Category: Overlapping Illnesses

The association between the number of symptoms and the severity of Post-COVID-Fatigue after SARS-CoV-2 infection treated in an outpatient setting

Abstract:

Background: Post-COVID-Fatigue (PCF) is one of the most reported symptoms following SARS-CoV-2 infection. Currently, research on persistent symptoms focuses mainly on severe infections, while outpatients are rarely included in observations.

Objective: To investigate whether the severity of PCF is related to the number of acute and persistent symptoms due to mild-to-moderate COVID-19 and to compare the most common symptoms during acute infection with the persistent symptoms in PCF patients.

Methods: A total of 425 participants were examined after COVID-19 treated as an outpatient (median 249 days [IQR: 135; 322] after acute disease) at the site of University Hospital Augsburg, Germany. The Fatigue Assessment Scale (FAS) was used to quantify the severity of PCF. The number of symptoms (maximum 41) during acute infection and persistent symptoms (during the last 14 days before examination) were added up to sum scores. Multivariable linear regression models were used to show the association between the number of symptoms and PCF.

Results: Of the 425 participants, 37% (n = 157) developed PCF; most were women (70%). The median number of symptoms was significantly higher in the PCF group than in the non-PCF group at both time points. In multivariable linear regression models, both sum scores were associated with PCF (acute symptoms: β-estimate per additional symptom [95%-CI]: 0.48 [0.39; 0.57], p < 0.0001); persistent symptoms: β-estimate per additional symptom [95%-CI]: 1.18 [1.02; 1.34], p < 0.0001). The acute symptoms strongest associated with PCF severity were difficulty concentrating, memory problems, dyspnea or shortness of breath on exertion, palpitations, and problems with movement coordination.

Conclusion: Each additional symptom that occurs in COVID-19 increases the likelihood of suffering a higher severity of PCF. Further research is needed to identify the aetiology of PCF.

Source: Schmidbauer L, Kirchberger I, Goßlau Y, Warm TD, Hyhlik-Dürr A, Linseisen J, Meisinger C. The association between the number of symptoms and the severity of Post-COVID-Fatigue after SARS-CoV-2 infection treated in an outpatient setting. J Neurol. 2023 May 23:1–9. doi: 10.1007/s00415-023-11752-9. Epub ahead of print. PMID: 37219607; PMCID: PMC10204671. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204671/ (Full text)

Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of “long-COVID” patients

Abstract:

Several disabling symptoms potentially related to dysautonomia have been reported in “long-COVID” patients. Unfortunately, these symptoms are often nonspecific, and autonomic nervous system explorations are rarely performed in these patients. This study aimed to evaluate prospectively a cohort of long-COVID patients presenting severe disabling and non-relapsing symptoms of potential dysautonomia and to identify sensitive tests.

Autonomic function was assessed by clinical examination, the Schirmer test; sudomotor evaluation, orthostatic blood pressure (BP) variation, 24-h ambulatory BP monitoring for sympathetic evaluation, and heart rate variation during orthostatism, deep breathing and Valsalva maneuvers for parasympathetic evaluation. Test results were considered abnormal if they reached the lower thresholds defined in publications and in our department. We also compared mean values for autonomic function tests between patients and age-matched controls.

Sixteen patients (median age 37 years [31–43 years], 15 women) were included in this study and referred 14.5 months (median) [12.0–16.5 months] after initial infection. Nine had at least one positive SARS-CoV-2 RT-PCR or serology result. Symptoms after SARS-CoV-2 infection were severe, fluctuating and disabling with effort intolerance. Six patients (37.5%) had one or several abnormal test results, affecting the parasympathetic cardiac function in five of them (31%). Mean Valsalva score was significantly lower in patients than in controls.

In this cohort of severely disabled long-COVID patients, 37.5% of them had at least one abnormal test result showing a possible contribution of dysautonomia to these nonspecific symptoms. Interestingly, mean values of the Valsalva test were significantly lower in patients than in control subjects, suggesting that normal values thresholds might not be appropriate in this population.

Source: Zanin, A., Amah, G., Chakroun, S. et al. Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of “long-COVID” patients. Sci Rep 13, 8251 (2023). https://doi.org/10.1038/s41598-023-35086-8 https://www.nature.com/articles/s41598-023-35086-8 (Full text)

Multidisciplinary Center Care for Long COVID Syndrome – a Retrospective Cohort Study

Abstract:

Background: Persistent multi-organ symptoms after COVID-19 have been termed “long COVID” or “post-acute sequelae of SARS-CoV-2 infection” (PASC). The complexity of these clinical manifestations posed challenges early in the pandemic as different ambulatory models formed out of necessity to manage the influx of patients. Little is known about the characteristics and outcomes of patients seeking care at multidisciplinary post-COVID centers.

Methods: We performed a retrospective cohort study of patients evaluated at our multidisciplinary Comprehensive COVID-19 Center (CCC) in Chicago, IL, between May 2020 and February 2022. We analyzed specialty clinic utilization and clinical test results according to severity of acute COVID-19.

Results: We evaluated 1802 patients a median of 8 months from acute COVID-19 onset, including 350 post-hospitalization and 1452 non-hospitalized patients. Patients were seen in 2361 initial visits in 12 specialty clinics, with 1151 (48.8%) in neurology, 591 (25%) in pulmonology, and 284 (12%) in cardiology. Among patients tested, 742/878(85%) reported decreased quality of life, 284/553(51%) had cognitive impairment, 195/434(44.9%) had alteration of lung function, 249/299(83.3%) had abnormal CT chest scans, and 14/116(12.1%) had elevated heart rate on rhythm monitoring. Frequency of cognitive impairment and pulmonary dysfunction was associated with severity of acute COVID-19. Non-hospitalized patients with positive SARS-CoV-2 testing had similar findings than those with negative or no test results.

Conclusions: The CCC experience shows common utilization of multiple specialists by long COVID patients, who harbor frequent neurologic, pulmonary, and cardiologic abnormalities. Differences in post-hospitalization and non-hospitalized groups suggest distinct pathogenic mechanisms of long COVID in these populations.

Source: Bailey J, Lavelle B, Miller J, Jimenez M, Lim PH, Orban ZS, Clark JR, Tomar R, Ludwig A, Ali ST, Lank GK, Zielinski A, Mylvaganam R, Kalhan R, Muayed ME, Mutharasan RK, Liotta EM, Sznajder JI, Davidson C, Koralnik IJ, Sala MA; Northwestern Medicine Comprehensive COVID Center Investigators. Multidisciplinary Center Care for Long COVID Syndrome – a Retrospective Cohort Study. Am J Med. 2023 May 21:S0002-9343(23)00328-5. doi: 10.1016/j.amjmed.2023.05.002. Epub ahead of print. PMID: 37220832; PMCID: PMC10200714. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200714/ (Full text)

Ginkgo Biloba and Long COVID: In Vivo and In Vitro Models for the Evaluation of Nanotherapeutic Efficacy

Abstract:

Coronavirus infections are neuroinvasive and can provoke injury to the central nervous system (CNS) and long-term illness consequences. They may be associated with inflammatory processes due to cellular oxidative stress and an imbalanced antioxidant system. The ability of phytochemicals with antioxidant and anti-inflammatory activities, such as Ginkgo biloba, to alleviate neurological complications and brain tissue damage has attracted strong ongoing interest in the neurotherapeutic management of long COVID.
Ginkgo biloba leaf extract (EGb) contains several bioactive ingredients, e.g., bilobalide, quercetin, ginkgolides A–C, kaempferol, isorhamnetin, and luteolin. They have various pharmacological and medicinal effects, including memory and cognitive improvement. Ginkgo biloba, through its anti-apoptotic, antioxidant, and anti-inflammatory activities, impacts cognitive function and other illness conditions like those in long COVID. While preclinical research on the antioxidant therapies for neuroprotection has shown promising results, clinical translation remains slow due to several challenges (e.g., low drug bioavailability, limited half-life, instability, restricted delivery to target tissues, and poor antioxidant capacity).
This review emphasizes the advantages of nanotherapies using nanoparticle drug delivery approaches to overcome these challenges. Various experimental techniques shed light on the molecular mechanisms underlying the oxidative stress response in the nervous system and help comprehend the pathophysiology of the neurological sequelae of SARS-CoV-2 infection.
To develop novel therapeutic agents and drug delivery systems, several methods for mimicking oxidative stress conditions have been used (e.g., lipid peroxidation products, mitochondrial respiratory chain inhibitors, and models of ischemic brain damage). We hypothesize the beneficial effects of EGb in the neurotherapeutic management of long-term COVID-19 symptoms, evaluated using either in vitro cellular or in vivo animal models of oxidative stress.
Source: Akanchise T, Angelova A. Ginkgo Biloba and Long COVID: In Vivo and In Vitro Models for the Evaluation of Nanotherapeutic Efficacy. Pharmaceutics. 2023; 15(5):1562. https://doi.org/10.3390/pharmaceutics15051562 https://www.mdpi.com/1999-4923/15/5/1562 (Full text)

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Abstract:

Background: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.

Methods: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n=41, matched out of n = 204).

Measurements and main results: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vmax; 3.42% ± 1.77% vs. 4.64 % ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5 – 190.2] vs. 189.1 [179.4 – 197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8 – 0.9] vs. 0.88 [0.8 – 0.9], p = 0.007). When combining AVR and vmax, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R= -0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.

Conclusion: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.

Source: Timon Kuchler, Roman Günthner, Andrea Ribeiro et al. Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation, 22 May 2023, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2952588/v1 (Full text)

De-black-boxing health AI: demonstrating reproducible machine learning computable phenotypes using the N3C-RECOVER Long COVID model in the All of Us data repository

Abstract:

Machine learning (ML)-driven computable phenotypes are among the most challenging to share and reproduce. Despite this difficulty, the urgent public health considerations around Long COVID make it especially important to ensure the rigor and reproducibility of Long COVID phenotyping algorithms such that they can be made available to a broad audience of researchers. As part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative, researchers with the National COVID Cohort Collaborative (N3C) devised and trained an ML-based phenotype to identify patients highly probable to have Long COVID. Supported by RECOVER, N3C and NIH’s All of Us study partnered to reproduce the output of N3C’s trained model in the All of Us data enclave, demonstrating model extensibility in multiple environments. This case study in ML-based phenotype reuse illustrates how open-source software best practices and cross-site collaboration can de-black-box phenotyping algorithms, prevent unnecessary rework, and promote open science in informatics.

Source: Pfaff ER, Girvin AT, Crosskey M, Gangireddy S, Master H, Wei WQ, Kerchberger VE, Weiner M, Harris PA, Basford M, Lunt C, Chute CG, Moffitt RA, Haendel M; N3C and RECOVER Consortia. De-black-boxing health AI: demonstrating reproducible machine learning computable phenotypes using the N3C-RECOVER Long COVID model in the All of Us data repository. J Am Med Inform Assoc. 2023 May 22:ocad077. doi: 10.1093/jamia/ocad077. Epub ahead of print. PMID: 37218289. https://pubmed.ncbi.nlm.nih.gov/37218289/

The Renin-Angiotensin-System in COVID-19: Can Long COVID Be Predicted?

Abstract:

(1) Background: Co-morbidities such as hypertension and cardiovascular disease are major risk factors for severe COVID-19. The renin-angiotensin-system (RAS) is critically involved in their pathophysiology and is counterbalanced by both angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and the kallikrein-kinin-system (KKS). Considerable research interest with respect to COVID-19 treatment is, thus, currently directed towards the components of these systems. In an earlier study, we noticed significantly reduced carboxypeptidase N (CPN, KKS member) activity and partially excessive angiotensin-converting enzyme (ACE, RAS member) activity in the sera of both hospitalized (HoP) COVID-19 patients and a sub-group of covalescent patients, while in the majority of the probands recovering from the disease these values had returned to normal. The data had been obtained using bradykinin (BK) as a reporter peptide, which is a target of both CPN and ACE, and they were supplemented by serum proteomics of the same patient cohort. We hypothesized that the data could be indicative of Long COVID, which had not been fully appreciated at the time of our study.;

(2) Methods: The data were re-evaluated in the light of Long COVID. The recent literature on the RAS in COVID-19, antihypertensiva, and Long COVID was briefly reviewed.;

(3) Results: While the levels of the BK serum degradation products should return to normal concentrations during convalescence, this was not true for some patients. This could be due to persisting liver problems, because CPN is synthesized there, but also to a dysregulated RAS. This was not reflected in the levels of selected RAS/KKS serum proteins like angiotensinogen (AGT), although AGT correlated with disease severity in HoP. However, standard tests in routine patient care in Long COVID often come back normal, and it may be that BK degradation is specific in some pathophysiologies. Moreover, the HoP group was sub-divided based on the serum protein profiles and COVID-19 severity.;

(4) Conclusions: We point out two insights: 1) Sensitive technology such as omics methods might provide unexpected significant differences within the pre-defined patient groups of a clinical study. Those can only be explored, if the cohorts are large enough and properly matched with respect to the parameters known beforehand (e.g., age, gender, co-morbidities). 2) Results of the BK-reporter serum protease activity assay could be indicative of persisting liver problems and/or potentially of Long COVID. Clinical studies are required to test this hypothesis.

Source: König, S.; Vollenberg, R.; Tepasse, P. The Renin-Angiotensin-System in COVID-19: Can Long COVID Be Predicted?. Preprints.org 2023, 2023051298. https://doi.org/10.20944/preprints202305.1298.v1 (Full text available as PDF file)

Long COVID: An Epidemic within the Pandemic

Introduction:

Coronavirus disease 2019 (COVID-19), a life-threatening infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in the Chinese city of Wuhan in late 2019 and has subsequently spread worldwide, reaching pandemic proportions [1]. At the time of writing (i.e., May 2023), COVID-19 has already caused nearly 7 million official deaths, according to World Health Organization (WHO) statistics [2]. Although the WHO COVID-19 emergency committee recently decided to no longer classify COVID-19 as an international public health emergency, SARS-CoV-2 infections and/or reinfections still cause a large number of deaths worldwide, with an excess mortality still estimated at approximately 10,000 deaths per day [3]. In addition to the still significant organic injuries that can develop during an acute SARS-CoV-2 infection, particularly in frail, old and unvaccinated individuals, there is now established evidence that the so-called post-viral syndrome (i.e., a common consequence of many viral infections encompassing a kaleidoscope of organic and psychiatric disorders) [4] is a fairly common sequela of COVID-19 in officially recovered patients, variously termed “post-COVID”, “long-haul COVID”, “long COVID” and so forth.

Source: Mattiuzzi C, Lippi G. Long COVID: An Epidemic within the Pandemic. COVID. 2023; 3(5):773-776. https://doi.org/10.3390/covid3050057  (Full text)

First study results of the P4O2 long COVID cohort

Abstract:

Introduction: Several studies indicate that the acute phase of COVID-19 may be followed by persistent symptoms. However, the impact of COVID-19 on long-term health outcomes remains to be elucidated.

Aims: The Precision Medicine for more Oxygen (P4O2) COVID-19 study aims to identify long COVID patients that are that are at risk for developing chronic lung disease and to identify treatable traits and innovative personalized therapeutic strategies for prevention and treatment. This study describes the baseline characteristics of the P4O2 COVID-19 cohort.

Methods: Long COVID patients were recruited from 5 different hospitals in The Netherlands at 3-6 months post-COVID. Data from medical records and biological samples were collected, pulmonary function tests and chest computed tomography scans were performed and questionnaires were administered during 2 study visits.

Results: 95 long COVID patients were enrolled between May 2021 and September 2022. Study participants were aged 54.2 years on average and of female sex in 49.5% of all cases. Most patients were hospitalized(89.5%) for COVID-19 with a mean hospital stay duration of 8 days. The current study showed persistence of clinical symptoms and signs of pulmonary function test/radiological abnormalities in long COVID patients(81%). The most frequently reported symptom categories were respiratory(80%) and fatigue(69.5%). Both female sex and infection with the Delta, compared with the Beta, SARS-CoV-2 variant were significantly associated with more persisting symptoms.

Conclusions: The first descriptive results of the P4O2 COVID-19 cohort show that long COVID patients show signs of radiological/functional abnormalities and can suffer from a wide range of persisting symptoms.

Source: N Baalbaki, J Blankestijn, M Abdel-Aziz, J De Backer, S Bazdar, I Beekers, R Beijers, J Van Den Bergh, L Bloemsma, H J Bogaard, J Van Bragt, V Van Den Brink, J P Charbonnier, M Cornelissen, Y Dagelet, E H Davies, A Van Der Does, G Downward, C Van Drunen, D Gach, M Geelhoed, J Glastra, K Golebski, I Heijink, J Holtjer, S Holverda, L Houweling, J Jacobs, R Jonker, R Kos, R Langen, I Van Der Lee, A Leliveld, F Mohamed Hoesein, A Neerincx, L Noij, J Olsson, M Van De Pol, S Pouwels, E Rolink, M Rutgers, H Șahin, D Schaminee, A Schols, L Schuurman, P Skipp, G Slingers, O Smeenk, B Sondermeijer, M Tamarit, I Verkouter, R Vermeulen, R De Vries, E Weersink, M Van De Werken, Y De Wit-Van De Wijck, S Young, E Nossent, A Maitland-Van Der Zee. ERJ Open Research 2023 9: 68; DOI: 10.1183/23120541.LSC-2023.68 https://openres.ersjournals.com/content/9/suppl_10/68

 

Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID

Simple Summary:

In this study, we looked at how persistent inflammation affects peripheral body temperature and sympathovagal balance in individuals with long COVID. Increased temperature and reduced heart rate variability were directly related to the increase in inflammatory cytokines and reduction in anti-inflammatory cytokines. We identified a possible “molecular signature” for long COVID, characterised by a Th17 inflammatory profile with a reduced anti-inflammatory response, resulting in alterations in homeostatic functions and sympathovagal balance.

Abstract:

A persistent state of inflammation has been reported during the COVID-19 pandemic. This study aimed to assess short-term heart rate variability (HRV), peripheral body temperature, and serum cytokine levels in patients with long COVID. We evaluated 202 patients with long COVID symptoms categorized them according to the duration of their COVID symptoms (≤120 days, n = 81; >120 days, n = 121), in addition to 95 healthy individuals selected as controls.
All HRV variables differed significantly between the control group and patients with long COVID in the ≤120 days group (p < 0.05), and participants in the long COVID ≤120 days group had higher temperatures than those in the long COVID >120 days group in all regions analysed (p < 0.05).
Cytokine analysis showed higher levels of interleukin 17 (IL-17) and interleukin 2 (IL-2), and lower levels of interleukin 4 (IL-4) (p < 0.05). Our results suggest a reduction in parasympathetic activation during long COVID and an increase in body temperature due to possible endothelial damage caused by the maintenance of elevated levels of inflammatory mediators.
Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 appear to constitute a long-term profile of COVID-19 cytokines, and these markers are potential targets for long COVID-treatment and prevention strategies.
Source: Neves PFMd, Quaresma JAS, Queiroz MAF, Silva CC, Maia EV, Oliveira JSdS, Neves CMAd, Mendonça SdS, Falcão ASC, Melo GS, Santos IBF, Sousa JRd, Santos EJMd, Vasconcelos PFdC, Vallinoto ACR, Falcão LFM. Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID. Biology. 2023; 12(5):749. https://doi.org/10.3390/biology12050749 https://www.mdpi.com/2079-7737/12/5/749 (Full text)