Tag: 2023

Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization

Abstract:

Objective: Post-acute sequelae of SARS-COV-2 (PASC) are emerging as a major health challenge. Orthostatic intolerance secondary to autonomic failure has been found in PASC patients. This study investigated the effect of COVID-19 after recovery on blood pressure (BP) during the orthostatic challenge.

Research design and methods: Thirty-one out of 45 patients hospitalized due to COVID-19-related pneumonia that developed PASC and did not have hypertension at discharge were studied. They underwent a head-up tilt test (HUTT) at 10.8 ± 1.9 months from discharge. All met the PASC clinical criteria, and an alternative diagnosis did not explain the symptoms. This population was compared with 32 historical asymptomatic healthy controls.

Results: Exaggerated orthostatic blood pressure response (EOPR)/orthostatic hypertension (OHT) was detected in 8 out of 23 (34.7 %) patients, representing a significantly increased prevalence (7.67-fold increase p = 0.009) compared to 2 out of 32 (6.4 %) asymptomatic healthy controls matched by age, who underwent HUTT and were not infected with SARS-CoV-2.

Conclusions: This prospective evaluation in patients with PASC revealed abnormal blood pressure rise during the orthostatic challenge, suggesting of autonomic dysfunction in a third of the studied subjects. Our findings support the hypothesis that EOPR/OHT may be a phenotype of neurogenic hypertension. Hypertension in PASC patients may adversely affect the cardiovascular burden in the world.

Source: González-Hermosillo G JA, Galarza EJ, Fermín OV, González JMN, Tostado LMFÁ, Lozano MAE, Rabasa CR, Martínez Alvarado MDR. Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization. Auton Neurosci. 2023 Apr 21;247:103094. doi: 10.1016/j.autneu.2023.103094. Epub ahead of print. PMID: 37137186; PMCID: PMC10121145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121145/ (Full text)

Transcranial direct current stimulation for post-COVID fatigue: a randomized, double-blind, controlled pilot study

Abstract:

Fatigue is one of the most frequent and disabling symptoms of the post-COVID syndrome. In this study, we aimed to assess the effects of transcranial direct current stimulation on fatigue severity in a group of patients with post-COVID syndrome and chronic fatigue.

We conducted a double-blind, parallel-group, sham-controlled study to evaluate the short-term effects of anodal transcranial direct current stimulation (2 mA, 20 min/day) on the left dorsolateral prefrontal cortex. The modified fatigue impact scale score was used as the primary endpoint. Secondary endpoints included cognition (Stroop test), depressive symptoms (Beck depression inventory) and quality of life (EuroQol-5D).

Patients received eight sessions of transcranial direct current stimulation and were evaluated at baseline, immediately after the last session, and one month later. Forty-seven patients were enrolled (23 in the active treatment group and 24 in the sham treatment group); the mean age was 45.66 ± 9.49 years, and 37 (78.72%) were women. The mean progression time since the acute infection was 20.68 ± 6.34 months.

Active transcranial direct current stimulation was associated with a statistically significant improvement in physical fatigue at the end of treatment and 1 month as compared with sham stimulation. No significant effect was detected for cognitive fatigue.

In terms of secondary outcomes, active transcranial direct current stimulation was associated with an improvement in depressive symptoms at the end of treatment. The treatment had no effects on the quality of life. All the adverse events reported were mild and transient, with no differences between the active stimulation and sham stimulation groups.

In conclusion, our results suggest that transcranial direct current stimulation on the dorsolateral prefrontal cortex may improve physical fatigue. Further studies are needed to confirm these findings and optimize stimulation protocols.

Source: Oliver-Mas S, Delgado-Alonso C, Delgado-Álvarez A, Díez-Cirarda M, Cuevas C, Fernández-Romero L, Matias-Guiu A, Valles-Salgado M, Gil-Martínez L, Gil-Moreno MJ, Yus M, Matias-Guiu J, Matias-Guiu JA. Transcranial direct current stimulation for post-COVID fatigue: a randomized, double-blind, controlled pilot study. Brain Commun. 2023 Apr 10;5(2):fcad117. doi: 10.1093/braincomms/fcad117. PMID: 37091591; PMCID: PMC10116605. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10116605/ (Full text)

Persistent post-COVID-19 dysosmia: Practices survey of members of the French National Union of Otorhinolaryngology-Head and Neck Surgery Specialists. CROSS analysis

Abstract:

Introduction: Persistent dysosmia more than 3 months after SARS-CoV-2 disease (COVID-19) is considered as long-COVID olfactory disease (LCOD). The primary objective of this study was to evaluate the diagnostic and therapeutic management of LCOD in the daily clinical practice of members of the National Union of Otorhinolaryngology-Head and Neck Surgery Specialists (Syndicat national des médecins spécialisés en ORL et chirurgie cervico-faciale) (SNORL). The secondary objective was to identify factors influencing management within the descriptive survey data.

Materials and methods: A questionnaire was designed (GoogleForm®) and e-mailed to all 715 SNORL members in January 2022.

Results: The response rate was 7.4% (n=53/715). In total, 94.3% of respondents (n=50) had managed LCOD cases, and 56% (n=28) used psychophysical olfactory tests. Specific olfactory medical therapy involved local corticosteroid nasal sprays in 49.1% of cases (n=26) and oral corticosteroids in 32.1% (n=17). Olfactory self-training was prescribed by 81.1% of respondents, with associated speech pathologist therapy in 15.1% (n=8) of cases. No predictive factors for specific management were identified.

Conclusion: Olfactometry is currently under-applied. Consistent with guidelines, non-drug therapy (olfactory training) is the first-line treatment for LCOD.

Source: Vandersteen C, Dubrulle C, Manera V, Castillo L, Payne M, Gros A. Persistent post-COVID-19 dysosmia: Practices survey of members of the French National Union of Otorhinolaryngology-Head and Neck Surgery Specialists. CROSS analysis. Eur Ann Otorhinolaryngol Head Neck Dis. 2023 Apr 7:S1879-7296(23)00052-2. doi: 10.1016/j.anorl.2023.04.002. Epub ahead of print. PMID: 37087365; PMCID: PMC10080269. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080269/ (Full text)

Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status

Abstract:

Post-COVID-19 syndrome (PCS) fatigue is typically most severe <6 months post-infection. Combining magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging with the glucose analog [18F]-Fluorodeoxyglucose (FDG) provides a comprehensive overview of the effects of PCS on regional brain volumes and metabolism, respectively. The primary purpose of this exploratory study was to investigate differences in MRI/PET outcomes between people < 6 months (N = 18, 11 female) and > 6 months (N = 15, 6 female) after COVID-19.
The secondary purpose was to assess if any differences in MRI/PET outcomes were associated with fatigue symptoms. Subjects > 6 months showed smaller volumes in the putamen, pallidum, and thalamus compared to subjects < 6 months. In subjects > 6 months, fatigued subjects had smaller volumes in frontal areas compared to non-fatigued subjects. Moreover, worse fatigue was associated with smaller volumes in several frontal areas in subjects > 6 months.
The results revealed no brain metabolism differences between subjects > 6 and < 6 months. However, both groups exhibited both regional hypo- and hypermetabolism compared to a normative database. These results suggest that PCS may alter regional brain volumes but not metabolism in people > 6 months, particularly those experiencing fatigue symptoms.
Source: Deters JR, Fietsam AC, Gander PE, Boles Ponto LL, Rudroff T. Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status. Brain Sciences. 2023; 13(4):675. https://doi.org/10.3390/brainsci13040675 https://www.mdpi.com/2076-3425/13/4/675 (Full text)

Autonomic Dysfunction related to Post-Acute SARS-CoV-2 Syndrome

Introduction:

The SARS-CoV-2 virus, a member of the coronavirus family, has been responsible for the Coronavirus Disease-19 (COVID-19) pandemic with an acute phase causing pneumonia and pulmonary disorders, but it has been shown to extrapulmonary manifestations including cardiovascular and neurological diseases. Moreover, residual symptoms have been reported to persist past the acute phase. In a cross-sectional study of SARS-CoV-2 positive patients, at 48 days post-discharge the most common persistent symptoms were fatigue, difficulty breathing, and psychological distress.
 In a cohort study of 1,733 COVID-19 patients from Wuhan, China, patients reported persistence of fatigue, muscle weakness, sleeping difficulties, palpitations, anxiety, or depression at 6 months after initial onset.
 Numerous other studies now indicate the presence of persistent symptoms following COVID-19 infection, with over 200 symptoms reported. This syndrome has been coined as the Post-Acute SARS-CoV-2 Syndrome (PASC) and has been defined as the persistence of symptoms or development of new symptoms after the time of infection, which can include fatigue, brain fog, palpitations, and a plethora of other manifestations.
Source: Justin Haloot, DO, MS, MS, Ratna Bhavaraju-Sanka, MD, Jayasree Pillarisetti, MD Msc, Monica Verduzco-Gutierrez, MD. Autonomic Dysfunction related to Post-Acute SARS-CoV-2 Syndrome. Physical Medicine and Rehabiliation Clinics. Published: April 18, 2023. DOI:https://doi.org/10.1016/j.pmr.2023.04.003 (Full text)

Cardiovascular Manifestations of the Long COVID Syndrome.

Abstract:

While most coronavirus 2019 (COVID-19) survivors have had complete resolution of symptoms, a significant proportion have suffered from incomplete recovery. Cardiopulmonary symptoms, such as dyspnea, chest pain, and palpitations are responsible for a substantial symptom burden in COVID-19 survivors.

Studies have revealed persistent myocardial injury with late gadolinium enhancement and myocardial scar on cardiac magnetic resonance in a significant proportion of patients. Evidence of myocardial edema, active inflammation, left ventricular dysfunction, and right ventricular dysfunction, is limited to a minority of patients.

Large observational studies of COVID-19 survivors have indicated an increased risk of cardiovascular disease compared to the general population, including the risk of coronary artery disease, cardiomyopathy, and arrhythmias. Management of long COVID is focused on supportive therapy to reduce systemic inflammation. Patients with high cardiovascular risk, namely, those who had cardiovascular complications during acute illness, patients who have new onset cardiopulmonary symptoms in the postinfectious period, and competitive athletes, should be evaluated by a cardiovascular specialist.

Management of cardiovascular sequelae is currently based on general expert guideline recommendations given the lack of evidence specific to long COVID syndrome. In this review, we outline the cardiovascular manifestations of long COVID, the current evidence supporting cardiac abnormalities in the postinfectious period, and the recommended management of these patients.

Source: Lorente-Ros M, Das S, Elias J, Frishman WH, Aronow WS. Cardiovascular Manifestations of the Long COVID Syndrome. Cardiol Rev. 2023 Apr 10. doi: 10.1097/CRD.0000000000000552. Epub ahead of print. PMID: 37071080.

Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis

Abstract:

Background: Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, the correlation between IL-6 and long COVID-19 is unknown. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19.

Methods: Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran’s Q test and the Higgins I-squared (I2) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger’s test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results.

Results: An increase in IL-6 levels was observed after SARS-CoV-2 infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30-32.54 pg/ml, I2 = 100%, P < 0.01) for long COVID-19 patients. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75-13.75 pg/ml, I2 = 100%, P < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22-6.42 pg/ml, I2 = 88%, P = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups.

Conclusions: This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on the “early stage” of long COVID-19.

Source: Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty. 2023 Apr 24;12(1):43. doi: 10.1186/s40249-023-01086-z. PMID: 37095536; PMCID: PMC10123579. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123579/ (Full text)

Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection

Abstract:

Background and Objectives SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC).

Methods Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology.

Results Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3–12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses.

Discussion CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.

Source: Yair Mina, Yoshimi Enose-Akahata, Dima A. Hammoud, Anthony J. Videckis, Sandeep R. Narpala, Sarah E. O’Connell, Robin Carroll, Bob C. Lin, Cynthia Chen McMahan, Govind Nair, Lauren B. Reoma, Adrian B. McDermott, Brian Walitt, Steven Jacobson, David S. Goldstein, Bryan R. Smith, Avindra Nath. Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection. Neurol Neuroimmunol Neuroinflamm Jul 2023, 10 (4) e200097; DOI: 10.1212/NXI.0000000000200097 

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis

Abstract:

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes.

Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy.

This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

Source: Achleitner, M., Steenblock, C., Dänhardt, J. et al. Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02084-1 https://www.nature.com/articles/s41380-023-02084-1 (Full text)

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome

Abstract:

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear.

We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET.

PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated.

In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Source: Singh I, Leitner BP, Wang Y, Zhang H, Joseph P, Lutchmansingh DD, Gulati M, Possick JD, Damsky W, Hwa J, Heerdt PM, Chun HJ. Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. Pulm Circ. 2023 Apr 1;13(2):e12220. doi: 10.1002/pul2.12220. PMID: 37091121; PMCID: PMC10113513. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113513/ (Full text)