key: cord-0927709-12k81rac authors: Wang, Shao-Cheng; Su, Kuan-Pin; Pariante, Carmine M. title: The three frontlines against COVID-19: Brain, Behavior, and Immunity date: 2021-02-04 journal: Brain Behav Immun DOI: 10.1016/j.bbi.2021.01.030 sha: faeaa115dd96a2352c5d7d7a0970b479d032ae73 doc_id: 927709 cord_uid: 12k81rac The pandemic outbreak of coronavirus disease 2019 (COVID-19) is raising global anxiety and fear of both real and perceived health threat from the virus. Overwhelming evidence shows infected patients experiencing neuropsychiatric complications, suggesting that the “psychoneuroimmunity” model might be beneficial in understanding the impact of the virus. Therefore, this Special Issue on “Immunopsychiatry of COVID-19 Pandemic” was launched immediately after the pandemic was declared, with the first paper accepted on the March 25th, 2020. A total of ninety-three papers were accepted, the last one was on the July 10th, 2020 when the initial acute phase started declining. The papers of this Special Issue have illuminated the social impact, psychopathology, neurological manifestation, immunity responses, and potential treatments and prevention on COVID-19. For example, anxiety disorders, mood disorders, and suicidal ideation are most common psychiatric manifestations. COVID-19 infection can have central and/or peripheral nervous system symptoms, including headache, sleep disorders, encephalopathy, and loss of taste and smell. A “three-steps” Neuro-COVID infection model (neuro-invasion, clearance and immune response) was established. The current therapeutic interventions for COVID-19 include supportive intervention, immunomodulatory agents, antiviral therapy, and plasma transfusion. Psychological support should be implemented, improving the psychological wellbeing, as well as to enhance psychoneuroimmunity against COVID-19. 4 cut off transfection (Zhu, Wang et al. 2020) . Controversially, a relative high prevalence of mental illnesses was found in the quarantined individuals, due to the impacts on daily life, rather than the control measure of quarantine (Zhu, , and social isolation strategies decreased the likelihood of clinically dysfunctional coronavirus anxiety, even when the individuals were under stressful event (Milman, Lee et al. 2020) . To improve mental health during the lockdown, Chen et al. used the online questionnaire and reported physical exercise might be beneficial (Chen, Zheng et al. 2020) , while a family-centered approach might have the potential benefits to optimize the psychological management ). In addition, Ren and his colleagues' found that it is necessary to make the information open, transparent and timely (Ren, Zhou et al. 2020) , although the intensity of exposure to media COVID-19 information was positively associated with the individuals' distress (Yao 2020) . Applying health belief such as encouraging lifestyle modification also helped stress appraisal and coping strategies (Mukhtar 2020) . Screening tools or effective diagnostic instruments are urgently needed, because the COVID-19 pandemic and mitigation efforts carry a mental health toll among medical staff, patients, and general population (Ransing, Ramalho et al. 2020) . It is very important to continue tracking the development of vicarious traumatization in medical staff as well as the general public (Ghaffari, Mortezapour et al. 2020 , Li, Ge et al. 2020 . For example, Joob et al. reported that traumatization was caused among the Thailand medical staff by high workload, lack of protective devices, non-effective infection control system, and direct insult by patients (Joob and Wiwanitkit 2020). In addition, the impact of COVID-19 on different people such as African Americans, individuals with low cognitive function, and elite athletes, suggested that the COVID-19 is a heterogeneous disease; therefore, a standard screening tool is urgently needed (Ajilore and Thames 2020, Batty, Deary et al. 2020 , Lassale, Gaye et al. 2020 , Mehrsafar, Gazerani et al. 2020 , Sominsky, Walker et al. 2020 . The medical staff, as well as the volunteer medical staff, were at high risk of mental health problems during the COVID-19 pandemic, and the majority of mental health workers lacked professional training for psychological crisis intervention (Li, Yu et al. 2020) . Noninfectious disease specialists have experienced varying, but increased levels of depression, anxiety and insomnia during this COVID-19 pandemic, which could be reduced by sufficient levels of protective equipment and workplace training (Liu, Zheng et al. 2020) . The targeted psychological intervention measures should be developed to improve the mental health of non-medical workers on the front-line of COVID-19 epidemic, especially the females and younger individuals (Fang, Zhang et al. 2020) . Thus, expanding the availability of wellprepared mental health professionals is needed (Yang, Tong et al. 2020) , and all medical staff must have complete and accurate knowledge on COVID-19; using telepsychiatry for practice (Kinoshita, Cortright et al. 2020 ) and the internet and television for public health education is helpful (Ko, Lu et al. 2020) . Rapid mental health interventions could improve the medical staff's mental health and physical health perceptions (Kang, Ma et al. 2020 ). In the United States, a National Suicide Prevention Lifeline was activated (Montemurro 2020) . The first longitudinal study on the mental health of general population was reported by Wang et al. during the COVID-19 pandemic in China; they focused on mental illnesses and the impact of quarantine and lockdown, suggesting that governments should focus on effective methods of disseminating COVID-19 knowledge and teaching correct containment methods (Wang, Pan et al. 2020) . Then, the first data available on the Italian population showed that affective temperament and attachment style predict psychological impact during the COVID-19 pandemic (Moccia, Janiri et al. 2020) . Anxiety disorders, mood disorders, and suicidal ideation were the most common psychiatric manifestations during the COVID-19 pandemic (Nalleballe, Reddy Onteddu et al. 2020 ); even the convalescent COVID-19 patients had high self-reported depression (Yuan, Li et al. 2020) . Too much or repetitive COVID-19 thinking could induce anxiety and cause clinical dysfunction (Lee 2020). Poor sleep quality among COVID-19 patients was also associated with a slow recovery and an increased need for intensive care (Zhang, Xu et al. 2020 ). Among patients with mental disorders, the COVID-19 pandemic appeared to disrupt daily routines, cut social ties, and increase financial worries and fears of the future (Frank, Fatke et al. 2020 ). The predictive models created by Gonzalez-Sanguino et al. showed that the greatest protector was spiritual well-being, while loneliness was the strongest predictor of mental illnesses (Gonzalez-Sanguino, Ausin et al. 2020); physical health, mental health, and job satisfaction of healthcare staff were other potential predictors . Geographical variation was also present: compared with China, Jahanshahi et al. reported that the Iranian adults have more distress (Jahanshahi, Dinani et al. 2020) ; in Croatia, during the earthquake co-occurring with COVID-19 pandemic, more people showed mental illnesses than the infection; furthermore, mental illnesses might impede recovery process (Marko, Kosec et al. 2020) . Timely identification of psychological distress and precise classifying of the mental health needs will facilitate development of targeted psychological interventions (Zhang, Lu et al. 2020 ). In some cases, the central and/or peripheral nervous system dysfunction by was similar to Guillain-Barré syndrome; thus, plasma therapy was applied in severely affected patients. Several COVID-19 patients with pneumonia had fair clinical response to plasma therapy; however, among COVID-19 patients with Guillain-Barré syndrome, the effect of plasma therapy has not yet been reported (Coen, Jeanson et al. 2020 , Gupta, Paliwal et al. 2020 . COVID-19 is highly contagious because most persons lack immunity against this novel Furthermore COVID-19 may induce potential pain sensation (Su, Cui et al. 2020) . However, currently no obvious pathological evidence was found to support viral infection in nerve tissue, and only short-term effects of COVID-19 on nervous system were reported . A potential "three-steps" Neuro-COVID infection model (neuroinvasion, clearance and immune response) was also proposed (Panciani, Saraceno et al. 2020) . From a neurological point of view, the hypercoagulation and aneurysm instability partially due to systemic COVID-19 inflammation might induce severe brain hemorrhage, with a case with concomitant subarachnoid hemorrhage and COVID-19 reported (Muhammad, Petridis et al. 2020) , and the physicians and medical staff should pay attention to potential risk of thromboembolic complications among COVID-19 patients (Mongan, Cannon et al. 2020 ). The COVID-19 patients could present with cerebrovascular accidents to minimize their mortality and morbidity; therefore, timely assessment and hyperacute treatment should be performed (Avula, Nalleballe et al. 2020) . neuropsychiatric manifestations, such as psychosis, insomnia, and mood changes (Oxley, Mocco et al. 2020 , Xiang, Yang et al. 2020 , Zhao, Shen et al. 2020 . The Special Issue described potential therapeutic interventions for COVID-19, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion (Chen, Wang et al. 2020 . Immunomodulatory medications for rheumatoid arthritis and other targets, such as CCL2, CCR5 or EGFR inhibitors, may have the potential to treat severe COVID-19 patients (Ray, Wangzhou et al. 2020 ). Immunoglobulin A vaccination inducing a local protective immunity within the mucosa where pathogenic infection is initiated may have potential benefit (Chao, Rotzschke et al. 2020 ). Cannabinoids was found as a plausible option to be added as an adjunct on COVID-19 patients with lung inflammation (Byrareddy and Mohan 2020). Supportive intervention such as Ayurveda could positively influence immunity (Golechha 2020, Rajkumar 2020); recognizing the uniqueness of each individual would also help them adapt and promote mental health (Zhai and Du 2020) . Moreover, Qiu et al. summarized the recent systemic supportive interventions to maintain mental wellness in public population, isolated patients, and frontline medical staff (Qiu, Zhou et al. 2020) . The internet media such as Facebook, Google, and Twitter have been growing rapidly in the past decade and have become relevant to potential disease prevention. Google related methods were performed to investigate the population interest and the COVID-19 disease spreading, suggesting the importance of public awareness of "hand washing", "COVID-19 symptoms", "social distancing" and "lock down" and medical therapeutic direction (Lin, Liu et al. 2020 ). More online information seeking was related to insomnia, rather than depression and suicide . In Twitter, Bhat et al. performed sentiment analysis, and found that even though users are quarantined, yet they are hopeful (Bhat, Qadri et al. 2020 ). An unhealthy lifestyle was identified as a risk factor for COVID-19 hospitalization, suggesting that adopting simple lifestyle changes can have potential benefit (Hamer, Kivimaki et al. 2020) ; physical activity could also help maintain emotional stability, counteract the negative effects of isolation, and improve immune competency (Simpson and Katsanis 2020) . Healthy foods and eating habits might have the potential to reduce susceptibility to severe complications (Butler and Barrientos 2020). Specific nutritional interventions (e.g. omega-3 polyunsaturated fatty acids) have immunomodulation effects and may potentially improve the immunity to counteract both physical and mental impact of COVID-19 (Chang, Pariante et al. 2020 ). In addition, Tan et al. found that the psychoneuroimmunity prevention measures in China had the potential to maintain the low prevalence of psychiatric symptoms among the workforce who returned to work (Tan, Hao et al. 2020 ). The history of face mask and its related information was reviewed (Goh, Tan et al. 2020) ; face mask restrictions have the potential to protect against the COVID-19 and increase the level of perceived self-protection, as well as the level of social solidarity, improving mental health wellbeing (Szczesniak, Ciulkowicz et al. 2020) . We linked the psychoneuroimmunity model to the three frontlines: Brain, Behavior, and Immunity, and described the detail below. Brain involves both psychology and neurology. The medical staff, as well as the general population, felt anxious and low mood under the stress of COVID-19. The direct neuroinvasion of COVID-19 induced headache, sleep disorder, olfactory and gustatory impairments, and more severe encephalopathy. In addition to neuroinvasion, the COVID-19 infection triggered the immunity, causing massive inflammation of lung and brain; the former is the main death cause of COVID-19 and the latter can induce brain hemorrhage. The hypercoagulation and aneurysm instability partially due to systemic COVID-19 inflammation might be the potential cause of mental illnesses. During the COVID-19 pandemic, the individuals performed specific behavioral patterns to relieve stress and anxiety; they were more likely to browse internet to seek health information such as face mask and hand washing. Healthy lifestyle and psychological intervention were recommended to boost the immune system against COVID-19. Furthermore, the government locked down the cities. Though lockdown seems to be positive against COVID-19, it had a deep impact on both the general populations' social interaction and psychological wellbeing. The connection between Brain, Behavior, and Immunity showed in Figure 1 . COVID-19 therapy involves prevention, symptomatic treatments, and supportive care. Besides the targeted vaccinations that have been made available just recently, a healthy lifestyle and psychological interventions have the potential to improve psychoneuroimmunity. Although social distancing or wearing masks might help us to prevent infection, quality interpersonal connection should be fostered not only among the medical staff but also the general population, to improve the psychological wellbeing and also to enhance psychoneuroimmunity against COVID-19. Social isolation as a means of reducing dysfunctional coronavirus anxiety and increasing psychoneuroimmunity The COVID-19 outbreak and Google searches: Is it really the time to worry about global mental health? Affective temperament, attachment style, and the psychological impact of the COVID-19 outbreak: an early report on the Italian general population COVID-19, hypercoagulation and what it could mean for patients with psychotic disorders The emotional impact of COVID-19: From medical staff to common people Letter to editor: Severe brain haemorrhage and concomitant COVID-19 Infection: A neurovascular complication of COVID-19 Mental health and emotional impact of COVID-19: Applying Health Belief Model for medical staff to general public of Pakistan Spectrum of neuropsychiatric manifestations in COVID-19 Large-vessel stroke as a presenting feature of Covid-19 in the young Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report SARS-CoV-2: "Three-steps" infection model and CSF diagnostic implication Mental wellness system for COVID-19 Ayurveda and COVID-19: Where psychoneuroimmunology and the meaning response meet Can COVID-19 related mental health issues be measured? A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction Letter to the Editor "A longitudinal study on the mental health of general population during the COVID-19 epidemic in China The immunological case for staying active during the COVID-19 pandemic One size does not fit all -Patterns of vulnerability and resilience in the COVID-19 pandemic and why heterogeneity of disease matters Google Trends provides a tool to monitor population concerns and information needs during COVID-19 pandemic Google Trends reveals: Focus of interest in the population is on treatment options rather than theories about COVID-19 animal origin Pain: A potential new label of COVID-19 The neuroinvasive potential of severe acute respiratory syndrome coronavirus 2 Psychopathological responses and face mask restrictions during the COVID-19 outbreak: Results from a nationwide survey Is returning to work during the COVID-19 pandemic stressful? A study on immediate mental health status and psychoneuroimmunity prevention measures of Chinese workforce Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms Host proteases as determinants of coronaviral neurotropism and virulence Potentially irreversible olfactory and gustatory impairments in COVID-19: Indolent vs. fulminant SARS-CoV-2 neuroinfection COVID-19 pandemic and mental health consequences: Systematic review of the current evidence A longitudinal study on the mental health of general population during the COVID-19 epidemic in China Nervous system involvement after infection with COVID-19 and other coronaviruses Nervous system damage after COVID-19 infection: Presence or absence? Timely mental health care for the 2019 novel coronavirus outbreak is urgently needed Characteristics and challenges of psychological first aid in China during the COVID-19 outbreak The more exposure to media information about COVID-19, the more distressed you will feel Correlation between immune response and self-reported depression during convalescence from COVID-19 Loss and grief amidst COVID-19: A path to adaptation and resilience The differential psychological distress of populations affected by the COVID-19 pandemic Current status of potential therapeutic candidates for the COVID-19 crisis Poor-sleep is associated with slow recovery from lymphopenia and an increased need for ICU care in hospitalized patients with COVID-19: A retrospective cohort study At the height of the storm: Healthcare staff's health conditions and job satisfaction and their The authors of this work were supported by the following grants: