CoChat
Sign Up
Cited by 526Long-Term Effects of COVID-19COVID-19 and Mental HealthCOVID-19 Clinical Research Studies

Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up

Open access
Mazza, Mario Gennaro, Palladini, Mariagrazia, De Lorenzo, Rebecca, Magnaghi, Cristiano, Poletti, Sara, Furlan, Roberto, Ciceri, Fabio, Rovere-Querini, Patrizia +1 more·2021·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2021.02.021PMC PMC7903920
Open this paper in CoChat — free account

Abstract

COVID-19 outbreak is associated with mental health implications during viral infection and at short-term follow-up. Data on psychiatric and cognitive sequelae at medium-term follow-up are still lacking. During an ongoing prospective cohort study, the psychopathological and cognitive status of 226 COVID-19 pneumonia survivors (149 male, mean age 58) were prospectively evaluated one and three months after hospital discharge. Psychiatric clinical interview, self-report questionnaires, and neuropsychological profiling of verbal memory, working memory, psychomotor coordination, executive functions, attention and information processing, and verbal fluency were performed. Three months after discharge from the hospital, 35.8% still self-rated symptoms in the clinical range in at least one psychopathological dimension. We observed persistent depressive symptomatology, while PTSD, anxiety, and insomnia decreased during follow-up. Sex, previous psychiatric history, and the presence of depression at one month affected the depressive symptomatology at three months. Regardless of clinical physical severity, 78% of the sample showed poor performances in at least one cognitive domain, with executive functions and psychomotor coordination being impaired in 50% and 57% of the sample. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, predicted self-rated depressive symptomatology and cognitive impairment at three-months follow-up; and changes of SII predicted changes of depression during follow-up. Neurocognitive impairments associated with severity of depressive psychopathology, and processing speed, verbal memory and fluency, and psychomotor coordination were predicted by baseline SII. We hypothesize that COVID-19 could result in prolonged systemic inflammation that predisposes patients to persistent depression and associated neurocognitive dysfunction. The linkage between inflammation, depression, and neurocognition in patients with COVID-19 should be investigated in long-term longitudinal studies, to better personalize treatment options for COVID-19 survivors.

Integrity signals

Registry

Crossref · 10.1016/j.bbi.2021.02.021

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 65 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Insomnia symptoms decreased significantly from one to three months after discharge.

    “We observed persistent depressive symptomatology, while PTSD, anxiety, and insomnia decreased during follow-up.”
    • Also stated in: § Psychopathology and need for treatment · plain
      “From the one-month to the three-month follow-up, patients showed a significant decrease over time of PTSD symptoms (IES-R: F = 21.29, p = 0.001; PCL-5: F = 9.07, p = 0.003), anxiety (STAI-state: F = 11.28, p = 0.001), and insomnia (WHIIRS: F = 9.36, p = 0.003), irrespectively of sex and previous psychiatric history”
    Quote in the paperSubstantial claim
  • Findingown data

    Obsessive-compulsive symptoms worsened significantly from one to three months after discharge.

    “In contrast, depression (according to ZSDS and BDI) did not significantly change; and obsessive–compulsive symptomatology significantly worsened (F = 4.84, p = 0.030) with no effect of sex and psychiatric history”
    Quote in the paperSubstantial claim
  • Findingown data

    PTSD symptoms decreased significantly from one to three months after discharge.

    “We observed persistent depressive symptomatology, while PTSD, anxiety, and insomnia decreased during follow-up.”
    • Also stated in: § Psychopathology and need for treatment · plain
      “From the one-month to the three-month follow-up, patients showed a significant decrease over time of PTSD symptoms (IES-R: F = 21.29, p = 0.001; PCL-5: F = 9.07, p = 0.003)”
    Quote in the paperSubstantial claim
  • Findingown data

    Anxiety symptoms decreased significantly from one to three months after discharge.

    “We observed persistent depressive symptomatology, while PTSD, anxiety, and insomnia decreased during follow-up.”
    • Also stated in: § Psychopathology and need for treatment · plain
      “From the one-month to the three-month follow-up, patients showed a significant decrease over time of PTSD symptoms (IES-R: F = 21.29, p = 0.001; PCL-5: F = 9.07, p = 0.003), anxiety (STAI-state: F = 11.28, p = 0.001), and insomnia (WHIIRS: F = 9.36, p = 0.003), irrespectively of sex and previous psychiatric history”
    Quote in the paperSubstantial claim
  • Findingown data

    Depressive symptoms did not change significantly between one and three months after discharge.

    “In contrast, depression (according to ZSDS and BDI) did not significantly change”
    Quote in the paperSubstantial claim
  • May combine two claims. 27
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 33

  • May combine two claims.

    Findingown data

    At low levels of systemic inflammation, depression ratings were widely dispersed, and more severe depressive symptoms occurred at higher inflammation levels.

    “Inspection of data (Fig. 1 ) shows highly dispersed depression ratings at low levels of inflammation, with more severe symptoms at higher levels of inflammation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    9% of patients with no previous psychiatric history and 32% with a positive previous psychiatric history were prescribed psychotropic drugs.

    “Overall, 9% of patients with no previous psychiatric history and 32% of patients with positive previous psychiatric history were prescribed psychotropic drugs (selective serotonin reuptake inhibitors alone, or combined with sleep-inducing benzodiazepines).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Patients with a marked decrease in SII showed a decrease in depression severity, whereas patients with minor changes in SII had persistent or worsening depression.

    “patients who showed a marked decrease of SII also showed a decrease of depression severity, while patients who showed minor changes of SII showed persistent or worsening depression.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Previous psychiatric history predicted worse persistence of depressive symptoms at three months after discharge.

    “Sex, previous psychiatric history, and the presence of depression at one month affected the depressive symptomatology at three months.”
    • Also stated in: § Psychopathology and need for treatment · plain
      “in patients with previous lifetime psychiatric history (ZSDS: β = 0.15, F = 4.66, p = 0.32; BDI-13: β = 0.23, F = 10.65, p = 0.001)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Best performing models according to AIC included SII and significantly explained variation in depression severity.

    “A GLZM analysis of the effects of SII at hospital admission on severity of depression at three months, also considering sex, hospitalization, and age as factors, showed that best performing models according to AIC always included SII and significantly explained the variation of depression severity (χ2 = 56.536, p < 0.0001 for BDI; χ2 = 42.417, p < 0.0001 for ZSDS index scores).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingreasoning

    PTSD, insomnia, and anxiety decrease over time.

    “other symptoms probably more related to acute psychological stressors such as PTSD, insomnia, and anxiety decrease over time”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Attention and information processing, verbal memory, and psychomotor coordination were among the affected cognitive domains.

    “attention and information processing, verbal memory, and psychomotor coordination were among the affected domains”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Females, patients with a positive psychiatric history, patients with shorter hospitalization, and patients with psychopathology at one-month follow-up had higher depressive symptomatology.

    “we observed that females, patients with positive psychiatric history, patients with shorter hospitalization, and patients who presented psychopathology at one-month follow-up showed higher depressive symptomatology (Mazza et al., 2020)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mazza et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    At three months, a high rate of cognitive deficits was observed in COVID-19 survivors regardless of medical severity, with only 22% performing well in all investigated domains.

    “Consistently with previous literature, we observed a high rate of cognitive deficits in COVID-19 survivors at three months, irrespective of medical severity of the illness, with only 22% of the sample showing a good performance in all the investigated domains.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Levels of significance were corrected for multiple comparisons using the FDR method.

    “When appropriate, levels of significance were corrected for multiple comparisons with the method of the adaptive linear step-up procedures that control the FDR and q-values (FDR-adjusted p-value) were considered.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Validated self-report questionnaires were used to assess psychopathology.

    “Validated self-report questionnaires were used to assess psychopathology: Impact of Event Scale - Revised (IES-R) (Creamer et al., 2003), PTSD Checklist for DSM-5 (PCL-5) (Armour et al., 2016), Zung Self-Rating Depression Scale (ZSDS) (Zung, 1965), 13-item Beck’s Depression Inventory (BDI-13) (Beck and Steer, 1984), State-Trait Anxiety Inventory form Y (STAI-Y) (Vigneau and Cormier, 2008), Women’s”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Creamer et al., 2003 source

      Not checked in the free run.

    • cites Armour et al., 2016 source

      Not checked in the free run.

    • cites Zung, 1965 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The three-month follow-up cohort did not differ from the drop-out group or the initial cohort in sociodemographic characteristics, clinical severity, or one-month psychopathology after FDR correction.

    “The three-month follow-up cohort did not differ from the drop-out group and from the initial cohort in terms of sociodemographic characteristics, clinical severity, and one-month psychopathology after False Discovery Rate (FDR) correction (See Supplementary material).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Cognitive assessment used the Brief Assessment of Cognition in Schizophrenia (BACS) with normative Italian scores, and patients older than 70 years were excluded.

    “Considering that domain scores were adjusted according to normative Italian scores for the BACS subtests in patients aged 18–70 years, we did not perform cognitive assessment in patients older than 70 years (Anselmetti et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Anselmetti et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    COVID-19 is associated with delirium, fatigue, confusion, depression, anxiety, PTSD, obsessive-compulsive symptoms, and insomnia in acute infection or short-term follow-up.

    “Emerging data show that COVID-19 outbreak is associated with delirium, fatigue, confusion, depression, anxiety, post-traumatic stress disorder (PTSD), obsessive–compulsive symptoms, and insomnia in the context of acute viral infection or at short-term follow-up after clinical recovery”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites De Lorenzo et al., 2020 source

      Not checked in the free run.

    • cites Ma et al., 2020

      Not checked in the free run.

    • cites Mazza et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The host immune response to SARS-CoV-2, persistent psychological stress, and possible direct viral infection of the central nervous system are possible mechanisms for neuropsychiatric sequelae.

    “The host immune response to SARS-CoV-2 infection, the persistent psychological stress before and during infection (Korman et al., 2020, Vai et al., 2020), and a possible direct viral infections of the central nervous system represent possible mechanisms to induce neuropsychiatric sequelae (Troyer et al., 2020).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Korman et al., 2020 source

      Not checked in the free run.

    • cites Vai et al., 2020

      Not checked in the free run.

    • cites Troyer et al., 2020 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    T helper (Th)-1 and Th-2 cytokines are elevated in the serum of COVID-19 patients in a cytokine storm typically associated with the illness.

    “T helper (Th)-1 cytokines, including Interleukin (IL)-1β, IL-6, Interferon (IFN)-γ, Tumor Necrosis Factor (TNF)-α, CXCL10, and CCL2; and Th-2 cytokines, including IL-4, IL-10, and IL-1 receptor antagonist are all elevated in the serum of COVID-19 patients (Coperchini et al., 2020) in a “cytokine storm” typically associated with the illness.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Coperchini et al., 2020 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Peripheral cytokines involved in the host anti-viral response may elicit psychiatric symptoms by precipitating inflammation in the periphery and central nervous system.

    “Peripheral cytokines involved in the host anti-viral response may elicit psychiatric symptoms by precipitating inflammation in the periphery and in central nervous system (CNS) (Dantzer, 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dantzer, 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Significant stressors such as fear of severe and unknown disease, loneliness, stigma, and denial contribute to widespread emotional distress and increased risk for psychiatric illness in COVID-19 patients.

    “Moreover, significant stressors such as fear of severe and unknown disease, loneliness, stigma, and the denial contribute to widespread emotional distress and increased risk for psychiatric illness in COVID-19 patients (Pfefferbaum and North, 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pfefferbaum and North, 2020 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PTSD, anxiety, and insomnia decreased in parallel over time, suggesting specific long-lasting depressive sequelae in COVID-19 survivors.

    “A parallel decrease of PTSD, anxiety and insomnia over time suggests specific long lasting depressive sequelae in COVID-19 survivors.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Higher immune/inflammatory setpoints with higher circulating biomarkers of inflammation are observed in mood disorders and are investigated as pathogenetic mechanisms for depressive psychopathology.

    “Higher immune/inflammatory setpoints with higher circulating biomarkers of inflammation are observed in mood disorders in the absence of known triggering factors, and are currently investigated as underpinning pathogenetic mechanisms for depressive psychopathology (Gibney and Drexhage, 2013, Grosse et al., 2015, Poletti et al., 2020b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gibney and Drexhage, 2013

      Not checked in the free run.

    • cites Grosse et al., 2015 source

      Not checked in the free run.

    • cites Poletti et al., 2020b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The quality of the statistical model was checked using the Akaike information criterion (AIC).

    “The quality of the statistical model was checked using the entropy maximization principle of the Akaike information criterion (AIC) (Akaike, 1974).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Akaike, 1974 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PTSD, insomnia, and anxiety are probably more related to acute psychological stressors.

    “other symptoms probably more related to acute psychological stressors such as PTSD, insomnia, and anxiety”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Convalescent COVID-19 patients with elevated NLR have been reported to have more depression.

    “This finding is consistent with the reported higher depression in convalescent COVID-19 patients with higher NLR (Yuan et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yuan et al., 2020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In COVID-19, a dysexecutive syndrome was described in one third of survivors.

    “In COVID-19, a dysexecutive syndrome in a third of survivors was described (Helms et al., 2020)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Helms et al., 2020 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In hospitalized male survivors of severe life-threatening COVID-19, cytokine-blocking agents anakinra and tocilizumab had a protective effect against depression, possibly by reducing SII.

    “We also observed a protective effect against depression of cytokine-blocking agents (anakinra, a recombinant version of the human IL-1β receptor antagonist, and tocilizumab, a monoclonal antibody targeting the IL-6 receptor), possibly associated with their effect in dampening SII, in hospitalized male patients surviving severe, life-threatening COVID-19 (Benedetti et al., 2020b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Benedetti et al., 2020b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The study used an unstructured interview format instead of a structured clinical interview because of limited health care resources and patient compliance.

    “The limited health care resources and patient’s compliance related to the clinical setting forced us to choose an unstructured interview format instead of a structured clinical interview.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    In patients with a depressive episode in major depressive disorder or bipolar disorder, IL-8, IL-10, TNF-α, and IFN-γ are associated with white matter microstructure.

    “and of IL-8, IL-10, TNF-α, IFN-γ with white matter (WM) microstructure, with levels of inflammatory cytokines being inversely related with measures of WM integrity (Benedetti et al., 2016)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Benedetti et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SII, by combining three complementary cell types that mediate different immune or inflammatory pathways, is less affected by confounding conditions and more predictive of chronic systemic inflammatory status than neutrophils, platelets, or lymphocytes separately.

    “Considering together three complementary cells mediating different immune or inflammatory pathways, SII is less affected by confounding conditions, and more predictive in evaluating chronic systemic inflammatory status than neutrophils, platelets or lymphocytes separately (Gibson et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gibson et al., 2007 source

      Not checked in the free run.

    • Rests on an assumption: Platelets act as a nonspecific early inflammatory marker, mediating endothelial permeability and drawing neutrophils and macrophages and their effector functions.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In COVID-19, cognitive dysfunction in sustained attention has been described, possibly linked to underlying inflammatory processes measured with CRP.

    “as well as cognitive dysfunction in sustained attention domain possibly linked to the underlying inflammatory processes measured with CRP (Zhou et al., 2020a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhou et al., 2020a

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many studies have suggested that inflammation activation is linked to cognitive dysfunction, with a primary role for IL-1β, IL-6, IL-18, and TNF-α.

    “Many studies have implied that inflammation activation is inextricably linked to cognitive dysfunction suggesting a primary role of IL-1β, IL-6, IL-18, and TNF-α (Beydoun et al., 2019, Gorelick, 2010, McAfoose and Baune, 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Beydoun et al., 2019 source

      Not checked in the free run.

    • cites Gorelick, 2010 source

      Not checked in the free run.

    • cites McAfoose and Baune, 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In previous work, higher SII-quantified inflammation was associated with greater depression in COVID-19 survivors.

    “In this context, we have previously found that higher inflammation, quantified by SII, is associated with higher depression in COVID-19 survivors (Mazza et al., 2020).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mazza et al., 2020 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Lifetime speed of information processing is closely associated with white matter microstructure in humans and animal models.

    “the lifetime speed of information processing closely associates with WM microstructure in humans and in animal models (Bartzokis et al., 2012, Kochunov et al., 2007, Lu et al., 2013)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bartzokis et al., 2012 source

      Not checked in the free run.

    • cites Kochunov et al., 2007 source

      Not checked in the free run.

    • cites Lu et al., 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elevated NLR has been described in mild cognitive impairment, and platelet/lymphocyte ratio and SII have been associated with dementia risk in the general population.

    “Recently, elevated NLR was described in mild cognitive impairment, while platelet/lymphocyte ratio and SII associated with risk of dementia in the general population (An et al., 2019, van der Willik et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites An et al., 2019

      Not checked in the free run.

    • cites van der Willik et al., 2019 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The white matter phenotype is associated with neurocognitive dysfunctions.

    “We also associated this WM phenotype with neurocognitive dysfunctions (Poletti et al., 2015)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Poletti et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In patients with a depressive episode in major depressive disorder or bipolar disorder, peripheral levels of IL-8, TNF-α, CCL2, and CCL4 are associated with cortical thickness.

    “In patients with a depressive episode in course of Major Depressive Disorder (MDD) or Bipolar Disorder (BD), we have previously reported an association of peripheral IL-8, TNF-α, CCL2, CCL4 with cortical thickness (Poletti et al., 2019)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poletti et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In the same patient group, IL-1β, IL-9, and CCL5 are associated with brain glutamate, N-acetylaspartate, and Myo-Inositol levels.

    “of IL‐1β, IL-9, CCL5 with brain glutamate, N-acetylaspartate, and Myo-Inositol levels (Poletti et al., 2020a)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poletti et al., 2020a

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neutrophils are critical for initiating and regulating innate immune defense through phagocytosis, apoptosis, chemotaxis, oxidative stress, and secretion of inflammatory mediators.

    “Neutrophils are critical for starting and regulating the innate immune defense through phagocytosis, apoptotic action, chemotactic role, oxidative stress, and secretion of inflammatory mediators (Nathan, 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nathan, 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Changes in structural and functional brain connectivity might mediate how COVID-19 harms neurocognition.

    “we can surmise that subtle effects on structural and functional brain connectivity could mediate the detrimental effects of COVID-19 on neurocognition”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the same patient group, inflammatory cytokine levels are inversely related to measures of white matter integrity.

    “with levels of inflammatory cytokines being inversely related with measures of WM integrity (Benedetti et al., 2016)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Benedetti et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The observed cognitive effects were influenced by both psychopathology and systemic inflammation, supporting a connection among depression, inflammation, and cognition.

    “These effects were influenced both, by the presence of psychopathology, and by systemic inflammation, thus confirming the connection between depression, inflammation, and cognition.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Depressed patients have higher cytokine levels than healthy controls, with consistent literature findings for IL-1β, IL-6, IL-10, CCL2, TNF-α, and TGF-β.

    “Depressed patients are characterized by higher levels of cytokines when compared to healthy controls with consistent results in literature when considering IL-1β, IL-6, IL-10, CCL2, TNF-α, and transforming growth factor-β (TGF-β) (Enache et al., 2019, Eyre et al., 2016, Howren et al., 2009, Kohler et al., 2017, Poletti et al., 2020b).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Enache et al., 2019 source

      Not checked in the free run.

    • cites Eyre et al., 2016 source

      Not checked in the free run.

    • cites Howren et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Neurocognition was assessed only in a subsample, not in all patients.

    “we were not able to assess the neurocognition in all patients but only in a subsample”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    SII, which combines neutrophils, platelets, and lymphocytes, is an objective marker of the balance between systemic inflammation and immune response.

    “SII, considering together neutrophil, platelet, and lymphocyte, is an objective marker of the balance between host systemic inflammation and immune response (Huang et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huang et al., 2019 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Recruitment was in a single center, raising the possibility of population stratification.

    “Recruitment was in a single center, thus raising the possibility of population stratification”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Several studies have shown that inflammatory ratios can be used as biomarkers in depression.

    “Several studies have proven that these inflammatory ratios can be used as inflammatory biomarkers in depression (Mazza et al., 2018, Wang et al., 2021, Zhou et al., 2020b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mazza et al., 2018 source

      Not checked in the free run.

    • cites Wang et al., 2021 source

      Not checked in the free run.

    • cites Zhou et al., 2020b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Lymphocytes mainly serve adaptive immunity and have a regulatory or protective role.

    “Finally, lymphocytes are primarily involved in adaptive immunity, with a regulatory or protective function (Alberts, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Alberts, 2008

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Inflammation is associated with depression through mechanisms including blood-brain barrier disruption, microglial activation, altered neurotransmission, IDO activation, and oxidative stress.

    “Inflammation is known to be associated to depression inducing brain-blood-barrier disruption, microglia activation, neurotransmission alteration, indoleamine 2,3-dioxygenase 1 (IDO) activation, and oxidative stress (Benedetti et al., 2020a, Miller and Raison, 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Benedetti et al., 2020a

      Not checked in the free run.

    • cites Miller and Raison, 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Serotonin, dopamine, glutamate, cytokines, and P-selectin mediate platelet activation, and all are important in psychiatric disorders.

    “Platelet activation is mediated by serotonin, dopamine, glutamate, cytokines and P-selectin, all of them plays an important role in psychiatric disorders (Dietrich-Muszalska and Wachowicz, 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dietrich-Muszalska and Wachowicz, 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The effect on neurocognitive dysfunctions is proportional to illness duration.

    “an effect proportional to illness duration (Melloni et al., 2019)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Melloni et al., 2019 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    These effects will have substantial and demanding public health implications for psychiatric services.

    “the public health implications of such effects will be significant and demanding for the psychiatric services”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: COVID-19 infection has a global burden.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NLR, MLR, and SII are low-cost, reproducible markers of systemic inflammation suitable for routine clinical analysis and easily derived from blood cell assays under simple laboratory conditions.

    “NLR, MLR and SII are low-cost, suitable for clinical routine analysis, and reproducible markers of the systemic inflammatory response, which can be easily derived from blood cell essay and determined under simple laboratory conditions (Balta et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Balta et al., 2013 source

      Not checked in the free run.

51 of 51

  • The paper relies on this without support.

    The delayed or long-term incidence of neuropsychiatric complications in COVID-19 survivors is unknown.

    “Beyond acute or sub-acute sequelae, the delayed or long-term incidence of neuropsychiatric complications in COVID-19 survivors are still unknown.”

  • The paper relies on this without support.

    This was the first prospective study to investigate psychiatric and neurocognitive sequelae at medium-term follow-up in COVID-19 survivors.

    “This is the first study to prospectively investigate the psychiatric and neurocognitive sequelae at a medium-term follow-up in COVID-19 survivors.”

  • The paper relies on this without support.

    Platelets act as a nonspecific early inflammatory marker, mediating endothelial permeability and drawing neutrophils and macrophages and their effector functions.

    “Platelets are an aspecific first line inflammatory marker that mediate endothelial permeability and recruitment of neutrophils and macrophages and their effector functions.”

  • The paper relies on this without support.

    Depression is associated with a markedly increased risk of all-cause and cause-specific mortality.

    “depression associates with a markedly increased risk of all-cause and cause-specific mortality”

  • The paper relies on this without support.

    COVID-19 infection has a global burden.

    “given the global burden of COVID-19 infection”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • This sensitivity analysis corroborates Mazza et al. (2021), who found that PCL-5-reported PTSD declined with longer follow-up in COVID-19 patients.

    “This confirms results from Mazza et al. (2021) where PTSD reported using PCL-5 decreased with longer follow-up in COVID-19 patients.”

    From Long-term effects of COVID-19 on mental health: a systematic review (2022) · cites this paper as Mazza et al., 2021

  • The neurological sequelae of SARS-CoV-2 infection are proving to be both common and debilitating.

    “It is thus not surprising that the neurological sequelae of SARS-CoV-2 infection are proving to be both common and debilitating (Nasserie et al., 2021; Mazza et al., 2021; Qureshi et al., 2022; Becker et al., 2021; Tabacof et al., 2022).”

    From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Mazza et al., 2021

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentz = 2.98reported p = .0026 · recomputed p = .003

    “Z = 2.980, p = .0026”

    The paper states an exact rank test

1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • BDI-13 clinical cutoff changes between methods and results

    Minor

    The methods define the BDI-13 cutoff as at least 9, but Table 1 counts patients using a cutoff of at least 8.

  • Cognitive-performance categories omit 21 assessed patients

    Minor

    The listed mutually exclusive categories total 109 patients, although the paper says cognitive functions were assessed in 130 patients. The account does not identify a category for the remaining 21.

    Reported 130 · recomputed 109

  • Share with normal cognition changes from 19% to 22%

    Minor

    The results say 19% performed normally in every domain, while the discussion describes the same outcome as 22% of the sample.

3 of 3

Cites

Flagged first, then by citations

3 of the 78 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Mazza, M. G., Palladini, M., De Lorenzo, R., Magnaghi, C., Poletti, S., Furlan, R., Ciceri, F., Rovere-Querini, P., & Benedetti, F.
Affiliations
  • Vita-Salute San Raffaele University (IT)
  • IRCCS Ospedale San Raffaele (IT)
Corresponding author
Mazza, Mario Gennaro
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2021-05
Volume
94
Pages
138-147
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2021.02.021
PMC
PMC7903920
OpenAlex
W3129342553
Semantic Scholar
2c34e539a6d09867be7208e71f8a551c08e53ca0
Cited by
513
References
78
Citations by year
2026: 23 · 2025: 66 · 2024: 109 · 2023: 148 · 2022: 115 · 2021: 50
FWCI
50.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
  • Social Sciences › Psychology › Clinical Psychology › COVID-19 and Mental Health
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
COVID-19 pandemic, post-COVID-19 mental health, dysthymia, neurocognitive impairment, systemic inflammation, inflammatory markers, systemic immune-inflammation index, executive function, psychomotor coordination, verbal memory, verbal fluency, processing speed, long COVID
MeSH terms
COVID-19, SARS-CoV-2, Mental Disorders, Child, Preschool, Cognition Disorders, Follow-Up Studies, Humans, Male, Neuropsychological Tests, Prospective Studies, Biomarkers, Survivors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review