Tag: post-infectious sequelae

Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis

Abstract:

Billions of years of co-evolution has made mitochondria central to the eukaryotic cell and organism life playing the role of cellular power plants, as indeed they are involved in most, if not all, important regulatory pathways. Neurological disorders depending on impaired mitochondrial function or homeostasis can be caused by the misregulation of “endogenous players”, such as nuclear or cytoplasmic regulators, which have been treated elsewhere. In this review, we focus on how exogenous agents, i.e., viral pathogens, or unbalanced microbiota in the gut-brain axis can also endanger mitochondrial dynamics in the central nervous system (CNS).

Neurotropic viruses such as Herpes, Rabies, West-Nile, and Polioviruses seem to hijack neuronal transport networks, commandeering the proteins that mitochondria typically use to move along neurites. However, several neurological complications are also associated to infections by pandemic viruses, such as Influenza A virus and SARS-CoV-2 coronavirus, representing a relevant risk associated to seasonal flu, coronavirus disease-19 (COVID-19) and “Long-COVID”.

Emerging evidence is depicting the gut microbiota as a source of signals, transmitted via sensory neurons innervating the gut, able to influence brain structure and function, including cognitive functions. Therefore, the direct connection between intestinal microbiota and mitochondrial functions might concur with the onset, progression, and severity of CNS diseases.

Source: Righetto I, Gasparotto M, Casalino L, Vacca M, Filippini F. Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis. Biomolecules. 2023 Jan 13;13(1):169. doi: 10.3390/biom13010169. PMID: 36671555; PMCID: PMC9855674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9855674/ (Full text)

Gastrointestinal and Hepatobiliary Symptoms and Disorders with Long (Chronic) COVID Infection

Abstract:

Long COVID is a novel syndrome characterizing new or persistent symptoms weeks after COVID-19 infection and involving multiple organ systems. This review summarizes the gastrointestinal and hepatobiliary sequelae of long COVID syndrome. It describes potential biomolecular mechanisms, prevalence, preventative measures, potential therapies, and health care and economic impact of long COVID syndrome, particularly of its gastrointestinal (GI) and hepatobiliary manifestations.

Source: Rizvi A, Ziv Y, Crawford JM, Trindade AJ. Gastrointestinal and Hepatobiliary Symptoms and Disorders with Long (Chronic) COVID Infection. Gastroenterol Clin North Am. 2023 Mar;52(1):139-156. doi: 10.1016/j.gtc.2022.09.002. PMID: 36813422; PMCID: PMC9940919. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940919/ (Full text)

COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients

Abstract:
Background: Better understanding of long-term health effects after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become one of the healthcare priorities in the current pandemic. We analyzed large and diverse patient cohort to study health effects related to SARS-CoV-2 infection occurring more than one month post-infection.
Methods: We analyzed 17,487 patients who received diagnoses for SARS-CoV-2 infection in a total of 122 healthcare facilities in the United States prior to April, 14,2022. Patients were propensity score matched with patients diagnosed with the common cold, influenza, or viral pneumonia from March 1, 2020, to April 1, 2021. For each outcome, SARS-CoV-2 was compared to a generic Viral Respiratory Infection (VRI) by predicting diagnoses in the period between 30 and 365 days post-infection. Both COVID-19 and VRI patients were propensity score matched with patients with no record of COVID-19 or VRI and the same methodology was applied. Diagnoses where COVID-19 infection was a significant positive predictor in both COVID-19 vs VRI and COVID-19 vs Control comparisons were considered COVID-19-specific effects.
Results: Compared to common VRIs, SARS-CoV-2 was associated with diagnoses palpitations, hair loss, fatigue, chest pain, dyspnea, joint pain, and obesity in the post-infectious period.
Conclusions: We identify that some diagnoses commonly described as “long COVID” do not appear significantly more frequent post-COVID-19 infection compared to other common VRIs. We also identify sequelae which are specifically associated with a prior SARS-CoV-2 infection.
Source: William I Baskett, MS, Adnan I Qureshi, MD, Daniel Shyu, MD, Jane M Armer, PhD, RN, Chi-Ren Shyu, PhD, COVID-Specific Long-Term Sequelae in Comparison to Common Viral Respiratory Infections: An Analysis of 17,487 Infected Adult Patients, Open Forum Infectious Diseases, 2022;, ofac683, https://doi.org/10.1093/ofid/ofac683 (Full text)

Autoimmune Autonomic Dysfunction Syndromes: Potential Involvement and Pathophysiology Related to Complex Regional Pain Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Silicone Breast Implant-Related Symptoms and Post-COVID Syndrome

Abstract:

The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant-related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them.

The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned.

Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant-related symptoms, and post-COVID syndrome, namely “autoimmune autonomic dysfunction syndromes”. Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.

Source: Mahroum N, Shoenfeld Y. Autoimmune Autonomic Dysfunction Syndromes: Potential Involvement and Pathophysiology Related to Complex Regional Pain Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Silicone Breast Implant-Related Symptoms and Post-COVID Syndrome. Pathophysiology. 2022 Jul 28;29(3):414-425. doi: 10.3390/pathophysiology29030033. PMID: 35997389. https://www.mdpi.com/1873-149X/29/3/33/htm (Full text)

Post-acute Sequelae of SARS-CoV-2 Infection: A Neglected Public Health Issue

Introduction:

The COVID-19 pandemic has caused at least 508,827,830 infections and is associated with a 1.2% mortality rate worldwide (). New SARS-CoV-2 variants have driven new waves of the pandemic as a result of their increased transmissibility and ability to evade the immune response (). The post-acute sequelae of SARS-CoV-2 infection (PASC) is an important but underestimated public health issue that can have a long-term impact on pulmonary and multiple extrapulmonary tissues and organs through several potential mechanisms (, ). Recent studies demonstrate that approximately 4–69% of patients (including children, adolescents, adults, and senior) suffer from PASC (–). There is considerable evidence concerning post-acute sequelae that will likely outlast the current pandemic and need to be addressed. This article reviews the clinical sequelae of COVID-19 survivors and provides valuable insights required to fill the gaps in medical knowledge.

Source: Wang Z, Yang L. Post-acute Sequelae of SARS-CoV-2 Infection: A Neglected Public Health Issue. Front Public Health. 2022 Jun 17;10:908757. doi: 10.3389/fpubh.2022.908757. PMID: 35784200; PMCID: PMC9247346. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9247346/ (Full text)

Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: a controlled prospective cohort study

Abstract:

Objectives: To investigate whether acute infection with Giardia lamblia is associated with fibromyalgia 10 years after infection and whether fibromyalgia is associated with irritable bowel syndrome (IBS) and chronic fatigue (CF) in this setting.

Methods: A cohort study was established after an outbreak of G. lamblia in Bergen, Norway, 2004. Laboratory-confirmed cases and a matched control group were followed for 10 years. The main outcome was fibromyalgia 10 years after giardiasis, defined by the 2016 revisions of the fibromyalgia diagnostic criteria using the Fibromyalgia Survey Questionnaire (FSQ).

Results: The prevalence of fibromyalgia was 8.6% (49/572) among Giardia exposed compared to 3.1% (21/673) in controls (p<0.001). Unadjusted odds for having fibromyalgia was higher for Giardia exposed compared to controls (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.72, 4.91), but adjusted for IBS and CF it was not (OR: 1.05, 95% CI: 0.57, 1.95). Among participants without CF the odds for fibromyalgia was 6.27 times higher for participants with IBS than those without (95% CI: 3.31, 11.91) regardless of exposure. Among participants without IBS the odds for fibromyalgia was 4.80 times higher for those with CF than those without (95% CI: 2.75, 8.37).

Conclusions: We found a higher prevalence of fibromyalgia among Giardia exposed compared to controls 10 years after the acute infection. Fibromyalgia was strongly associated with IBS and CF, and the difference between the exposed and controls can be attributed to the high prevalence of IBS and CF among the Giardia exposed. Notably, this study was not designed to establish causality between Giardia exposure and the outcomes.

Source: Hunskar GS, Rortveit G, Litleskare S, Eide GE, Hanevik K, Langeland N, Wensaas KA. Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: a controlled prospective cohort study. Scand J Pain. 2021 Oct 21;22(2):348-355. doi: 10.1515/sjpain-2021-0122. PMID: 34679267. https://www.degruyter.com/document/doi/10.1515/sjpain-2021-0122/html (Full text)

Unexplained post-acute infection syndromes

Abstract:

SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine.

The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis.

In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.

Source: Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat Med. 2022 May;28(5):911-923. doi: 10.1038/s41591-022-01810-6. Epub 2022 May 18. PMID: 35585196. https://www.nature.com/articles/s41591-022-01810-6 (Full text)

Small fiber neuropathy underlying dysautonomia in COVID-19 and in post-SARS-CoV-2 vaccination and long-COVID syndromes

Letter:

We eagerly read the excellent editorial by Gemignani and the corresponding original article by Abrams et al. about the suspected involvement of small fibers (small fiber neuropathy [SFN]) in acute severe, acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and in long-coronavirus disease (COVID) syndrome.1, 2 It was speculated that at least some of the clinical manifestations of long-COVID syndrome could be attributed to involvement of small nerve fibers by the viral infection. The authors believe that studies are needed that investigate the role of autonomic dysfunction in long-COVID syndrome and the prevalence of SFN by means of the 13-item SFN symptom inventory questionnaire. The papers are appealing but raise some concerns that require discussion.

I do not agree with the notion that long-COVID syndrome is the same as post-COVID syndrome.1 Acute COVID-19 usually lasts one to 4 wk. Subacute COVID-19 lasts 5 to 12 wk. When clinical manifestations of COVID-19 persist beyond 12 wk, the condition is termed post-COVID syndrome. Both subacute COVID-19 and post-COVID syndrome are included under the overarching term long-COVID-syndrome. Differentiating long-COVID syndrome from post-COVID-syndrome is crucial for their management and for assessing long-term outcomes.

An issue not addressed in the paper is Guillain-Barre syndrome (GBS) due to an infection with SARS-CoV-2.3 There is ample evidence that the immune response to the virus can trigger autoimmune reactions, including those that are involved in the development of GBS. There is evidence accumulating that mRNA- and vector-based anti-SARS-CoV-2 vaccines can trigger the development of GBS.4 GBS can affect not only motor and sensory fibers, but also peripheral autonomic fibers, particularly in the GBS subtype of acute motor and sensory axonal neuropathy (AMSAN). There is a subtype of GBS that may exclusively affect autonomic fibers and present with pure dysautonomia.5 Because GBS may be mild, it can go unrecognized; because patients often have a long recovery time, autonomic manifestations in long COVID syndrome could be explained by incomplete recovery from autonomic involvement in abortive GBS.

Not addressed in the articles is the involvement of the central autonomic nervous system (ANS). There are several reports demonstrating that a SARS-CoV-2 infection can be complicated by hypophysitis.6 Furthermore, patients with a pre-existing pituitary micro- or macro-adenoma have an increased risk of pituitary apoplexy during SARS-CoV-2 infection.7 Accordingly, the hypophysial-pituitary-adrenergic axis can be impaired,8 thus leading to autonomic dysfunction.

Autonomic dysfunction may not always be recognized by those involved in the management of COVID-19 patients. Thus, patients with SARS-CoV-2 infection are often not investigated sufficiently for their symptoms of autonomic dysfunction, such as insomnia, fatigue, cognitive impairment, hypersensitivity to light, blurred vision, dry eyes or mouth, drooling, palpitations, syncope, orthostatic dizziness, hot flashes, dysphagia, bowel or bladder dysfunction, sexual dysfunction, changes in skin, hair, and nails, or abnormalities of sweating. Studies that may be performed to assess ANS involvement are a contrast-enhanced magnetic resonance imaging (MRI) of the pituitary gland, determination of releasing factors, pituitary stimulating hormones, and hormones of peripheral endocrine organs, and diagnostic testing for involvement of the peripheral ANS. Several of the latter tests are not widely available and their sensitivity and specificity may be low if portions of the peripheral ANS are tested that are not affected.

Not addressed was the role of anti-COVID-19 drugs in the development of SFN. There is increasing evidence that some of the compounds administered to infected patients are neurotoxic and can be responsible for polyneuropathy. Some of these compounds, such as lopinavir, ritonavir, daptomycin, and linezolid, may also damage autonomic fibers.

I agree that there is a need to investigate the involvement of the central and peripheral ANS in some patients with acute SARS-CoV-2 infections or long-COVID syndrome. Such patients should be investigated not only by use of questionnaires and the Quantitative Sudomotor Axon Reflex Test (QSART) but particularly by quantitative sensory testing (QST), micro-neurography of C-fibers of the superficial peroneal nerve, sensory stimulation tests, the deep breathing test, the Valsalva maneuver, tilt testing, cerebral blood flow velocity measurements, pain-related evoked potentials (PREP), laser speckle contact analysis (LASCA), laser Doppler flowmetry, laser Doppler imaging, contact heat-evoked potentials (CHEP), corneal confocal microscopy (CCM), and proximal or distal skin biopsy stained with protein gene product (PGP) 9.5. Furthermore, hormone levels should be determined and autopsy of COVID-19 patients should include histological investigations of central and peripheral autonomic pathways.

Source: Finsterer J. Small fiber neuropathy underlying dysautonomia in COVID-19 and in post-SARS-CoV-2 vaccination and long-COVID syndromes. Muscle Nerve. 2022 Apr 6. doi: 10.1002/mus.27554. Epub ahead of print. PMID: 35385125.  https://onlinelibrary.wiley.com/doi/10.1002/mus.27554 (Full text)

Studying severe long COVID to understand post-infectious disorders beyond COVID-19

To the Editor — As the COVID Human Genetic Effort consortium (https://www.covidhge.com/), we have studied genetic and immunological determinants of life-threatening COVID-19 pneumonia1, multisystem inflammatory syndrome (MIS-C)2, resistance to SARS-CoV-2 infection3 and ‘COVID toes’4, and here we present our efforts to investigate post-acute COVID-19 syndrome, or ‘long COVID’.

Most people infected with SARS-CoV-2 experience a mild to moderate acute infection, while ~10% develop hypoxemic pneumonia and 3% develop critical illness, which are outcomes associated with older age and male sex. Inborn errors of type I interferon immunity involving the viral sensors TLR7 or TLR3 can explain critical disease in 1–5% of people less than 60 years of age, whereas neutralizing autoantibodies to the type I interferons IFN-α, IFN-β and IFN-ω are seen in 15–20% of people over 70 years of age1, which highlights the importance of type I interferon immunity for protective immunity against acute SARS-CoV-2 infection in the respiratory tract.

Although hypoxemic pneumonia typically occurs 2 weeks after infection, a small fraction of children and young adults develop MIS-C at about 4 weeks after infection. This disorder overlaps Kawasaki disease and superantigen-mediated toxic shock syndrome. Immunological analyses have revealed hyperinflammatory immune responses, distinct from those of acute COVID-19 and Kawasaki disease5, and activation of T cells, possibly by a SARS-CoV-2 superantigen6. There is massive expansion of T cells expressing the T cell receptor (TCR) β-chain variable region TRBV11-2 in combination with variable TCR α-chains and broadly reactive autoantibodies2. Intriguingly, the delayed presentation of MIS-C after infection is at odds with other superantigen-mediated disorders, which might be explained by viral persistence specifically in the intestine and repeated superantigen-mediated activation through a leaky gut. Viral persistence has been proposed to be associated with the degree of activation of the immune system during acute infection with SARS-CoV-27.

Signs and symptoms after SARS-CoV-2 infection have been reported to also persist even longer in some children and adults. The World Health Organization defines the ‘post COVID’ condition as one that “occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis” (https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1). Long COVID spans from very mild to severely debilitating disease with objective organ damage, but sometimes the distinction between recovery from post–intensive care unit syndrome and ongoing pathology is not clearly defined or reported in studies.

Interestingly, an acute multi-organ phenotype encompassing multiple neurological, neuropsychological–neurocognitive, cardiopulmonary, gastrointestinal and dermatological complaints during acute COVID-19 correlates with longer persistence of signs and symptoms8.

The World Health Organization’s definition of long COVID is vague, which leads to concerns that a variety of conditions, including psychosomatic complaints, become intermixed with more severe, post-infectious organ dysfunction. To maximize our chances of identifying the human genetic immunological determinants of disease, we will focus our efforts on the most severe cases of long COVID available through our international network of collaborators and clinics. We will include patients with over 3 months of persistent signs and symptoms after PCR-verified SARS-CoV-2 infection. We will also limit our studies to patients with severe organ damage or dysfunction that can be objectively verified by imaging and physiological or biochemical–molecular tests (Fig. 1a). Finally, to distinguish these patients with severe long COVID from patients with post–critical illness syndromes, we will include only patients whose persistent organ dysfunction cannot be explained by the severity of the preceding SARS-CoV-2 infection or by the treatments or medical interventions experienced.

Read the rest of this article HERE.

Source: Brodin P, Casari G, Townsend L, O’Farrelly C, Tancevski I, Löffler-Ragg J, Mogensen TH, Casanova JL; COVID Human Genetic Effort. Studying severe long COVID to understand post-infectious disorders beyond COVID-19. Nat Med. 2022 Apr 5. doi: 10.1038/s41591-022-01766-7. Epub ahead of print. PMID: 35383311. https://www.nature.com/articles/s41591-022-01766-7 (Full article)

Long-term outcomes of pediatric infections: from traditional infectious diseases to long covid

Abstract:

There is limited evidence available on the long-term impact of SARS-CoV-2 infection in children. In this article, the authors analyze the recent evidence on pediatric long covid and lessons learnt from a pediatric post-covid unit in Rome, Italy. To gain a better understanding of the concerns raised by parents and physicians in relation to the potential long-term consequences of this novel infection, it is important to recognize that long-term effect of a post-infectious disease is not a new phenomenon.

Source: Buonsenso D, Di Gennaro L, Rose C, Morello R, D’Ilario F, Zampino G, Piazza M, Boner AL, Iraci C, O’Connell S, Cohen VB, Esposito S, Munblit D, Reena J, Sigfrid L, Valentini P. Long-term outcomes of pediatric infections: from traditional infectious diseases to long covid. Future Microbiol. 2022 Mar 10:10.2217/fmb-2022-0031. doi: 10.2217/fmb-2022-0031. Epub ahead of print. PMID: 35264003; PMCID: PMC8910780.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8910780/ (Full text)