Tag: long covid symptoms

Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition

Abstract:

With an estimated 65 million individuals affected by post-COVID-19 condition (also known as long COVID), non-invasive biomarkers are direly needed to guide clinical management. To address this pressing need, we used blood transcriptomics in a general practice-based case-control study. Individuals with long COVID were diagnosed according to WHO criteria, and validated clinical scales were used to quantify patient-reported outcomes.

Whole blood samples were collected from 48 individuals with long COVID and 12 control individuals matched for age, sex, time since acute COVID-19, severity, vaccination status, and comorbidities (appendix 1 p 2). Digital transcriptomic analysis was performed using the nCounter (Nanostring Technologies, Seattle, WA, USA) platform, as described for critical COVID-19.

Consequently, 212 genes were identified to be differentially expressed between individuals with long COVID and controls (figure A), of which 70 remained significant after adjustment for false discovery rate correction (appendix 1). Several viral RNAs were upregulated: nucleocapsid, ORF7a, ORF3a, Mpro (a nirmatrelvir plus ritonavir [Paxlovid] target), and antisense ORF1ab RNA. Specifically, the upregulation of antisense ORF1ab RNA suggests ongoing viral replication. SARS-CoV-2-related host RNAs (ACE2/TMPRSS2 receptors, DPP4/FURIN proteases) and RNAs prototypical for memory B-cells and platelets were also upregulated (figure A).

Multivariable logistic regression identified antisense SARS-CoV-2 and FYN RNA concentrations as independent predictors of long COVID (corrected for age and sex; appendix 1 p 2). Receiver operating characteristic curve analysis showed significant discrimination (area under curve [AUC] 0·94, 95% CI 0·86–1·00) between individuals with long COVID (n=48) and controls (n=12), with 93·8% sensitivity and 91·7% specificity (figure B).

Single biomarkers antisense SARS-CoV-2 (AUC 0·78, 0·65–0·90) and FYN RNA (AUC 0·89, 0·79–0·99) were significant predictors with lower sensitivity (52·1% and 72·9%, respectively) but similar specificity (91·7% and 100%, respectively; figure B). Upon summarising transcriptomic results into biological pathways, we found significantly decreased immunometabolism in individuals with long COVID, which was negatively correlated with the blood viral load (appendix 1 p 3).

A qualitative analysis of individual SARS-CoV-2 transcript positivity revealed significant differences between individuals with long COVID and controls for antisense (65% vs 25%), ORF7a (60% vs 25%), and nucleocapsid (50% vs 8%) RNAs (figure C). Similarly, the SARS-CoV-2 transcript positivity with respect to the total blood viral load was also significantly different (60% vs 8%).

By use of multivariable logistic regression, we found that age and sex were not associated with the distinction between a low and high viral RNA load status. Conversely, the number of comorbidities (odds ratio [OR] 1·61, 95% CI 1·14–2·49) and COVID vaccine doses (OR 0·36, 0·14–0·79) emerged as independent predictors of distinguishing between low and high viral RNA load status (appendix 2).

We found that viral and immune parameters, such as the antisense Orf1ab RNA concentrations and immunometabolism score, were also linked to the patient-reported anxiety or depression score. Individuals classified as having severe anxiety or depression (with a score of 4 and 5) displayed significantly higher antisense RNA concentrations and lower immunometabolism scores (p<0·05) than those categorised as mild (with scores of 1–3; figure D).

In conclusion, the associations among persistent viral RNA, immunometabolism, and patient-reported outcomes provide mechanistic insights for addressing the challenges posed by long COVID.

Source: Menezes SM, Jamoulle M, Carletto MP, Moens L, Meyts I, Maes P, Van Weyenbergh J. Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition. Lancet Microbe. 2024 Apr 24:S2666-5247(24)00055-7. doi: 10.1016/S2666-5247(24)00055-7. Epub ahead of print. PMID: 38677304. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00055-7/fulltext (Full text)

Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study

Abstract:

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear.

Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Source: Maffitt NJ, Germann M, Baker AME, Baker MR, Baker SN, Soteropoulos DS. Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study. Sci Rep. 2024 Apr 17;14(1):8874. doi: 10.1038/s41598-024-59232-y. PMID: 38632415; PMCID: PMC11024107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024107/ (Full text)

Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19

Abstract:

Objectives: To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment.

Methods: A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention.

Results: Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02).

Discussion: Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN.

Classification of evidence: This study provides Class III evidence. It is a retrospective cohort study.

Source: McAlpine L, Zubair AS, Joseph P, Spudich S. Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200244. doi: 10.1212/NXI.0000000000200244. Epub 2024 Apr 17. PMID: 38630952. https://www.neurology.org/doi/10.1212/NXI.0000000000200244 (Full text)

Exploring Cognitive Dysfunction in Long COVID Patients: Eye Movement Abnormalities and Frontal-Subcortical Circuits Implications via Eye-Tracking and Machine Learning

Abstract:

Background: Cognitive dysfunction is regarded as one of the most severe aftereffects following coronavirus disease 2019 (COVID-19). Eye movements, controlled by various brain regions, including the dorsolateral prefrontal cortex and frontal-thalamic circuits, offer a potential metric for evaluating cognitive dysfunction. We aimed to examine the utility of eye movement measurements in identifying cognitive impairments in long COVID patients.

Methods: We recruited 40 long COVID patients experiencing subjective cognitive complaints and 40 healthy controls and used a certified eye-tracking medical device to record saccades and antisaccades. Machine learning was applied to enhance the analysis of eye movement data.

Results: Patients did not differ from the healthy controls regarding age, sex, and years of education. However, the patients’ Montreal Cognitive Assessment total score was significantly lower than healthy controls. Most eye movement parameters were significantly worse in patients: the latencies, gain, and velocity of visually and memory-guided saccades, the number of correct memory saccades, the latencies and duration of reflexive saccades, and the number of errors in the antisaccade test. Machine learning permitted distinguishing between long COVID patients experiencing subjective cognitive complaints and healthy controls.

Conclusion: Our findings suggest impairments in frontal subcortical circuits in long COVID patients experiencing subjective cognitive complaints. Eye-tracking, combined with machine learning, offers a novel, efficient way to assess and monitor long COVID patients’ cognitive dysfunctions, suggesting its utility in clinical settings for early detection and personalized treatment strategies. Further research is needed to determine the long-term implications of these findings and the reversibility of cognitive dysfunctions.

Source: Benito-León J, Lapeña J, García-Vasco L, Cuevas C, Viloria-Porto J, Calvo-Córdoba A, Arrieta-Ortubay E, Ruiz-Ruigómez M, Sánchez-Sánchez C, García-Cena C. Exploring Cognitive Dysfunction in Long COVID Patients: Eye Movement Abnormalities and Frontal-Subcortical Circuits Implications via Eye-Tracking and Machine Learning. Am J Med. 2024 Apr 5:S0002-9343(24)00217-1. doi: 10.1016/j.amjmed.2024.04.004. Epub ahead of print. PMID: 38583751. https://pubmed.ncbi.nlm.nih.gov/38583751/

Cluster analysis of long COVID symptoms for deciphering a syndrome and its long-term consequence

Abstract:

The long-term symptoms of COVID-19 are the subject of public and scientific discussions. Understanding how those long COVID symptoms co-occur in clusters of syndromes may indicate the pathogenic mechanisms of long COVID. Our study objective was to cluster the different long COVID symptoms. We included persons who had a COVID-19 and assessed long-term symptoms (at least 4 weeks after first symptoms). Hierarchical clustering was applied to the symptoms as well as to the participants based on the Euclidean distance h of the log-values of the answers on symptom severity. The distribution of clusters within our cohort is shown in a heat map.

From September 2021 to November 2023, 2371 persons with persisting long COVID symptoms participated in the study. Self-assessed long COVID symptoms were assigned to three symptom clusters. Cluster A unites rheumatological and neurological symptoms, cluster B includes neuro-psychological symptoms together with cardiorespiratory symptoms, and a third cluster C shows an association of general infection signs, dermatological and otology symptoms. A high proportion of the participants (n = 1424) showed symptoms of all three clusters.

Clustering of long COVID symptoms reveals similarities to the symptomatology of already described syndromes such as the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or rheumatological autoinflammatory diseases. Further research may identify serological parameters or clinical risk factors associated with the shown clusters and might improve our understanding of long COVID as a systemic disease. Furthermore, multimodal treatments can be developed and scaled for symptom clusters and associated impairments.

Source: Niewolik J, Mikuteit M, Klawitter S, Schröder D, Stölting A, Vahldiek K, Heinemann S, Müller F, Behrens G, Klawonn F, Dopfer-Jablonka A, Steffens S. Cluster analysis of long COVID symptoms for deciphering a syndrome and its long-term consequence. Immunol Res. 2024 Apr 16. doi: 10.1007/s12026-024-09465-w. Epub ahead of print. PMID: 38627327. https://link.springer.com/article/10.1007/s12026-024-09465-w (Full text)

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

Abstract:

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered.

Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms.

Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms.

Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Source: Liew F, Efstathiou C, Fontanella S, Richardson M, Saunders R, Swieboda D, Sidhu JK, Ascough S, Moore SC, Mohamed N, Nunag J, King C, Leavy OC, Elneima O, McAuley HJC, Shikotra A, Singapuri A, Sereno M, Harris VC, Houchen-Wolloff L, Greening NJ, Lone NI, Thorpe M, Thompson AAR, Rowland-Jones SL, Docherty AB, Chalmers JD, Ho LP, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard LS, Wootton DG, Quint JK, de Silva TI, Ho A, Chiu C, Harrison EM, Greenhalf W, Baillie JK, Semple MG, Turtle L, Evans RA, Wain LV, Brightling C, Thwaites RS, Openshaw PJM; PHOSP-COVID collaborative group; ISARIC investigators. Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease. Nat Immunol. 2024 Apr;25(4):607-621. doi: 10.1038/s41590-024-01778-0. Epub 2024 Apr 8. PMID: 38589621; PMCID: PMC11003868. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11003868/ (Full text)

Pituitary–Adrenal Axis and Peripheral Immune Cell Profile in Long COVID

Abstract:

In Long COVID, dysfunction in the pituitary–adrenal axis and alterations in immune cells and inflammatory status are warned against. We performed a prospective study in a cohort of 42 patients who suffered COVID-19 at least 6 months before attending the Long COVID unit at Althaia Hospital.
Based on Post-COVID Functional Status, 29 patients were diagnosed with Long COVID, while 13 were deemed as recovered. The hormones of the pituitary–adrenal axis, adrenocorticotropin stimulation test, and immune cell profiles and inflammatory markers were examined. Patients with Long COVID had significantly lower EuroQol and higher mMRC scores compared to the recovered individuals. Their symptoms included fatigue, myalgia, arthralgia, persistent coughing, a persistent sore throat, dyspnoea, a lack of concentration, and anxiety.
We observed the physiological levels of cortisol and adrenocorticotropin in individuals with or without Long COVID. The results of the adrenocorticotropin stimulation test were similar between both groups. The absolute number of neutrophils was lower in the Long COVID patients compared to recovered individuals (p < 0.05). The total count of B lymphocytes remained consistent, but Long COVID patients had a higher percentage of mature B cells compared to recovered participants (p < 0.05) and exhibited a higher percentage of circulating resident memory CD8+ T cells (p < 0.05) and Treg-expressing exonucleases (p < 0.05).
Our findings did not identify adrenal dysfunction related to Long COVID, nor an association between adrenal function and clinical symptoms. The data indicated a dysregulation in certain immune cells, pointing to immune activation. No overt hyperinflammation was observed in the Long COVID group.
Source: Alijotas-Reig J, Anunciacion-Llunell A, Esteve-Valverde E, Morales-Pérez S, Rivero-Santana S, Trapé J, González-García L, Ruiz D, Marques-Soares J, Miro-Mur F. Pituitary–Adrenal Axis and Peripheral Immune Cell Profile in Long COVID. Biomedicines. 2024; 12(3):581. https://doi.org/10.3390/biomedicines12030581 https://www.mdpi.com/2227-9059/12/3/581 (Full text)

The Effect of Sex on the Risk of Long-COVID and Cardiovascular Complications in Healthy Patients without Comorbidities: Data from a Polish Long-COVID Cardiovascular (PoLoCOV-CVD) Study

Abstract:

Background: The prevalence of long-COVID (LC) presents a significant challenge to healthcare systems globally. There are still some discrepancies on the role of sex as an independent risk factor of LC complications. Thus, we aimed to determine the differences in clinical and cardiovascular complications between males and females without comorbidities after COVID-19.
Methods: Clinical data on the course of the disease with the accompanying symptoms and post-COVID-19 symptoms were compiled from both male and female subjects with a minimum 12-week interval after COVID-19 recovery. Next, the patients were followed for 12 months. ECG, echocardiography, 24 h ECG monitoring, 24 h ambulatory blood pressure monitoring (ABPM), and selected biochemical tests were performed. LC was diagnosed based on the World Health Organization (WHO) definition. To reduce the impact of confounders, i.e., body mass index (BMI) and age, on the results of the study, the nearest neighbour (NN) propensity score matching (PSM) method with a 1:1 ratio was used.
Results: The results were obtained following the removal of cases with comorbidities from the database consisting of 1237 males and 2192 females, and PSM of the new database included 886 cases (443 males and 443 females). At both the 3-month and 1-year post-recovery marks, females consistently reported a higher frequency of LC symptoms compared to males (p < 0.001 for both comparisons). Moreover, after 1 year of follow-up, females exhibited a higher prevalence of LC compared to males, with rates of 14% versus 8.3%, respectively (p = 0.013).
The symptoms that significantly differed between females and males in the 12-month follow-up were hair loss (5.4 vs. 0.7%, p < 0.001), memory and concentration disturbances (8.4 vs. 4.3%, p = 0.013), and headaches (4.3 vs. 1.4%, p = 0.008). Females presented lower mean arterial pressure (MAP) [89 (83–95) mmHg versus (vs.) 94 (89–100); p < 0.001] and lower pulse pressure (PP) [46 (42–52) mmHg vs. 51 (48–57); p < 0.001] in 24 h ABPM and more elevated heart rates (HRs) in 24 h ECG monitoring as well as arrhythmia (p < 0.001 and p = 0.018, respectively). Males had a higher occurrence of ECG abnormalities such as QRS >= 120 ms, ST-T changes, T inversion, arrhythmia, and QRS fragmentation (27.3% vs. 19.2%; p = 0.004). No significant differences were observed between males and females concerning physical activity levels, stress, fatigue, alcohol consumption, and smoking habits.
Conclusions: One year post-COVID-19 recovery, regardless of age and BMI, healthy females more often suffered from LC symptoms than males. They had lower MAP and PP in 24 h ABPM, more often had higher HRs and arrhythmia in 24 h ECG monitoring, and fewer ECG abnormalities than males.
Source: Bielecka-Dabrowa A, Sakowicz A, Gryglewska-Wawrzak K, Kapusta J, Banach M, Jankowski P, Chudzik M. The Effect of Sex on the Risk of Long-COVID and Cardiovascular Complications in Healthy Patients without Comorbidities: Data from a Polish Long-COVID Cardiovascular (PoLoCOV-CVD) Study. Journal of Clinical Medicine. 2024; 13(6):1559. https://doi.org/10.3390/jcm13061559 https://www.mdpi.com/2077-0383/13/6/1559 (Full text)

Comparison of the muscle oxygenation during submaximal and maximal exercise tests in patients post-coronavirus disease 2019 syndrome with pulmonary involvement

Abstract:

Introduction: Pulmonary involvement is prevalent in patients with coronavirus disease 2019 (COVID-19). Arterial hypoxemia may reduce oxygen transferred to the skeletal muscles, possibly leading to impaired exercise capacity. Oxygen uptake may vary depending on the increased oxygen demand of the muscles during submaximal and maximal exercise.

Objective: This study aimed to compare muscle oxygenation during submaximal and maximal exercise tests in patients with post-COVID-19 syndrome with pulmonary involvement.

Methods: Thirty-nine patients were included. Pulmonary function (spirometry), peripheral muscle strength (dynamometer), quadriceps femoris (QF) muscle oxygenation (Moxy® device), and submaximal exercise capacity (six-minute walk test (6-MWT)) were tested on the first day, maximal exercise capacity (cardiopulmonary exercise test (CPET)) was tested on the second day. Physical activity level was evaluated using an activity monitor worn for five consecutive days. Cardiopulmonary responses and muscle oxygenation were compared during 6-MWT and CPET.

Results: Patients’ minimum and recovery muscle oxygen saturation were significantly decreased; maximum total hemoglobin increased, heart rate, blood pressure, breathing frequency, dyspnea, fatigue, and leg fatigue at the end-of-test and recovery increased in CPET compared to 6-MWT (p < .050). Peak oxygen consumption (VO2peak) was 18.15 ± 4.75 ml/min/kg, VO2peak; percent predicted < 80% was measured in 51.28% patients. Six-MWT distance and QF muscle strength were less than 80% predicted in 58.9% and 76.9% patients, respectively.

Conclusions: In patients with post-COVID-19 syndrome with pulmonary involvement, muscle deoxygenation of QF is greater during maximal exercise than during submaximal exercise. Specifically, patients with lung impairment should be evaluated for deoxygenation and should be taken into consideration during pulmonary rehabilitation.

Source: Kavalcı Kol B, Boşnak Güçlü M, Baytok E, Yılmaz Demirci N. Comparison of the muscle oxygenation during submaximal and maximal exercise tests in patients post-coronavirus disease 2019 syndrome with pulmonary involvement. Physiother Theory Pract. 2024 Mar 12:1-14. doi: 10.1080/09593985.2024.2327534. Epub ahead of print. PMID: 38469863. https://pubmed.ncbi.nlm.nih.gov/38469863/

Health outcomes for Long COVID are comparable with ME/CFS

Press Release: Griffith News

People with Long COVID in Australia have poor health outcomes that are comparable with another emerging disease known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), new Griffith University research has discovered.

PhD student Breanna Weigel from Griffith’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) will be presenting the findings in Singapore this month at the International Public Health Conference.

Ms Weigel said the study found people with Long COVID have the same health outcomes as ME/CFS over a 12-month period.

“Quality of life and disability scores were significantly poorer for both Long COVID and ME/CFS when compared with healthy people,” she said.

“However, there were no differences between ME/CFS and Long COVID groups which indicates considerable reductions in functional capacity and health and well-being among people living with these illnesses.”

The research found only a few differences in more than 25 different symptoms between Long COVID and ME/CFS participants.

Importantly, both ME/CFS and Long COVID groups had comparable prevalence with the severity of their illness.

Both groups over time had the same symptom presentation of significantly impaired cognition, mobility, bodily pain, and post-exertional malaise (PEM) which means symptoms get worse after physical or mental activity.

PEM is very disabling and causes changes in symptoms and a further reduction in ability to do everyday activities.

Director of the NCNED, Professor Sonya Marshall-Gradisnik, said: “This research highlighted the continued impact of Long COVID on peoples’ lives, which is especially poignant as today we recognise International Long COVID Awareness Day.”

“The research forms one of many Long COVID investigations and clinical trials being undertaken at the national centre where it is hoped these findings will provide pathways for those with Long COVID.

“We are uniquely positioned nationally as we are the only centre to undertake scientific laboratory and MRI research in Long COVID and ME/CFS in tandem, and monitor the health and economic impact of the patients.

“At the national centre we also undertake clinical trials and contribute to best practice guidelines such as the recently published guidelines in the British Medical Journal for ME.”

Dr Natalie Eaton-Fitch, who was an undergraduate student at Griffith University and is now an emerging researcher at the NCNED said: “Researchers are very fortunate to have wonderful opportunities at all stages of their careers and to know research can make a real-world difference for people.”

Ms Weigel’s work builds upon the Issues Brief she did in collaboration with the Deeble Institute that reported how patient experiences can guide the development of Long COVID health policy.