Tag: review

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 COVID: post-acute sequelae of COVID-19 with a cardiovascular focus

Abstract:

Emerging as a new epidemic, long COVID or post-acute sequelae of coronavirus disease 2019 (COVID-19), a condition characterized by the persistence of COVID-19 symptoms beyond 3 months, is anticipated to substantially alter the lives of millions of people globally. Cardiopulmonary symptoms including chest pain, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia are common and associated with significant disability, heightened anxiety, and public awareness. A range of cardiovascular (CV) abnormalities has been reported among patients beyond the acute phase and include myocardial inflammation, myocardial infarction, right ventricular dysfunction, and arrhythmias.

Pathophysiological mechanisms for delayed complications are still poorly understood, with a dissociation seen between ongoing symptoms and objective measures of cardiopulmonary health. COVID-19 is anticipated to alter the long-term trajectory of many chronic cardiac diseases which are abundant in those at risk of severe disease.

In this review, we discuss the definition of long COVID and its epidemiology, with an emphasis on cardiopulmonary symptoms. We further review the pathophysiological mechanisms underlying acute and chronic CV injury, the range of post-acute CV sequelae, and impact of COVID-19 on multiorgan health. We propose a possible model for referral of post-COVID-19 patients to cardiac services and discuss future directions including research priorities and clinical trials that are currently underway to evaluate the efficacy of treatment strategies for long COVID and associated CV sequelae.

Source: Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022 Feb 18:ehac031. doi: 10.1093/eurheartj/ehac031. Epub ahead of print. PMID: 35176758. https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehac031/6529562 (Full text)

Neurological manifestations of long-COVID syndrome: a narrative review

Abstract:

Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for ‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data.

The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae.

In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.

Source: Stefanou M-I, Palaiodimou L, Bakola E, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Therapeutic Advances in Chronic Disease. January 2022. doi:10.1177/20406223221076890 https://journals.sagepub.com/doi/full/10.1177/20406223221076890 (Full text)

Is It Useful to Question the Recovery Behaviour of Patients with ME/CFS or Long COVID?

Abstract:

For the last few decades, medical guidelines have recommended treating patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with graded exercise therapy (GET) and cognitive behavioural therapy (CBT). Moreover, doctors have questioned the recovery behaviour of these patients and stimulated them to follow these treatments so that they would be able to go back to work. In this article, we reviewed trials of GET and CBT for ME/CFS that reported on work status before and after treatment to answer the question of whether doctors should continue to question the recovery behaviour of patients with ME/CFS.

Our review shows that more patients are unable to work after treatment than before treatment with CBT and GET. It also highlights the fact that both treatments are unsafe for patients with ME/CFS. Therefore, questioning the recovery behaviour of patients with ME/CFS is pointless. This confirms the conclusion from the British National Institute for Health and Care Excellence (NICE), which has recently published its updated ME/CFS guideline and concluded that CBT and GET are not effective and do not lead to recovery.

Studies on CBT and GET for long COVID have not yet been published. However, this review offers no support for their use in improving the recovery of patients with an ME/CFS-like illness after infection with COVID-19, nor does it lend any support to the practice of questioning the recovery behaviour of these patients.

Source: Vink M, Vink-Niese F. Is It Useful to Question the Recovery Behaviour of Patients with ME/CFS or Long COVID? Healthcare (Basel). 2022 Feb 18;10(2):392. doi: 10.3390/healthcare10020392. PMID: 35207003. https://www.mdpi.com/2227-9032/10/2/392 (Full text)

Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects

Abstract:

Several diseases (such as diabetes, cancer, and neurodegenerative disorders) affect the morpho-functional aspects of red blood cells, sometimes altering their normal metabolism. In this review, the hematological changes are evaluated, with particular focus on the morphology and metabolic aspects of erythrocytes. Changes in the functionality of such cells may, in fact, help provide important information about disease severity and progression. The viral infection causes significant damage to the blood cells that are altered in size, rigidity, and distribution width. Lower levels of hemoglobin and anemia have been reported in several studies, and an alteration in the concentration of antioxidant enzymes has been shown to promote a dangerous state of oxidative stress in red blood cells.
Patients with severe COVID-19 showed an increase in hematological changes, indicating a progressive worsening as COVID-19 severity progressed. Therefore, monitored hematological alterations in patients with COVID-19 may play an important role in the management of the disease and prevent the risk of a severe course of the disease. Finally, monitored changes in erythrocytes and blood, in general, may be one of the causes of the condition known as Long COVID.
Source: Russo A, Tellone E, Barreca D, Ficarra S, Laganà G. Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects. International Journal of Molecular Sciences. 2022; 23(4):2171. https://doi.org/10.3390/ijms23042171 https://www.mdpi.com/1422-0067/23/4/2171/htm (Full text)

Long-COVID diagnosis: From diagnostic to advanced AI-driven models

Abstract:

SARS-COV 2 is recognized to be responsible for a multi-organ syndrome. In most patients, symptoms are mild. However, in certain subjects, COVID-19 tends to progress more severely. Most of the patients infected with SARS-COV2 fully recovered within some weeks. In a considerable number of patients, like many other viral infections, various long-lasting symptoms have been described, now defined as “long COVID-19 syndrome”. Given the high number of contagious over the world, it is necessary to understand and comprehend this emerging pathology to enable early diagnosis and improve patents outcomes.

In this scenario, AI-based models can be applied in long-COVID-19 patients to assist clinicians and at the same time, to reduce the considerable impact on the care and rehabilitation unit. The purpose of this manuscript is to review different aspects of long-COVID-19 syndrome from clinical presentation to diagnosis, highlighting the considerable impact that AI can have.

Source: Cau R, Faa G, Nardi V, Balestrieri A, Puig J, Suri JS, SanFilippo R, Saba L. Long-COVID diagnosis: From diagnostic to advanced AI-driven models. Eur J Radiol. 2022 Jan 19;148:110164. doi: 10.1016/j.ejrad.2022.110164. Epub ahead of print. PMID: 35114535; PMCID: PMC8791239. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791239/ (Full text)

Pathological sequelae of long-haul COVID

Abstract:

The world continues to contend with successive waves of coronavirus disease 2019 (COVID-19), fueled by the emergence of viral variants. At the same time, persistent, prolonged and often debilitating sequelae are increasingly recognized in convalescent individuals, named ‘post-COVID-19 syndrome’ or ‘long-haul COVID’. Clinical symptomatology includes fatigue, malaise, dyspnea, defects in memory and concentration and a variety of neuropsychiatric syndromes as the major manifestations, and several organ systems can be involved. The underlying pathophysiological mechanisms are poorly understood at present.

This Review details organ-specific sequelae of post-COVID-19 syndromes and examines the underlying pathophysiological mechanisms available so far, elaborating on persistent inflammation, induced autoimmunity and putative viral reservoirs. Finally, we propose diagnostic strategies to better understand this heterogeneous disorder that continues to afflict millions of people worldwide.

Source: Mehandru, S., Merad, M. Pathological sequelae of long-haul COVID. Nat Immunol (2022). https://doi.org/10.1038/s41590-021-01104-y https://www.nature.com/articles/s41590-021-01104-y (Full text)

Commonalities in the Features of Cancer and Chronic Fatigue Syndrome (CFS): Evidence for Stress-Induced Phenotype Instability?

Abstract:

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Cancer-Related Fatigue (CRF) are syndromes with considerable overlap with respect to symptoms. There have been many studies that have compared the two conditions, and some of this research suggests that the etiologies of the conditions are linked in some cases. In this narrative review, CFS/ME and cancer are introduced, along with their known and putative mechanistic connections to multiple stressors including ionizing radiation.

Next, we summarize findings from the literature that suggest the involvement of HPA-axis dysfunction, the serotonergic system, cytokines and inflammation, metabolic insufficiency and mitochondrial dysfunction, and genetic changes in CRF and CFS/ME. We further suspect that the manifestation of fatigue in both diseases and its causes could indicate that CRF and CFS/ME lie on a continuum of potential biological effects which occur in response to stress. The response to this stress likely varies depending on predisposing factors such as genetic background.

Finally, future research ideas are suggested with a focus on determining if common biomarkers exist in CFS/ME patients and those afflicted with CRF. Both CFS/ME and CRF are relatively heterogenous syndromes, however, it is our hope that this review assists in future research attempting to elucidate the commonalities between CRF and CFS/ME.

Source: Rusin A, Seymour C, Cocchetto A, Mothersill C. Commonalities in the Features of Cancer and Chronic Fatigue Syndrome (CFS): Evidence for Stress-Induced Phenotype Instability? Int J Mol Sci. 2022 Jan 8;23(2):691. doi: 10.3390/ijms23020691. PMID: 35054876. https://pubmed.ncbi.nlm.nih.gov/35054876/

The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract:

Myalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear. The gut microbiome gained much attention in the last decade with manifold implications in health and disease. Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed.

We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses. Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS. Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway. We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations. Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria. Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients.

Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies. Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated.

Source: König RS, Albrich WC, Kahlert CR, Bahr LS, Löber U, Vernazza P, Scheibenbogen C, Forslund SK. The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Front Immunol. 2022 Jan 3;12:628741. doi: 10.3389/fimmu.2021.628741. PMID: 35046929; PMCID: PMC8761622. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761622/ (Full text)

 

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms.
These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.
Source: James N. Baraniuk. Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM) Brain Sci. 2022, 12(2), 132; https://doi.org/10.3390/brainsci12020132 (registering DOI) https://www.mdpi.com/2076-3425/12/2/132/htm (Full text)