key: cord-0882028-t5p6z0wv authors: Gennaro Mazza, Mario; De Lorenzo, Rebecca; Conte, Caterina; Poletti, Sara; Vai, Benedetta; Bollettini, Irene; Maria Teresa Melloni, Elisa; Furlan, Roberto; Ciceri, Fabio; Rovere-Querini, Patrizia; Benedetti, Francesco title: Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors date: 2020-07-30 journal: Brain Behav Immun DOI: 10.1016/j.bbi.2020.07.037 sha: dd1a5e9ea1f6a47c3490ce0a6c0b559b207691be doc_id: 882028 cord_uid: t5p6z0wv Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. We investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors. We screened for psychiatric symptoms 402 adults surviving COVID-19 (265male,meanage58), at one month follow-up after hospital treatment. A clinical interview and a battery of self-report questionnaires were used to investigate post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. We collected sociodemographic information, clinical data, baseline inflammatory markers and follow-up oxygen saturation levels. A significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more for both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil and platelet counts, positively associated with scores of depression and anxiety at follow-up. PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present obervation of worse inflammation leading to worse depression, we recommend to assess psychopathology of COVID-19 survivors and to deepen research on inflammatory biomarkers, in order to diagnose and treat emergent psychiatric conditions. Respiratory viral diseases are associated with both acute and long-lasting psychopathological consequences in the survivors (1) . Coronaviruses are negatively stranded RNA viruses, which cause infections ranging from common colds to severe acute respiratory syndrome (2) . Coronavirus exposure has also been implicated in neuropsychiatric diseases during and after Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks (3) . SARS survivors reported psychiatric symptoms, including post-traumatic stress disorder (PTSD), depression, panic disorder, and obsessive-compulsive disorder (OCD) at 1 to 50 months follow up (4) (5) (6) . Moreover, seropositivity for coronaviruses associated with suicide and psychosis persisting one year after SARS (7) . The recent spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID- 19) pandemic seems yet to be associated with psychiatric implication (8) . Preliminary data suggest that patients with COVID-19 might experience delirium, depression, anxiety, and insomnia (3) . Coronaviruses could induce psychopathological sequelae through direct viral infection of the central nervous system (CNS) or indirectly via an immune response (4) . Clinical, post-mortem, animal, in vitro, and cell culture studies demonstrated that coronaviruses are potentially neurotropic and can induce neuronal injuries (9) . Notwithstanding possible brain infiltration, "cytokines storm" involved in the immune response to coronaviruses may cause psychiatric symptoms by precipitating neuroinflammation (10, 11). Current insight into inflammation in psychiatry suggests that infection-triggered perturbation of the immune system could specifically foster psychopathology, adding to the psychological stress of enduring a potentially fatal disease, and to stress-associated inflammation (12) . The interaction between innate and adaptive immune systems and neurotransmitters emerged as a mechanism underpinning mood disorders, psychosis, and anxiety disorders (13) . In addition to the immunological mechanisms, fear of illness, uncertainty of the future, stigma, traumatic memories of severe illness, and social isolation experienced by patients during the COVID-19 are significant psychological stressors that may interact in defining psychopathological outcome (14, 15) . Taking into account the sparse preliminary studies on COVID-19 and considering the previous evidence about SARS and MERS outbreaks, we hypothesize that COVID-19 survivors will show a high prevalence of emergent psychiatric conditions including mood disorders, anxiety disorders, PTSD, and insomnia. Available data indicate that confusion and delirium are common features in the acute stage, while to date, no data exist on psychopathology in the post-illness phase (3, 16) . Thus, the present study aims to investigate the psychopathological impact of COVID-19 in survivors at one month follow up, also considering the effect of possible risk factors. We screened for psychiatric symptoms 402 patients surviving COVID-19 (265 male, mean age 57.8, age range from 18 to 87 years), from April 6 to June 9 2020, during an ongoing prospective cohort study at IRCCS San Raffaele Hospital in Milan. All patients included in the present study had been first evaluated at the Emergency Department (ED), where they underwent clinical evaluation, electrocardiogram, hemogasanalysis, and hematological analysis (complete blood cell count including differential white blood cell count, and C-reactive protein (CRP)). After that, patients were admitted for severe pneumonia (n=300, hospital stay 15.31±10.32 days) or managed at home (n=102). Psychiatric assessment was performed 31.29±15.7 days after discharge, or 28.56±11.73 days after ED. To keep a naturalistic study design, exclusion criteria were limited to patients under 18 years. Written informed consent was obtained from all participants, and the institutional review board approved the study in accordance with the principles in the Declaration of Helsinki. An unstructured clinical interview was conducted by well-trained psychiatrists in charge using the best estimation procedure, taking into account available charts, computerized medical records, and, if needed, the information provided by a relative. Sociodemographic and clinical data were collected using a data extraction form, including age, sex, psychiatric history, duration of hospitalization, baseline inflammatory markers, and follow-up oxygen saturation level. Baseline inflammatory markers during acute COVID-19 were extracted from ED charts: C-reactive Protein (CRP), neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and systemic immune-inflammation index (SII) (SII = platelets X neutrophils / lymphocytes) (17) . Oxygen saturation level was recorded at the follow-up visit, soon after the psychiatric evaluation, to provide an index of respiratory efficiency. Current psychopathology was measured using the following self-report questionnaire: Impact of Statistical analyses to compare group means and frequencies (Student's t-test, Pearson χ 2 test) exploring effects of sex, hospitalization, or previous history of psychiatric illness on symptoms severity were performed, and Pearson's correlation analysis was performed to explore the correlation between age, duration of hospitalization, time after discharge, baseline inflammatory marker, and oxygen saturation level and current psychopathology scores. To account for the multiple covarying variables, we also tested the effect of predictors (inflammatory markers, sex, previous psychiatric history) on the current psychopathological status (self-report scores) by modelling the influences of the predictors on the outcomes in the context of the General Linear Model (GLM) and calculating the statistical significance of the effect of the single independent factors on the dependent variables by parametric estimates of predictor variables (least squares method). Analyses of multivariate and univariate effects were perfomed by using a commercially available software package (StatSoft Statistica 12, Tulsa, OK, USA) and following standard computational procedures (26, 27) . Psychiatric symptoms in COVID-19 survivors and measures of inflammation at first clinical contact (ED evaluation) are resumed in Table 1 . A significant proportion of patients self-rated symptoms in the pathological range: overall, 55.7% scored in the clinical range in at least one psychopathological dimension (PTSD according to IES-R and/or PCL-5, depression according to ZSDS and/or BDI-13, anxiety according to STAI-Y state, and OC symptomatology according to OCI), 36.8% in two, 20.6% in three, and 10% in four. Severity of depression also included suicide ideation and planning, with 2.9% scoring 1 (suicidal ideation) at the BDI suicide item, 0.8% scoring 2 and 0.8% scoring 3 (suicidal planning). Clinical and demographic characteristics of the patients influenced the severity of psychopathological sequelae of COVID-19. Females, patients with a positive previous psychiatric diagnosis, and patients who were managed at home showed an increased score on most measures ( Baseline inflammatory markers (CRP, NLR, MLR, and SII) were higher in males and in patients that were treated as inpatients, while follow-up oxygen saturation level was higher in patients that were managed at home (Table 1 ). Baseline inflammatory marker as well as follow up oxygen saturation levels did not correlate with psychopathological scores except for a nominal direct correlation between OCI and baseline MLR, not surviving correction for multiple comparisons (Table 2) This is the first study that investigates psychopathology in a sample of COVID-19 survivors at one month follow-up after hospital treatment. We reported high rates of PTSD, depression, anxiety, insomnia, and OC symptomatology. Our findings mirror the results from previous coronaviruses outbreak studies, where the psychiatric morbidities ranged from 10% to 35% in the post-illness stage (3, 28) . (30, 31) . Higher concentrations of these cytokines seem to suggest a more severe clinical course (32) . Cytokines dysregulation (especially IL-1β, IL-6, IL-10, IFN-γ, TNF-α, and transforming growth factorβ (TGF-β)) are known to involve factors that others and we associated with psychiatric disorders (33) (34) (35) (36) (37) (38) . Neuroinflammation, blood-brain-barrier disruption, peripheral immune cell invasion into the CNS, neurotransmission impairment, hypothalamic-pituitary adrenal (HPA) axis dysfunction, microglia activation and indoleamine 2,3-dioxygenase (IDO) induction, all represent interaction pathways between immune systems and psychopathological mechanism underpinning psychiatric disorders (10, 13, 38, 39) . With regard to the risk factor related to psychopathology, consistently with previous epidemiological studies, we have found that females, and patients with positive previous psychiatric diagnoses, suffered more in all psychopathological dimensions (16, 40, 41) . Moreover, outpatients showed increased anxiety and sleep disturbances, while the duration of hospitalization inversely correlated with PTSD, depression, anxiety, and OC symptomatology. Also considering the worse severity of COVID-19 in hospitalized patients, this observation suggests that less healthcare support could have increased the social isolation and loneliness typical of COVID-patients showed higher levels of depression and sleep disturbances, in agreement with previous studies describing a worse psychological impact of COVID-19 pandemic in younger people (44) . Neither oxygen saturation level at follow up nor baseline inflammatory markers associated with depression, anxiety, PTSD nor insomnia, suggesting that psychiatric symptomatology was not a manifestation of physical symptoms, with the exception of baseline SII that positively associated with measures of anxiety and depression at follow-up. The SII is an objective marker of the balance between host systemic inflammation and immune response status considering together neutrophil, platelet, and lymphocyte all of them involved in different pathway of immune/inflammatory response (45) . Higher levels have been associated with worse prognosis in several medical diseases, in particular in the field of oncology. In a single study, higher SII levels were associated with major depressive disorder (MDD) (46) , suggesting that it could be a marker of the low-grade inflammation observed in mood disorders (47, 48) . Interestingly, we also found a direct correlation between OCI and MLR and a trend for a direct correlation between OCI and NLR and SII, suggesting that higher baseline inflammation could be associated whit later OC symptomatology. Recent evidence, in agreement with our observation, suggests an impact of COVID-19 on OCD related both to an immune and inflammatory dysregulation both to an increased perceived risk about contamination (49) (50) (51) . Moreover, baseline inflammatory parameters where higher among males and inpatients, who showed less psychopathology at follow-up, corroborating the complexity of the interaction between psychopathology and physical status. In the light of the above, interest to deepen research on biomarkers of inflammation is warranted, to investigate the possible association between possible persistent low-grade inflammation as observed in mood disorders (47, 48) , and psychopathological symptoms at follow-up in COVID-19 survivors. This approach could also allow to identify possible new specific targets for the treatment of inflammation-related neuropsychiatric conditions (52) . The main limitation of the present study is its cross-sectional nature that does not allow interpretation for causality. In conclusion, our study hypotheses were supported by the present results based on a cohort of 402 patients. As predicted, COVID-19 survivors presented a high prevalence of emergent psychiatric sequelae, with 55% of the sample presenting a pathological score for at least one disorder. Higher than average incidence of PTSD, major depression, and anxiety, all high-burden non-communicable conditions associated with years of life lived with disability, is expected in survivors. Moreover, depression associates with a markedly increased risk of all-cause and causespecific mortality (53) . Considering the alarming impact of COVID-19 infection on mental health, we now suggest assessing psychopathology of COVID-19 survivors, to diagnose and treat emergent psychiatric conditions, monitoring their changes over time, with the aim of reducing the disease burden, which is expected to be very high in patients with psychiatric conditions (54) . This will also allow investigating how the immune-inflammatory response translates into psychiatric illness improving our knowledge in the etiopathogenesis of these disorders. 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