Category: Overlapping Illnesses

Post-acute COVID-19 syndrome presented as a cerebral and systemic vasculitis: a case report

To the Editor,

Post-acute Coronavirus Disease of 2019 (COVID-19) syndrome is defined as the appearance of symptoms or an organ dysfunction, which occurs at least 4 weeks after the first COVID-19 manifestations and cannot be explained by any alternative diagnosis []. Neurological complications are also well recognized, and include acute cerebrovascular events, encephalopathy, meningoencephalitis, Guillain–Barre syndrome, demyelination, dementia, parkinsonism, and others []. On the other hand, cerebral vasculitis is one of the causes which can lead to brain damage related to COVID-19 infection []. We present a 69-year-old male with systemic vasculitis and central nervous system (CNS) involvement as a manifestation of post-acute COVID-19 syndrome.

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Source: Ivanovic, Jovana et al. “Post-acute COVID-19 syndrome presented as a cerebral and systemic vasculitis: a case report.” Acta neurologica Belgica, 1–3. 13 Mar. 2022, doi:10.1007/s13760-022-01923-2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8918071/ (Full text)

Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach

Abstract:

Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME/CFS in our recent review papers.

One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium-proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+/K+ATPase activity.

High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium-calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs.

Source: Wirth KJ, Scheibenbogen C. Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach. Medicina (Kaunas). 2022 Mar 12;58(3):419. doi: 10.3390/medicina58030419. PMID: 35334595. https://www.mdpi.com/1648-9144/58/3/419/htm (Full text)

Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study

Abstract:

Background: Estimations of Lyme disease incidence rates in the United Kingdom vary. There is evidence that this disease is associated with fatigue in its early stage but reports are contradictory as far as long-term fatigue is concerned.

Methods and findings: A population-based historical cohort study was conducted on patients treated in general practices contributing to IQVIA Medical Research Data: 2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018 and 8,510 randomly-sampled patients matched by age, sex, and general practice, followed-up for a median time of 3 years and 8 months. Main outcome measure was time to consultation for (1) any fatigue-related symptoms or diagnosis; or (2) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models. Average incidence rate for Lyme disease across the UK was 5.18 per 100,000 person-years, increasing from 2.55 in 2000 to 9.33 in 2018. In total, 929 events of any types of fatigue were observed, leading to an incidence rate of 307.90 per 10,000 person-years in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season: adjusted HRs were the highest in autumn and winter with 3.14 (95%CI: 1.92-5.13) and 2.23 (1.21-4.11), respectively. For ME/CFS, 17 events were observed in total. Incidence rates were 11.76 per 10,000 person-years in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17-55.60). Effects were attenuated 6 months after diagnosis but still clearly visible.

Conclusions: UK primary care records provided strong evidence that Lyme disease was associated with subsequent fatigue and ME/CFS. Albeit weaker on the long-term, these effects persisted beyond 6 months, suggesting patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.

Source: Brellier F, Pujades-Rodriguez M, Powell E, Mudie K, Mattos Lacerda E, Nacul L, Wing K. Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study. PLoS One. 2022 Mar 23;17(3):e0265765. doi: 10.1371/journal.pone.0265765. PMID: 35320297; PMCID: PMC8942220. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265765 (Full text)

Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS

Abstract

Purpose of Review: To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management.

Recent Findings: The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis.

Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning.

The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance).

Summary: We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments.

At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms.

Source: Morrow, A.K., Malone, L.A., Kokorelis, C. et al. Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS. Curr Pediatr Rep (2022). https://doi.org/10.1007/s40124-022-00261-4  (Full text)

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.

Methods: We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.

Results: Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.

Conclusion: A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

Source: Haffke M, Freitag H, Rudolf G, Seifert M, Doehner W, Scherbakov N, Hanitsch L, Wittke K, Bauer S, Konietschke F, Paul F, Bellmann-Strobl J, Kedor C, Scheibenbogen C, Sotzny F. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS). J Transl Med. 2022 Mar 22;20(1):138. doi: 10.1186/s12967-022-03346-2. PMID: 35317812. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03346-2 (Full text)

Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS

Abstract:

Purpose of review: To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management.

Recent findings: The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning. The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance).

Summary: We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments. At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms.

Supplementary information: The online version contains supplementary material available at 10.1007/s40124-022-00261-4.

Source: Morrow AK, Malone LA, Kokorelis C, Petracek LS, Eastin EF, Lobner KL, Neuendorff L, Rowe PC. Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS. Curr Pediatr Rep. 2022 Mar 9:1-14. doi: 10.1007/s40124-022-00261-4. Epub ahead of print. PMID: 35287333; PMCID: PMC8906524. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906524/ (Full text)

Long-term immunologic effects of SARS-CoV-2 infection: leveraging translational research methodology to address emerging questions

Abstract:

The current era of COVID-19 is characterized by emerging variants of concern, waning vaccine- and natural infection-induced immunity, debate over the timing and necessity of vaccine boosting, and the emergence of post-acute sequelae of SARS-CoV-2 infection. As a result, there is an ongoing need for research to promote understanding of the immunology of both natural infection and prevention, especially as SARS-CoV-2 immunology is a rapidly changing field, with new questions arising as the pandemic continues to grow in complexity.

The next phase of COVID-19 immunology research will need focus on clearer characterization of the immune processes defining acute illness, development of a better understanding of the immunologic processes driving protracted symptoms and prolonged recovery (ie, post-acute sequelae of SARS-CoV-2 infection), and a growing focus on the impact of therapeutic and prophylactic interventions on the long-term consequences of SARS-CoV-2 infection.

In this review, we address what is known about the long-term immune consequences of SARS-CoV-2 infection and propose how experience studying the translational immunology of other infections might inform the approach to some of the key questions that remain.

Source: Peluso MJ, Donatelli J, Henrich TJ. Long-term immunologic effects of SARS-CoV-2 infection: leveraging translational research methodology to address emerging questions. Transl Res. 2022 Mar;241:1-12. doi: 10.1016/j.trsl.2021.11.006. Epub 2021 Nov 12. PMID: 34780969; PMCID: PMC8588584.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588584/ (Full text)

Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations

Abstract:

BACKGROUND. After the initial surge in COVID-19 cases, large numbers of patients were discharged from a hospital without assessment of recovery. Now, an increasing number of patients report postacute neurological sequelae, known as “long COVID” — even those without specific neurological manifestations in the acute phase.

METHODS. Dynamic brain changes are crucial for a better understanding and early prevention of “long COVID.” Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.

RESULTS. Overall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.

CONCLUSION. Our study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of “long COVID” and early clinical guidance toward complete recovery.

Source: Tian Tian, et al. Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations. Published February 22, 2022
Citation Information: JCI Insight. 2022;7(4):e155827. https://doi.org/10.1172/jci.insight.155827. (Full text)

Long COVID 12 months after discharge: persistent symptoms in patients hospitalised due to COVID-19 and patients hospitalised due to other causes—a multicentre cohort study

Abstract:

Background: Long-term-specific sequelae or persistent symptoms (SPS) after hospitalisation due to COVID-19 are not known. The aim of this study was to explore the presence of SPS 12 months after discharge in survivors hospitalised due to COVID-19 and compare it with survivors hospitalised due to other causes.

Methods: Prospective cohort study, the Andalusian Cohort of Hospitalised patients for COVID-19 (ANCOHVID study), conducted in 4 hospitals and 29 primary care centres in Andalusia, Spain. The sample was composed of 906 adult patients; 453 patients hospitalised due to COVID-19 (exposed) and 453 hospitalised due to other causes (non-exposed) from March 1 to April 15, 2020, and discharged alive. The main outcomes were (1) the prevalence of SPS at 12 months after discharge and (2) the incidence of SPS after discharge. Outcome data at 12 months were compared between the exposed and non-exposed cohorts. Risk ratios were calculated, and bivariate analyses were performed.

Results: A total of 163 (36.1%) and 160 (35.3%) patients of the exposed and non-exposed cohorts, respectively, showed at least one SPS at 12 months after discharge. The SPS with higher prevalence in the subgroup of patients hospitalised due to COVID-19 12 months after discharge were persistent pharyngeal symptoms (p<0.001), neurological SPS (p=0.049), confusion or memory loss (p=0.043), thrombotic events (p=0.025) and anxiety (p=0.046). The incidence of SPS was higher for the exposed cohort regarding pharyngeal symptoms (risk ratio, 8.00; 95% CI, 1.85 to 36.12), confusion or memory loss (risk ratio, 3.50; 95% CI, 1.16 to 10.55) and anxiety symptoms (risk ratio, 2.36; 95% CI, 1.28 to 4.34).

Conclusions: There was a similar frequency of long-term SPS after discharge at 12 months, regardless of the cause of admission (COVID-19 or other causes). Nevertheless, some symptoms that were found to be more associated with COVID-19, such as memory loss or anxiety, merit further investigation. These results should guide future follow-up of COVID-19 patients after hospital discharge.

Source: Rivera-Izquierdo, M., Láinez-Ramos-Bossini, A.J., de Alba, I.GF. et al. Long COVID 12 months after discharge: persistent symptoms in patients hospitalised due to COVID-19 and patients hospitalised due to other causes—a multicentre cohort study. BMC Med 20, 92 (2022). https://doi.org/10.1186/s12916-022-02292-6  (Full text)

Neural Dysregulation in Post-Covid Fatigue

Abstract:

Following infection from SARS-CoV-2, a substantial minority of people develop lingering after-effects known as ‘long COVID’. Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear. We recruited volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems. In comparison to age and gender matched volunteers without fatigue, we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscles. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. These abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time.

Source: Anne M.E. Baker, Natalie J. Maffitt, Alessandro Del Vecchio, Katherine M. McKeating, Mark R. Baker, Stuart N. Baker, Demetris S. Soteropoulos. Neural Dysregulation in Post-Covid Fatigue.
medRxiv 2022.02.18.22271040; doi: https://doi.org/10.1101/2022.02.18.22271040 https://www.medrxiv.org/content/10.1101/2022.02.18.22271040v1.full-text (Full text)