Category: Overlapping Illnesses

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Abstract:

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection.

Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion – and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function.

Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Source: Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, Yalçın B, Taylor KR, Dutton S, Acosta-Alvarez L, Ni L, Contreras-Esquivel D, Gehlhausen JR, Klein J, Lucas C, Mao T, Silva J, Peña-Hernández MA, Tabachnikova A, Takahashi T, Tabacof L, Tosto-Mancuso J, Breyman E, Kontorovich A, McCarthy D, Quezado M, Hefti M, Perl D, Folkerth R, Putrino D, Nath A, Iwasaki A, Monje M. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. bioRxiv [Preprint]. 2022 Jan 10:2022.01.07.475453. doi: 10.1101/2022.01.07.475453. PMID: 35043113; PMCID: PMC8764721.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764721/ (Full text)

Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome

Abstract:

Many acute COVID-19 convalescents experience a persistent sequelae of infection, called post-acute COVID-19 syndrome (PACS). With incidence ranging between 31% and 69%, PACS is becoming increasingly acknowledged as a new disease state in the context of SARS-CoV-2 infection. As SARS-CoV-2 infection can affect several organ systems to varying degrees and durations, the cellular and molecular abnormalities contributing to PACS pathogenesis remain unclear.

Despite our limited understanding of how SARS-CoV-2 infection promotes this persistent disease state, mitochondrial dysfunction has been increasingly recognized as a contributing factor to acute SARS-CoV-2 infection and, more recently, to PACS pathogenesis. The biological mechanisms contributing to this phenomena have not been well established in previous literature; however, in this review, we summarize the evidence that NAD+ metabolome disruption and subsequent mitochondrial dysfunction following SARS-CoV-2 genome integration may contribute to PACS biological pathogenesis.

We also briefly examine the coordinated and complex relationship between increased oxidative stress, inflammation, and mitochondrial dysfunction and speculate as to how SARS-CoV-2-mediated NAD+ depletion may be causing these abnormalities in PACS. As such, we present evidence supporting the therapeutic potential of intravenous administration of NAD+ as a novel treatment intervention for PACS symptom management.

Source: Block T, Kuo J. Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome. Clin Pathol. 2022 Jun 24;15:2632010X221106986. doi: 10.1177/2632010X221106986. PMID: 35769168; PMCID: PMC9234841. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234841/ (Full text)

Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID

Abstract:

Background: There is currently no consensus on the diagnosis, definition, symptoms, or duration of COVID-19 illness. The diagnostic complexity of Long COVID is compounded in many patients who were or might have been infected with SARS-CoV-2 but not tested during the acute illness and/or are SARS-CoV-2 antibody negative.

Methods: Given the diagnostic conundrum of Long COVID, we set out to investigate SARS-CoV-2-specific T cell responses in patients with confirmed SARS-CoV-2 infection and/or Long COVID from a cohort of mostly non-hospitalised patients.

Findings: We discovered that IL-2 release (but not IFN-γ release) from T cells in response to SARS-CoV-2 peptides is both sensitive (75% +/-13%) and specific (88%+/-7%) for previous SARS-CoV-2 infection >6 months after a positive PCR test. We identified that 42-53% of patients with Long COVID, but without detectable SARS-CoV-2 antibodies, nonetheless have detectable SARS-CoV-2 specific T cell responses.

Interpretation: Our study reveals evidence (detectable T cell mediated IL-2 release) of previous SARS-CoV-2 infection in seronegative patients with Long COVID.

Funding: This work was funded by the Addenbrooke’s Charitable Trust (900276 to NS), NIHR award (G112259 to NS) and supported by the NIHR Cambridge Biomedical Research Centre. NJM is supported by the MRC (TSF MR/T032413/1) and NHSBT (WPA15-02). PJL is supported by the Wellcome Trust (PRF 210688/Z/18/Z, 084957/Z/08/Z), a Medical Research Council research grant MR/V011561/1 and the United Kingdom Research and a Innovation COVID Immunology Consortium grant (MR/V028448/1).

Source: Krishna BA, Lim EY, Mactavous L; NIHR BioResource Team, Lyons PA, Doffinger R, Bradley JR, Smith KGC, Sinclair J, Matheson NJ, Lehner PJ, Wills MR, Sithole N. Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID. EBioMedicine. 2022 Jul;81:104129. doi: 10.1016/j.ebiom.2022.104129. Epub 2022 Jun 27. PMID: 35772216; PMCID: PMC9235296. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9235296/ (Full text)

Disorders of gut-brain interaction in post-acute COVID-19 syndrome

Abstract:

The novel coronavirus SARS-CoV-2 is responsible for the devastating pandemic which has caused more than 5 million deaths across the world until today. Apart from causing acute respiratory illness and multiorgan dysfunction, there can be long-term multiorgan sequalae after recovery, which is termed ‘long COVID-19’ or ‘post-acute COVID-19 syndrome’. Little is known about long-term gastrointestinal (GI) consequences, occurrence of post-infection functional gastrointestinal disorders and impact the virus may have on overall intestinal health.

In this review, we put forth the various mechanisms which may lead to this entity and possible ways to diagnose and manage this disorder. Hence, making physicians aware of this spectrum of disease is of utmost importance in the present pandemic and this review will help clinicians understand and suspect the occurrence of functional GI disease post recovery from COVID-19 and manage it accordingly, avoiding unnecessary misconceptions and delay in treatment.

Source: Golla R, Vuyyuru SK, Kante B, Kedia S, Ahuja V. Disorders of gut-brain interaction in post-acute COVID-19 syndrome. Postgrad Med J. 2022 Jul 1:postgradmedj-2022-141749. doi: 10.1136/pmj-2022-141749. Epub ahead of print. PMID: 35777934. https://pmj.bmj.com/content/early/2022/07/01/pmj-2022-141749 (Full text)

Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment (“brain fog”), orthostatic intolerance (OI) and other symptoms (“Long COVID”). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing.

Methods: We evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app.

Participants: People with Long COVID (N = 42), ME/CFS (N = 26) and healthy control subjects (N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT.

Results: The NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects (p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time (p < 0.01).

Conclusions: A test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS.

Source: Vernon SD, Funk S, Bateman L, Stoddard GJ, Hammer S, Sullivan K, Bell J, Abbaszadeh S, Lipkin WI, Komaroff AL. Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne). 2022 Jun 23;9:917019. doi: 10.3389/fmed.2022.917019. PMID: 35847821; PMCID: PMC9285104. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9285104/ (Full text)

Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID

Abstract:

Background and Objectives: COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS. There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID.
Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022.
Results: Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females). The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS. The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS.
Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.
Source: Tokumasu K, Honda H, Sunada N, Sakurada Y, Matsuda Y, Yamamoto K, Nakano Y, Hasegawa T, Yamamoto Y, Otsuka Y, Hagiya H, Kataoka H, Ueda K, Otsuka F. Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID. Medicina. 2022; 58(7):850. https://doi.org/10.3390/medicina58070850 https://www.mdpi.com/1648-9144/58/7/850/htm (Full text)

An online survey of pelvic congestion support group members regarding comorbid symptoms and syndromes

Abstract:

Objectives: Patients with pelvic congestion syndrome (PCS) often report overlapping somatic symptoms and syndromes. The objective of this study was to explore the prevalence of co-existing symptoms and self-reported syndrome diagnoses among women with PCS and to inform future research hypotheses.

Methods: A brief online survey was offered to members of a PCS support group website. Responses were assessed for self-reported co-existing symptoms and formal diagnoses, including: chronic fatigue syndrome, fibromyalgia, postural tachycardia syndrome, irritable bowel syndrome, migraines, interstitial cystitis, and temporomandibular joint dysfunction.

Results: Of a total of 6000 members, there were 398 respondents; 232 (59%) had not yet been treated for PCS. Among these, the most prevalent co-existing symptoms were as follows: severe fatigue (72%), dizziness (63%), IBS symptoms (61%), brain fog (33%), migraines (49%), polyuria or dysuria (41%), excessive sweating (31%), TMJ pain (31%), and loose skin or lax joints (18%). These are much higher than reported for the general female population. The most commonly self-reported comorbid syndrome diagnoses for the overall group of 398 were: irritable bowel syndrome (29%), fibromyalgia (13%), spinal nerve problems (18%), interstitial cystitis (10%), postural tachycardia syndrome (9%), hypertension (11%), chronic fatigue syndrome (10%), and Ehlers-Danlos syndrome (6%). Other than with hypertension, these rates are variably higher than in the general population.

Conclusion: Several self-reported co-existing symptoms and syndromes are more prevalent in members of a PCS support group relative to the reported prevalence in the general population. More formal investigation is warranted to evaluate this finding and to investigate potential etiologic links. Ehlers-Danlos Syndrome appears to be common in self identifying PCS women.

Source: Smith SJ, Sichlau M, Sewall LE, Smith BH, Chen B, Khurana N, Rowe PC. An online survey of pelvic congestion support group members regarding comorbid symptoms and syndromes. Phlebology. 2022 Jul 13:2683555221112567. doi: 10.1177/02683555221112567. Epub ahead of print. PMID: 35831253. https://pubmed.ncbi.nlm.nih.gov/35831253/

Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study

Abstract:

Despite the increasing prevalence of patients with Long Covid Syndrome (LCS), to date the pathophysiology of the disease is still unclear, and therefore diagnosis and therapy are a complex effort without any standardization. To address these issues, we performed a broad exploratory screening study applying state-of-the-art post-genomic profiling methods to blood plasma derived from three groups: 1) healthy individuals vaccinated against SARS-CoV-2 without exposure to the full virus, 2) asymptomatic fully recovered patients at least three months after SARS-CoV-2 infection, 3) symptomatic patients at least 3 months after a SARS-CoV-2 infection, here designated as Long Covid Syndrome (LCS) patients.

Multiplex cytokine profiling indicated slightly elevated cytokine levels in recovered individuals in contrast to LCS patients, who displayed lowest levels of cytokines. Label-free proteome profiling corroborated an anti-inflammatory status in LCS characterized by low acute phase protein levels and a uniform down-regulation of macrophage-derived secreted proteins, a pattern also characteristic for chronic fatigue syndrome (CFS).

Along those lines, eicosanoid and docosanoid analysis revealed high levels of omega-3 fatty acids and a prevalence of anti-inflammatory oxylipins in LCS patients compared to the other study groups. Targeted metabolic profiling indicated low amino acid and triglyceride levels and deregulated acylcarnithines, characteristic for CFS and indicating mitochondrial stress in LCS patients. The anti-inflammatory osmolytes taurine and hypaphorine were significantly up-regulated in LCS patients.

In summary, here we present evidence for a specific anti-inflammatory and highly characteristic metabolic signature in LCS which could serve for future diagnostic purposes and help to establish rational therapeutic interventions in these patients.

Source: Johannes J Kovarik, Andrea Bileck, Gerhard Hagn, Samuel M Meier Menches, Tobias Frey, Anna Kaempf, Marlene Hollenstein, Tarik Shoumariyeh, Lukas Skos, Birgit Reiter, Marlene C Gerner, Andreas Spannbauer, Ena Hasimbegovic, Doreen Schmidl, Gerhard Garhoefer, Mariann Gyoengyoesi, Klaus G Schmetterer, Christopher Gerner. Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study. medRxiv 2022.07.11.22277499; doi: https://doi.org/10.1101/2022.07.11.22277499 (Full study available as PDF file)

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Abstract:

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation.

The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT-angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.

Source: Szewczykowski C, Mardin C, Lucio M, Wallukat G, Hoffmanns J, Schröder T, Raith F, Rogge L, Heltmann F, Moritz M, Beitlich L, Schottenhamml J, Herrmann M, Harrer T, Ganslmayer M, Kruse FE, Kräter M, Guck J, Lämmer R, Zenkel M, Gießl A, Hohberger B. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation. Int J Mol Sci. 2022 Jun 29;23(13):7209. doi: 10.3390/ijms23137209. PMID: 35806214. https://www.mdpi.com/1422-0067/23/13/7209/htm (Full text)

Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study

Abstract:

Background: Up to 37.7% of patients experience symptoms beyond 12 weeks after infection with SARS-CoV-2. To date care for people with long covid has centred around multidisciplinary rehabilitation, self care and self pacing. No pharmacotherapy has been shown to be beneficial.

Methods: In this single centre interventional pre post study, the safety of Low Dose Naltrexone (LDN) was explored in patients with Post COVID-19 Syndrome (PCS), defined by NICE as patients with ongoing symptoms 12 or more weeks after initial infections with SARS-CoV-2 where alternative explanation for symptoms cannot be found. Patients were recruited through a Post COVID clinic, had a baseline quality of life questionnaire in symmetrical Likert format, were prescribed 2 months (1 mg month one, 2 mg month two) of LDN and repeated the same questionnaire at the end of the second month. Patients were monitored to adverse events.

Findings: In total 52 patients participated of whom 40(76.9%) were female. The median age was 43.5 years(IQR 33.2–49). Healthcare workers represented the largest occupational cohort n = 16(34.8%). The median time from diagnosis of COVID-19 until enrolment was 333 days (IQR 171–396.5). Thirty-eight participants (73.1%) were known to commence LDN, two of whom (5.3%) stopped taking LDN post commencement due to new onset diarrhoea and also described fatigue. In total 36(69.2%) participants completed the questionnaire at the end of the two-month period. Improvement was seen in 6 of 7 parameters measured; recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance (p ≤ 0.001), improvement in mood approached but was not significant (p = 0.054).

Conclusions: LDN is safe in patients with PCS and may improve well-being and reduce symptomatology in this cohort. Randomised control trials are needed to further explore this.

Source: Brendan O’Kelly, Louise Vidal, Tina McHugh, James Woo, Gordana Avramovic, John S. Lambert. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study. Brain, Behavior, & Immunity – Health; Volume 24, October 2022, 100485 https://www.sciencedirect.com/science/article/pii/S2666354622000758  (Full text)