability Profiles Reflecting Autonomic Dysregulations: Differentiation by Linear Discriminant Analysis. Sensors. 2023; 23(11):5330. https://doi.org/10.3390/s23115330 https://www.mdpi.com/1424-8220/23/11/5330 (Full text)

Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms

Abstract:

Importance: Persistent depressive symptoms, often accompanied by cognitive symptoms, commonly occur after COVID-19 illness (hereinafter termed COVID-DC, DC for depressive and/or cognitive symptoms). In patients with COVID-DC, gliosis, an inflammatory change, was suspected, but measurements of gliosis had not been studied in the brain for this condition.

Objective: To determine whether translocator protein total distribution volume (TSPO VT), a marker of gliosis that is quantifiable with positron emission tomography (PET), is elevated in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus of persons with COVID-DC.

Design, setting, and participants: This case-control study conducted at a tertiary care psychiatric hospital in Canada from April 1, 2021, to June 30, 2022, compared TSPO VT of specific brain regions in 20 participants with COVID-DC with that in 20 healthy controls. The TSPO VT was measured with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) PET.

Main outcomes and measures: The TSPO VT was measured in the dorsal putamen, ventral striatum, prefrontal cortex, anterior cingulate cortex, and hippocampus. Symptoms were measured with neuropsychological and psychological tests, prioritizing outcomes related to striatal function.

Results: The study population included 40 participants (mean [SD] age, 32.9 [12.3] years). The TSPO VT across the regions of interest was greater in persons with COVID-DC (mean [SD] age, 32.7 [11.4] years; 12 [60%] women) compared with healthy control participants (mean [SD] age, 33.3 [13.9] years; 11 [55%] women): mean (SD) difference, 1.51 (4.47); 95% CI, 0.04-2.98; 1.51 divided by 9.20 (17%). The difference was most prominent in the ventral striatum (mean [SD] difference, 1.97 [4.88]; 95% CI, 0.36-3.58; 1.97 divided by 8.87 [22%]) and dorsal putamen (mean difference, 1.70 [4.25]; 95% CI, 0.34-3.06; 1.70 divided by 8.37 [20%]). Motor speed on the finger-tapping test negatively correlated with dorsal putamen TSPO VT (r, -0.53; 95% CI, -0.79 to -0.09), and the 10 persons with the slowest speed among those with COVID-DC had higher dorsal putamen TSPO VT than healthy persons by 2.3 (2.30 divided by 8.37 [27%]; SD, 2.46; 95% CI, 0.92-3.68).

Conclusions and relevance: In this case-control study, TSPO VT was higher in patients with COVID-DC. Greater TSPO VT is evidence for an inflammatory change of elevated gliosis in the brain of an individual with COVID-DC. Gliosis may be consequent to inflammation, injury, or both, particularly in the ventral striatum and dorsal putamen, which may explain some persistent depressive and cognitive symptoms, including slowed motor speed, low motivation or energy, and anhedonia, after initially mild to moderate COVID-19 illness.

Source: Braga J, Lepra M, Kish SJ, Rusjan PM, Nasser Z, Verhoeff N, Vasdev N, Bagby M, Boileau I, Husain MI, Kolla N, Garcia A, Chao T, Mizrahi R, Faiz K, Vieira EL, Meyer JH. Neuroinflammation After COVID-19 With Persistent Depressive and Cognitive Symptoms. JAMA Psychiatry. 2023 May 31:e231321. doi: 10.1001/jamapsychiatry.2023.1321. Epub ahead of print. PMID: 37256580; PMCID: PMC10233457. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10233457/ (Full text)

Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis

Abstract:

Introduction: The number of children with mental health problems has more than doubled since the COVID-19 pandemic. However, the effect of long Covid on children’s mental health is still debatable. Recognising long Covid as a risk factor for mental health problems in children will increase awareness and screening for mental health problems following COVID-19 infection, resulting in earlier intervention and lower morbidity. Therefore, this study aimed to determine the proportion of mental health problems post-COVID-19 infection in children and adolescents, and to compare them with the population with no previous COVID-19 infection.

Methodology: A systematic search was done in seven databases using pre-defined search terms. Cross-sectional, cohort and interventional studies reporting the proportion of mental health problems among children with long COVID in the English language from 2019 to May 2022 were included. Selection of papers, extraction of data and quality assessment were done independently by two reviewers. Studies with satisfactory quality were included in meta-analysis using R and Revman software programmes.

Results: The initial search retrieved 1848 studies. After screening, 13 studies were included in the quality assessments. Meta-analysis showed children who had previous COVID-19 infection had more than two times higher odds of having anxiety or depression, and 14% higher odds of having appetite problems, compared to children with no previous infection. The pooled prevalence of mental health problems among the population were as follows; anxiety: 9%(95% CI:1, 23), depression: 15%(95% CI:0.4, 47), concentration problems: 6%(95% CI: 3, 11), sleep problems: 9%(95% CI:5, 13), mood swings: 13% (95%CI:5, 23) and appetite loss: 5%(95% CI:1, 13). However, studies were heterogenous and lack data from low- and middle-income countries.

Conclusion: Anxiety, depression and appetite problems were significantly increased among post-COVID-19 infected children, compared to those without a previous infection, which may be attributed to long COVID. The findings underscore the importance of screening and early intervention of children post-COVID-19 infection at one month and between three to four months.

Source: Mat Hassan N, Salim HS, Amaran S, Yunus NI, Yusof NA, Daud N, et al. (2023) Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis. PLoS ONE 18(5): e0282538. https://doi.org/10.1371/journal.pone.0282538 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282538 (Full text)

Factors associated with psychiatric outcomes and coping in Long COVID

Abstract:

The relationship between Long COVID (LC) and psychiatric outcomes, as well as factors associated with presence and absence of these, has so far been insufficiently studied. Here we evaluated psychiatric symptoms and coping among patients with LC and patients recovered from COVID-19 who participated in a large international survey. Given increased rates of psychiatric illness with chronic medical conditions and known immune-inflammatory contributors to psychiatric disease, we hypothesized that a subset, but not the entirety, of LC respondents may have comorbid psychopathology.

A substantial minority of both groups experienced suicidality, depression and anxiety symptoms, with these symptoms being more common in the LC group. LC respondents used more adaptive coping styles. Psychiatric outcomes in LC were associated with younger age, greater reductions in overall health, higher symptom severity, limitations to physical capability, lower income, financial hardship, psychiatric history, employment impact, male sex, men and non-binary gender, and negative experiences with medical professionals, family, friends, partners and employers.

Source: Re’em, Y., Stelson, E.A., Davis, H.E. et al. Factors associated with psychiatric outcomes and coping in Long COVID. Nat. Mental Health 1, 361–372 (2023). https://doi.org/10.1038/s44220-023-00064-6 https://www.nature.com/articles/s44220-023-00064-6 (Full text)

Perceived Cognitive Deficits in Patients With Symptomatic SARS-CoV-2 and Their Association With Post-COVID-19 Condition

Abstract:

Importance: Neuropsychiatric symptoms are common in acute SARS-CoV-2 infection and in post-COVID-19 condition (PCC; colloquially known as long COVID), but the association between early presenting neuropsychiatric symptoms and PCC is unknown.

Objective: To describe the characteristics of patients with perceived cognitive deficits within the first 4 weeks of SARS-CoV-2 infection and the association of those deficits with PCC symptoms.

Design, setting, and participants: This prospective cohort study was conducted from April 2020 to February 2021, with follow-up of 60 to 90 days. The cohort consisted of adults enrolled in the University of California, Los Angeles, SARS-CoV-2 Ambulatory Program who had a laboratory-confirmed symptomatic SARS-CoV-2 infection and were either hospitalized in a University of California, Los Angeles, hospital or one of 20 local health care facilities, or were outpatients referred by a primary care clinician. Data analysis was performed from March 2022 to February 2023.

Exposure: Laboratory-confirmed SARS-CoV-2 infection.

Main outcomes and measures: Patients responded to surveys that included questions about perceived cognitive deficits modified from the Perceived Deficits Questionnaire, Fifth Edition, (ie, trouble being organized, trouble concentrating, and forgetfulness) and symptoms of PCC at 30, 60, and 90 days after hospital discharge or initial laboratory-confirmed infection of SARS-CoV-2. Perceived cognitive deficits were scored on a scale from 0 to 4. Development of PCC was determined by patient self-report of persistent symptoms 60 or 90 days after initial SARS-CoV-2 infection or hospital discharge.

Results: Of 1296 patients enrolled in the program, 766 (59.1%) (mean [SD] age, 60.0 [16.7] years; 399 men [52.1%]; 317 Hispanic/Latinx patients [41.4%]) completed the perceived cognitive deficit items at 30 days after hospital discharge or outpatient diagnosis. Of the 766 patients, 276 (36.1%) perceived a cognitive deficit, with 164 (21.4%) having a mean score of greater than 0 to 1.5 and 112 patients (14.6 %) having a mean score greater than 1.5. Prior cognitive difficulties (odds ratio [OR], 1.46; 95% CI, 1.16-1.83) and diagnosis of depressive disorder (OR, 1.51; 95% CI, 1.23-1.86) were associated with report of a perceived cognitive deficit. Patients reporting perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection were more likely to report symptoms of PCC than those without perceived cognitive deficits (118 of 276 patients [42.8%] vs 105 of 490 patients [21.4%]; χ21, 38.9; P < .001). Adjusting for demographic and clinical factors, perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 were associated with PCC symptoms (patients with a cognitive deficit score of >0 to 1.5: OR, 2.42; 95% CI, 1.62-3.60; patients with cognitive deficit score >1.5: OR, 2.97; 95% CI, 1.86-4.75) compared to patients who reported no perceived cognitive deficits.

Conclusions and relevance: These findings suggest that patient-reported perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection are associated with PCC symptoms and that there may be an affective component to PCC in some patients. The underlying reasons for PCC merit additional exploration.

Source: Turner GM, McMullan C, Aiyegbusi OL, Hughes SE, Walker A, Jeyes F, Adler Y, Chong A, Buckland L, Stanton D, Davies EH, Haroon S, Calvert M. Co-production of a feasibility trial of pacing interventions for Long COVID. Res Involv Engagem. 2023 Mar 30;9(1):18. doi: 10.1186/s40900-023-00429-2. PMID: 36997975; PMCID: PMC10061378. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061378/ (Full text)

Risk factors for psychiatric symptoms in patients with long COVID: A systematic review

Abstract:

Prolonged symptoms of COVID-19 have been found in many patients, often known as Long COVID. Psychiatric symptoms are commonly seen in Long COVID patients and could last for weeks, even months, after recovery. However, the symptoms and risk factors associated with it remain unclear.

In the current systematic review, we provide an overview of psychiatric symptoms in Long COVID patients and risk factors associated with the development of those symptoms. Articles were systematically searched on SCOPUS, PubMed, and EMBASE up to October 2021. Studies involving adults and geriatric participants with a confirmed previous COVID-19 diagnosis and reported psychiatric symptoms that persist for more than four weeks after the initial infection were included. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies. Prevalence rates and risk factors associated with psychiatric symptoms were collected. This present study was registered at PROSPERO (CRD42021240776). In total, 23 studies were included.

Several limitations in this review were the heterogeneity of studies’ outcomes and designs, studies limited to articles published in English, and the psychiatric symptoms mainly were assessed using self-report questionnaires. The most prevalent  reported psychiatric symptoms, from the most to the least reported, were anxiety, depression, post-traumatic stress disorder (PTSD), poor sleep qualities, somatic symptoms, and cognitive deficits. Being female and having previous psychiatric diagnoses were risk factors for the development of the reported symptoms.

Source: Zakia H, Pradana K, Iskandar S. Risk factors for psychiatric symptoms in patients with long COVID: A systematic review. PLoS One. 2023 Apr 7;18(4):e0284075. doi: 10.1371/journal.pone.0284075. PMID: 37027455; PMCID: PMC10081737. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081737/ (Full text)