What can neuroimmunology teach us about the symptoms of long-COVID?

Mondelli, Valeria; Pariante, Carmine

doi:10.1093/oxfimm/iqab004

Cited by 27 publications

(36 citation statements)

References 59 publications

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“…Viral reservoirs or lingering fragments of viral RNA/proteins could also contribute to this maladaptive response. 12 Gaebler et al 13 discussed immune evolution and possible influence of immunofluorescence and PCR-confirmed SARS-CoV-2 persistence in intestinal biopsies from asymptomatic individuals 4 months after the onset COVID-19. These reservoirs could repeatedly stimulate the immune system and be responsible for the fluctuating course of symptoms in long COVID patients.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long COVID

Viszlayová

Sojka

Dobrodenková³

et al. 2021

Therapeutic Advances in Infection

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Over 10% of COVID-19 convalescents report post-COVID-19 complications, namely, ‘long COVID’ or ‘post-COVID syndrome,’ including a number of neuro-psychiatric symptoms. The pathophysiology of COVID-19 in the central nervous system is poorly understood but may represent post-COVID injury, ongoing sterile maladaptive inflammation, or SARS-CoV-2 persistence. We describe a long COVID patient with SARS-CoV-2 RNA in the cerebrospinal fluid, which seems important, specifically due to recent reports of gray matter volume loss in COVID-19 patients. Further studies of SARS-CoV2 RNA, markers of inflammation, and neuronal damage in the CSF of patients with long COVID would be useful and should address whether the CNS can serve as a reservoir of SARS-CoV-2, clarify the pathway by which COVID-19 contributes to CNS dysfunction, and how best to therapeutically address it.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long COVID

Viszlayová

Sojka

Dobrodenková³

et al. 2021

Therapeutic Advances in Infection

View full text Add to dashboard Cite

show abstract

“…To understand how the sickness response may turn maladaptive a lot may to be learned from the depression model discussed by David Poon et al 51 and recently, with regards to Long Covid, also by Mondelli and Pariante. 409 Poon et al discuss the observation that during Interferon-alpha therapy for malignant melanoma all patients develop standard sickness behavior via the classical "infectious disease" inflammatory pathways: they withdraw socially, they become fatigued, anhedonic and anorexic, they sleep more etc. But a subset of the patients treated with TNFalpha goes on to develop overt clinical depression.…”

Section: Does Me/cfs Represent Connectome Failure?mentioning

confidence: 99%

“…These features may again point to an abnormal sickness response as core element in the inception of post-infectious ME/CFS, where, in the words of Mondelli and Pariante, "the individual sensitivity to immune activation might be more important than the absolute levels of immune activation per se." 409 I.e, the discriminatory feature between those who recover after a infection induced sickness response and those who do not may to be found in the fact that, in the latter, the peripheral inflammatory stimulation gets a) transduced into the CNS and b) there becomes sustained by additional immunological mechanisms "even when the initial trigger from peripheral immune activation has resolved." Here, Mondelli and Pariante suggest "central processes involving brain/microglia response".…”

Section: Does Me/cfs Represent Connectome Failure?mentioning

confidence: 99%

“…Some of these additional mechanisms that may confer susceptibility to some people may include a higher likelihood of glial activation, a higher likelihood of BBB disruption allowing crosstalk between peripheral immune processes and those in the CNS as well as the activation of the kynurenine pathway. 409 This is not to say that these are the only mechanism that may throw off the adaptive sickness response in some individuals, yet, the concept of vulnerability seems to be an important one. Also, the IDO pathway referred to in both of the hypotheses presented, has been implicated as a pathogenetic possibility in ME/CFS, too (see [4.6]).…”

Section: Does Me/cfs Represent Connectome Failure?mentioning

confidence: 99%

“…421 Also, the degree of neuroinvasion by SARS-CoV-2 does not seem to correlate with the severity of neuropathological changes. 409 A study of vaccine responses in PASC patients has been interpreted as support for viral persistence in the periphery. 422 So at this point viral persistence in either the periphery or the CNS are plausible contributors to PASC inception, at the same time there is no evidence that viral persistence may be a prerequisite for the development of the ME/CFS-like cases of PASC (given the fact that SARS-CoV-2 has been shown to use the olfactory nerve to enter the CNS it would be interesting to find out if loss of smell is associated with the development of Long Covid).…”

Section: Covid-19 To the Rescuementioning

confidence: 99%

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Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

Renz‐Polster¹

2021

Preprint

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In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified, yet, it remains unclear how they are related and which of them may be upstream or downstream.. In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final histological pathway of ME/CFS and suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration.For this "histological" approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit.Through this search we have identified the CNS neuroglia - microglia and astroglia - as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS. While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the neuroimmune basis of ME/CFS. After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.

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Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 Conditions

et al. 2022

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ImportanceFew risk factors for long-lasting (≥4 weeks) COVID-19 symptoms have been identified.ObjectiveTo determine whether high levels of psychological distress before SARS-CoV-2 infection, characterized by depression, anxiety, worry, perceived stress, and loneliness, are prospectively associated with increased risk of developing post–COVID-19 conditions (sometimes called long COVID).Design, Setting, and ParticipantsThis prospective cohort study used data from 3 large ongoing, predominantly female cohorts: Nurses’ Health Study II, Nurses’ Health Study 3, and the Growing Up Today Study. Between April 2020 and November 2021, participants were followed up with periodic surveys. Participants were included if they reported no current or prior SARS-CoV-2 infection at the April 2020 baseline survey when distress was assessed and returned 1 or more follow-up questionnaires.ExposuresDepression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at study baseline early in the pandemic, before SARS-CoV-2 infection, using validated questionnaires.Main Outcomes and MeasuresSARS-CoV-2 infection was self-reported during each of 6 monthly and then quarterly follow-up questionnaires. COVID-19–related symptoms lasting 4 weeks or longer and daily life impairment due to these symptoms were self-reported on the final questionnaire, 1 year after baseline.ResultsOf 54 960 participants, 38.0% (n = 20 902) were active health care workers, and 96.6% (n = 53 107) were female; the mean (SD) age was 57.5 (13.8) years. Six percent (3193 participants) reported a positive SARS-CoV-2 test result during follow-up (1-47 weeks after baseline). Among these, probable depression (risk ratio [RR], 1.32; 95% CI = 1.12-1.55), probable anxiety (RR = 1.42; 95% CI, 1.23-1.65), worry about COVID-19 (RR, 1.37; 95% CI, 1.17-1.61), perceived stress (highest vs lowest quartile: RR, 1.46; 95% CI, 1.18-1.81), and loneliness (RR, 1.32; 95% CI, 1.08-1.61) were each associated with post–COVID-19 conditions (1403 cases) in generalized estimating equation models adjusted for sociodemographic factors, health behaviors, and comorbidities. Participants with 2 or more types of distress prior to infection were at nearly 50% increased risk for post–COVID-19 conditions (RR, 1.49; 95% CI, 1.23-1.80). All types of distress were associated with increased risk of daily life impairment (783 cases) among individuals with post–COVID-19 conditions (RR range, 1.15-1.51).Conclusions and RelevanceThe findings of this study suggest that preinfection psychological distress may be a risk factor for post–COVID-19 conditions in individuals with SARS-CoV-2 infection. Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection symptoms.

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What can neuroimmunology teach us about the symptoms of long-COVID?

Cited by 27 publications

References 59 publications

SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long COVID

SARS-CoV-2 RNA in the Cerebrospinal Fluid of a Patient with Long COVID

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 Conditions

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