key: cord-1038485-untix58w
authors: Pourriyahi, Homa; Saghazadeh, Amene; Rezaei, Nima
title: Altered immunoemotional regulatory system in COVID-19: From the origins to opportunities
date: 2021-04-16
journal: J Neuroimmunol
DOI: 10.1016/j.jneuroim.2021.577578
sha: 94fce2b5bbc071a43cdcdde2b7a1f884653096c2
doc_id: 1038485
cord_uid: untix58w

The emergence of the novel coronavirus (SARS-CoV-2) and the worldwide spread of the coronavirus disease (COVID-19) have led to social regulations that caused substantial changes in daily life. The subsequent loneliness and concerns of the pandemic during social distancing, quarantine, and lockdown are psychosocial stressors that negatively affect the immune system. These effects occur through mechanisms controlled by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenocortical (HPA) axis that alter immune regulation, namely the conserved transcriptional response to adversity (CTRA), which promotes inflammation and diminishes antiviral responses, leading to inadequate protection against viral disease. Unhealthy eating habits, physical inactivity, sleep disturbances, and mental health consequences of COVID-19 add to the pathological effects of loneliness, making immunity against this lethal virus an even tougher fight. Therefore, social isolation, with its unintended consequences, has inherently paradoxical effects on immunity in relation to viral disease. Though this paradox can present a challenge, its acknowledgment can serve as an opportunity to address the associated issues and find ways to mitigate the adverse effects. In this review, we aim to explore, in detail, the pathological effects of the new social norms on immunity and present suggested methods to improve our physical, psychological, and healthcare abilities to fight a viral infection in the context of the COVID-19 pandemic.

With the emergence of a novel coronavirus, currently termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), since late December 2019, and the World Health Organization (WHO) declaration of this outbreak as a "public health emergency of international concern" on January 30, 2020, and consequently characterizing it as a pandemic on March 11, 2020, we are now in the midst of an unparalleled global situation, with catastrophic casualties [1, 2] . As of December 15, 2020, over 122 million coronavirus disease 2019 (COVID-19) cases and over 2.7 million deaths have been reported [3] .

As there existed no effective preventative measure in the face of this virus [4] [5] [6] [7] [8] [9] , such as a vaccine or other specific treatment , non-pharmacological interventions [39, 40] have been implemented to make the diagnosis of infection as early as possible [20, 41, 42] and limit the spread of the infection [43] . Namely, behavioral interventions aiming to separate people physically, generally referred to as "social distancing" [44] , are executed so that the interpersonal transmission is interrupted. Using masks, self-isolation, and quarantine or As observed in studies, there was a lower expression of genes related to antibody synthesis in objective isolation, which could be due to less contact with socially spread microbes, whereas subjective isolation was associated with a decreased expression of specific transcripts in immunoglobulin G1 (IgG1) synthesis and type I interferon (IFN) genes, and an elevated expression of pro-inflammatory genes [65, 86] . This socially regulated pattern, called the conserved transcriptional response to adversity (CTRA), involves the β-adrenergic receptors, the SNS, the HPA axis, and the glucocorticoid response [89] .

CTRA and its different implications are of evolutionary advantage [87] . Isolation puts us at a higher risk of getting harmed, i.e., attacked or wounded, where we do not have the protective circle of others around us [90] , and the resulting inflammation is the evolutionarily chosen shield of protection, adapted for times of loneliness and isolation [91] . Taken in today's context, inflammation heightens trait sensitivity to negative social experiences, shifting their perception into the psychological model of "threat" and therefore helping the individual avoid potentially harmful situations by further favoring isolation [91] . In other words, CTRA itself can lead to selfperceived isolation, meaning inflammation, and perceived social stress are interconnected, each leading to the other, mediated by CTRA in both directions [92] .

The diminished socially spread pathogen exposure in isolation reduces the need for robust antiviral immunity. Moreover, as potential wounding is more likely to occur and possibly more threatening to immediate survival in the context of social isolation, inflammation is prioritized at the expense of antiviral response [91] .

When reviewing the COVID-19 pandemic and related social issues and psychiatric outcomes under one umbrella, inflammatory cytokines and their interaction with neuroendocrine components become remarked [93] . More precisely, loneliness and inflammation have been found correlated [91, 94, 95] , such that loneliness enhances inflammatory responses to an acutely stressful event [96] , such as biological challenges, e.g., endotoxin [97] . Stress and troubled interpersonal connections could possibly heighten inflammatory responses synergistically [97] . Pro-inflammatory cytokines such as TNF-α [90, 98] , IL-6 [90, [98] [99] [100] [101] [102] [103] [104] and J o u r n a l P r e -p r o o f acute-phase reactants such as CRP [102, 104, 105] , fibrinogen [102, 106, 107] and IL-1RA [100] levels have been found significantly affected by loneliness.

Social isolation as a form of prolonged and chronic stress leads to sustained activation of the HPA axis, resulting in a reduced allostatic negative feedback through the elaboration of cortisol.

This allostatic overload results in a down-regulation of the glucocorticoid receptor gene, namely NR3C1 [108] . This phenomenon is referred to as functional glucocorticoid desensitization [92] and has been implicated in the context of CTRA gene expression [89] .

With the evolutionary explanation mentioned earlier, antiviral activity is diminished both in loneliness and social isolation [91] , with the down-regulation of type I and II IFNs [92] . This inadequate antiviral immunity has been studied about the immune response to different viruses, which have been found impaired in infection with simian immunodeficiency virus (SIV) [92] . Elevated antibody titers against some ubiquitous or latent viruses [109] , such as higher CMV antibody titers [110] which were associated with a more severe symptom cluster of depression, fatigue, and pain [111] , and higher EBV [110] and HSV-1 antibody titers [110, 112] have also been observed in lonelier individuals.

With loneliness causing a poorer subjective adaptation to stressful challenges, another observed aspect of immune dysregulation, rather than suppression, was that the balance between type 1 (IFN-gamma) and type 2 (IL-10) cytokines shifts toward type 2 in stress, and this could be a potential explanation for the higher observed type 2 mediated immune reactions in times of elevated stress, such as viral infection, expression of latent viruses, autoimmunity and allergic or asthmatic reactions [113] .

It is rather unfortunate that infection with viruses of social stigmas, such as HIV or HCV, consequently leads to further isolation and loneliness. The mere diagnosis of HCV has been associated with feelings of loneliness and social isolation [114] , and it is much the same when living with HIV through the years [115] . The internalized stigma of HIV infection and subsequent suboptimal adherence to antiretroviral therapy is another studied situation in this context [11, 116, 117] . The same phenomenon with the stigma has been happening with a COVID-19 diagnosis [118] . Loneliness has been found related to lower preventative behaviors toward J o u r n a l P r e -p r o o f infection during COVID-19 [119] , which leads us to believe that the relation between antiviral immunity and loneliness, although controlled differently in each direction through distinct mechanisms of immunity and behavior, is nonetheless reciprocal.

Loneliness can affect the proper activity of innate immunity through reduced natural killer cell functionality [120] , and cellular and humoral immunity through decreased plasma IgG, IgM [121] , and IgA [121] levels and diminished lymphocyte activity such as decreased mitogen stimulation [109] .

Focusing again on CTRA, another way it affects immunity is through transcriptome shifts that are primarily mediated by myeloid lineage immune cells, e.g., dendritic cells and monocytes [88] , and it has been confirmed, through studies on isolated subpopulations of leukocytes, that changes in transcription in response to human social adversity are mediated by monocytes [122, 123] . In addition, animal models have shown an up-regulation in the production of distinct immature, pro-inflammatory monocytes by the SNS through changing hematopoietic mechanisms, mediated by β-adrenergic signals that enhance the differentiation and development of monocytes through increased transcription of the myelopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF) [124] . GM-CSF has been associated with loneliness in other studies, as well [125] .

Along with the aforementioned immunological adaptations to the newly set social circumstances, it is vital to take consequent behavioral and environmental changes into account when analyzing the COVID-19 situation [126] .

Keeping a healthy diet has proven to be exceedingly difficult during the pandemic [127] . The main changes in diet have been a lower intake of fresh fruits, vegetables, and protein-rich foods of high quality, e.g., fish or meat, and higher consumption of snacks and sugary, high-fat foods, making the diet progressively imbalanced. These changes can possibly affect immunity and the management of chronic underlying diseases, subsequent to inadequate content of micronutrients and the resultant disproportionate calorie intake [127] , eventually leading to a J o u r n a l P r e -p r o o f lack of sufficient nutrients to support the immune system [128] and causing weight gain [129] , respectively.

The use of food as a defective coping mechanism to re-establish a sense of control over the uncertain circumstances we are currently living through is possible and should be carefully considered regarding those with eating disorders [130] .

The catastrophic lifestyle changes in the settings of COVID-19 have led to increased sedentary behavior and decreased levels of physical activity [131] , and resultant weight gain [129] . These behaviors come with consequences for the immune system, causing immunosuppression through a heightened inflammatory state, oxidative stress, and other processes [132] , making the individual more susceptible to viral infection [133] . In contrast, increased levels of physical activity have been shown to improve markers of immunity, leading to lower levels of inflammatory markers, namely CRP, IL-6, IL-18, and TNF-α, along with decreased leukocyte counts [134] .

A mediator for the effects of sedentarism on immunity, especially during a viral pandemic, is obesity [133] . In an article on influenza and influenza-like viruses, a reciprocal connection between viral infection and obesity was observed, meaning the illness would lead to obesity, and obesity, in turn, through prolonged viral shedding, increased viral load in a breath, and higher viral variability, caused greater infection spread [133] .

Sleep disturbances and insomnia are common consequences of quarantine, experienced by many [135] . Loneliness due to COVID-19 is associated with more troubles around sleep [136] .

Higher scores of insomnia are reported among people with concerns of having themselves or a loved one been infected. Other predictors of insomnia are loneliness, heightened intolerance to uncertainty, worries of COVID-19, and higher severity of depression [137] . As sleeping is arguably the most basic behavior of restorative value, the resultant sleep deprivation, as seen in the times of COVID-19 and loneliness [138] , can impair immune functions through decreased cytokine release [139] .

Moreover, increased duration of sleep has been observed in a study on nursing students. This is concurrent with a longer time spent in bed and increased sleep latency, meaning it takes longer for them to fall asleep; therefore, sleep efficiency, which is the ratio between time spent asleep and time spent in bed, is lower in lockdown [140] .

As with the stresses of contagion and stay-at-home orders, daily life took on a completely different look in lockdown [141] , with the isolation consequently affecting mental health [142] .

Poor mental health outcomes have been thoroughly studied in the context of COVID-19, from loneliness, anxiety, and depression [143] to suicidal ideation [144] . Self-reported alcohol and substance use increased significantly in lockdown due to boredom, loneliness, a lack of social contact, or daily structure loss [56] . Lack of movement and long hours of sitting were associated with worse depression, stress, and loneliness, as the self-reported physical activity among previously active people was significantly lower after the pandemic [145] . A higher screen time had the same mental health outcomes [145] .

Social adversity, with its resultant inflammatory response through CTRA, as discussed earlier in the case of loneliness, could also be a cause for the development of anxiety and consequent depression and has been studied as an etiological theory for depression [146] . This theory can explain the emergence of depression and anxiety in the settings of COVID-19. However, it also signifies the shared underlying pathology and resultant compromise of the immune system in social isolation, anxiety, and depression, portraying them as conjoined phenomena in mental health outcomes of COVID-19.

It is worth noting that self-isolation and quarantine lead to more severe depression and anxiety in comparison with social distancing [145] , which could also be explained by the theory mentioned above, concerning levels of social adversity and human connection in each of those settings. Similarly, a role takes place in social platforms when one might feel fear by obtaining fake news about the disease [147, 148] . There appears to be highly important such that the term infodemic came to exist further worsening the pandemic situation.

J o u r n a l P r e -p r o o f Journal Pre-proof When investigating immunity against COVID-19, the very nature of the disease should also be taken into consideration. The virus attacks the immune system in such a way that results in a systemic inflammatory response, with disproportionately high levels of inflammatory cytokines, often referred to as a "cytokine storm," which is one of the most prominent features of the disease and can ultimately lead to severe COVID-19 outcomes like the acute respiratory distress syndrome (ARDS) [149] . In severe cases of COVID-19, macrophage activation syndrome, along with NK cell and CD4 cell lymphopenia, are also present, ultimately leading to a major dysregulation of the immune system [150] .

This pro-inflammatory profile and impaired immunity are also present in people with certain conditions like obesity, which is associated with chronic low-grade systemic inflammation and consequently poorer COVID-19 outcomes [151] , or in times of social isolation or loneliness [91, 94, 95] , which are all prevalent observations in times of COVID-19.

The cytokine storm in COVID-19 almost imitates an exaggerated image of the aforementioned pro-inflammatory profile. This shared pathology of the immune system, present in different magnitudes, makes the impaired immune profile in the social settings of COVID-19 almost look like an invitation to a more drastic progression of symptoms in the case of contraction, given that a basic level of dysregulation is already present and is more likely to be exacerbated. Likewise, the virus itself and its social consequences compound each other's negative effects.

Taken together, the aforementioned psychosocial factors lead to an altered immunoemotional regulatory system (IMMERS, [152] ) in times of COVID-19, making the achievement of immunity against this lethal virus an even tougher fight.

Nutrients are essential to the immune system, as they are needed in cell division and cytokine and antibody production and release [128] . The importance of micronutrients is evident in their necessary presence for many enzymes to function properly. Selected vitamins and minerals have been known for their roles in maintaining the immune system's functionality, of which are zinc, iron, selenium, copper [21] , and vitamins A, B2, B6, B12, C, D, and E [153, 154] . Therefore, J o u r n a l P r e -p r o o f a diet that provides the necessary nutrients is recommended to boost immunity against viral infection [155] . Viral and bacterial infections cause an immune response marked by the production of inflammatory cytokines. It is also the case in COVID-19 patients who often display increased pro-and anti-inflammatory cytokines [156] . It becomes challenging especially in those with a severe disease who require intensive care unit (ICU) admission and nutritional interventions via enteral tubes; therefore, guidelines and recommendations emerged for this purpose, for example [157] .

The production of pro-inflammatory cytokines, namely TNF-α and IL-1, has been found inhibited by vitamin D [26] , in addition to its other anti-inflammatory effects [158] . Vitamin D can also help maintain pulmonary arterial blood pressure and inhibit cystic fibrosis and emphysema [159] through regulating the renin-angiotensin system [160] , thus strengthening the lungs [159] . Deficiency of vitamin D could lead to an increased risk of infection, especially in the respiratory system [161, 162] ; therefore, vitamin D is suggested as a preventative factor in the face of COVID-19 [12] and also in mitigating the potentially deleterious outcomes [163] , so sun exposure in times of quarantine or taking vitamin D supplements should be considered [49] . The recommended guideline for people at risk of infection is rapidly raising vitamin D concentrations by taking 10,000 IU/d of vitamin D3, reduced to 5000 IU/d after a few weeks, with the goal concentration being above 40-60 ng/mL (100-150 nmol/L) [12] .

Vitamin C, present in citrus fruits, acts as an antioxidant and is also well-known for its therapeutic effects on upper respiratory tract infections (URTIs), reducing both the severity of symptoms and duration of the illness [164] .

Melatonin has also been studied in this regard. Melatonin can rejuvenate the glutathione redox system and restore the function of neutrophils in times of heightened oxidative stress, and therefore has been hypothetically suggested as a potential immune booster in the face of COVID-19 [165] .

In the pursuit of intact host defense against COVID-19, dietary recommendations other than micronutrient supplementation have also been studied.

Functional foods are foods with biologically active ingredients. They are physiologically beneficial to health and can help prevent chronic diseases, namely, type 2 diabetes mellitus [166] . Some functional foods have been associated with anti-inflammatory and anti-oxidative properties, such as polyphenol-rich herbs, e.g., coffee and green or black tea [166] , or antimicrobial properties such as bioactive peptides in natural food proteins, which are also available as nutraceuticals [167] . These properties could potentially be protective against COVID-19.

Of the functional foods that have been studied in light of the immune system and used as immune boosters are spices and herbs. Higher ginger, turmeric, garlic, curcumin, and cloves consumption are associated with fewer COVID-19 cases per million population [168] . Curcumin was studied both when used with zinc, as an immunity booster [169] , and alone, showing additional anti-depressant properties [170] . Garlic has been recommended in times of COVID-19 for having antimicrobial, anti-inflammatory, and all-around immunomodulatory properties [171] .

against COVID-19, namely propolis, which is the resinous substance that bees make from botanical exudates [172] .

Eating patterns such as intermittent fasting (IF) and calorie restriction (CR), have been suggested as methods to boost immunity. IF was found to affect immunity in multiple regards, affecting inflammation and oxidative stress, metabolic rate, and body weight, as well as composition [173] . Inflammation, for example, was depressed with IF, as shown in reduced CRP and IL-6 levels in prolonged [174] and short-term IF [175] . Other markers of inflammation (TNFα), along with oxidative stress biomarkers such as nitrotyrosine, 8-isoprostane and protein carbonyls, and metabolic markers such as serum cholesterol and triglycerides, were also reduced with an alternate-day pattern of CR, which lead to better medical outcomes in patients with asthma [176] .

IF can activate immune responses [177] and induce autophagy, which is the elimination of dysfunctional organelles and proteins, as well as invading pathogens [178] , and through distinct J o u r n a l P r e -p r o o f mechanisms, stimulates the immune system and primes host defense; therefore, along with the other effects mentioned above, IF could be a potential preventative approach to COVID-19 [179] . However, this is not recommended for everyone, as spontaneous fasting could have adverse effects even among healthy individuals. Moreover, the CR that happens in IF can be detrimental to the condition of underlying diseases and it is strongly advised for COVID-19

patients not too fast, as there is a risk of inadequate nutrient supply [179] . The net benefits of IF in prevention of COVID-19 should be further studied appropriately.

The previously mentioned immune consequences of obesity due to physical inactivity can be mitigated by moderate physical exercise and drugs commonly used to treat obesity-related diabetes, namely metformin and pioglitazone [133] . Although any physical exercise can be considered favorable compared to inactivity in times of COVID-19 [180] , it is vital to keep a certain level of physical activity to mitigate the immune consequences of inactivity and isolation [181] .

In terms of exercise recommendations in these conditions, a mild to moderate intensity has been suggested, as excessive exercise may negatively affect immunity through subsequent higher cortisol levels [182] and an increased risk of infection [183] . It is advisable to exercise at home, not to put oneself at the risk of exposure to the airborne virus. Targeting balance, strength, control, stretching, or a mix of these, some of the activities achievable at home are those using own body weight, such as sit-ups, push-ups, chair squats, climbing the stairs, lunges, or just walking around the house. One could also choose to walk to necessary places like the store and carry the groceries as a weight-bearing exercise [184] . To keep the recommended moderate intensity, the exercise should use 64-76% of the maximum heart rate, which can be calculated individually by subtracting one's age from 220 [185] .

A gradually increased exercise volume during lockdown can cause a higher maximal oxygen consumption (V O 2max ) [180] . It can be particularly beneficial in individuals who have had lowgrade inflammation for a long time, with more inflammasomes and higher pro-inflammatory J o u r n a l P r e -p r o o f Journal Pre-proof cytokine levels, and are susceptible to higher risks of infection and poorer outcomes, i.e., those with obesity, diabetes, and metabolic syndrome [186] .

With the previously mentioned immune advantages of adequate sleep and the observed sleep disturbances in times of COVID-19 [138] , maintaining a healthy sleep pattern should be prioritized. The recommended sleep duration for adults is usually 7 to 9 hours per night, though this depends on age, gender, and physical activity and should be individualized [187] .

The current circumstances demand different strategies for different groups of people to cope [188] . WHO has shared mental health considerations for the general population, advising to minimize their exposure to outbreak news to reduce anxiety and healthcare workers, recommending them to take care of themselves and rest between shifts, along with considerations for other groups [189] .

Certain groups of people, namely adults who live alone, those with lower income, and young adults (18 to 30 years old), are known to be more likely to experience loneliness, and these groups are even more at risk of loneliness during the COVID-19 pandemic. In addition, other groups, e.g., students, also felt lonelier during lockdown than before the pandemic. It has been suggested that interventions to mitigate loneliness should target these groups of people [146] particularly. The COVID-19 pandemic has made feelings of loneliness and social isolation more prominent, and various interventions in this regard have been studied, namely social prescription by medical professionals, individual and group-oriented therapy, and different strategies involving information and communication technologies (ICT). However, there is still uncertainty about which of these methods works best for each target group [190] . Nonetheless, the stressors present in the context of COVID-19 implicate the urgent need to focus on resilience, both on an individual and a societal level [191] .

Social prescribing is incorporating non-medical interventions, e.g., physical activities, the arts, or other forms of engaging with the community, in the course of therapy, to tackle more J o u r n a l P r e -p r o o f extensive determinants of health while turning to resources that are already present in communities, and thus improving well-being [67] .

A study suggests turning to poetry to combat loneliness in these times of solitude [192] . Singing was also utilized in the COVID-19 lockdown, as the silence of Italian cities was broken by people singing together, apart, each at their own windows, bringing people together at heart and improving the feeling of social cohesion [193] . Along with these social suggestions, dog ownership was also found to be protective against loneliness for people living alone in times of COVID-19 [194] .

Telemedicine can be defined as the act of health care professionals providing health care services through ICT so that valid information is being exchanged, where there is a distance between the provider and the recipient of the care [195] . The distancing nature of the new social norms demanded new ways of health care delivery, as those not infected with the virus, and even more so people at higher risks of infection, like people with underlying diseases, still required care from their medical professionals without risking exposure in hospitals [196] ; thus remotely-delivered interventions were necessary during the COVID-19 lockdown [143, 197] .

The remote management of people with chronic diseases through telemedicine has been studied before this situation [198] . It has been brought to attention in times of COVID-19 for the management of type 1, type 2, and gestational diabetes [199] , and in programs to decrease anxiety in at-risk patients with scleroderma [200] .

With the strain of COVID-19 on mental health and the lack of immediate access to necessary psychiatric care, the use of telemedicine in the context of psychiatry, referred to as telepsychiatry, has been studied. However, it is still underused and can be potentially promoted in current circumstances [201] . The emotional, interpersonal, and economic burden of the current living conditions has led to neglect and thus worsening of mental health and ultimately a higher risk of suicide, as mentioned earlier. Therefore, proper follow-up is vital in the face of psychiatric disorders, and telemedicine can be a useful platform in ensuring this aim in times of COVID-19 [202] .

Brief 30-minute phone calls with clinicians were studied as a connection plan to provide care during social distancing restrictions, thus reducing the risk of suicide [203] . As regular visits are also required in patients with psychosis for their treatment and preventing relapse, an intervention called "Phone Pal" was studied to provide communication between patients and volunteers, as this patient population is particularly isolated in their daily lives and face social stigma. However, the intervention can be implemented for other disorders as well [204] .

Dialectical behavior therapy, a type of cognitive-behavioral therapy, was also studied among patients with borderline personality disorder before and during confinement. During the confinement period of 8 weeks, video and phone calls were used, and patients felt decreased levels of fear and tension and had lower addictive or compulsive behaviors like alcohol consumption or binge-eating, along with an increased feeling of distress, which could be associated with loneliness [205] .

Among people aged 60 and older, COVID-19 has been observed to have substantially higher infection rates, symptom severity, and mortality [206] . Comorbidity is the main cause of this observation. However, it could also be attributed to immunosenescence, which is the decline in the immune system of the elderly and the overall consequences of aging such as lower fitness and general functionality along with the resultant frailty and weakness. Immunosenescence can also affect response to vaccination and the outcome of infectious diseases [207] .

Moreover, an individual's subjective age can affect the association between perceived feelings of isolation or loneliness and the observed psychiatric symptoms during the COVID-19

pandemic. Compared to their actual age, those who felt younger showed a weaker correlation between loneliness and psychiatric symptoms, and those feeling older showed a stronger association. In other words, those with an older age identity are at higher risk of loneliness affecting their mental health. Therefore, higher subjective, as well as objective, age can be risk factors for adverse effects of loneliness in times of COVID-19 [208] .

It explains the need for interventions aimed at the elderly to mitigate the increased feeling of loneliness during the pandemic in this population, many of whom live in nursing homes and may feel even lonelier. To fight this feeling of isolation, self-guided therapy sessions, along with J o u r n a l P r e -p r o o f interventions involving phone calls and video calls, are suggested [143] . To name a few, "The Telephone Outreach in the COVID-19 Outbreak Program" implemented weekly phone calls for the elders at nursing homes to talk with volunteer students, which resulted in the senior residents looking forward to phone calls every week and feeling more socially connected [209] .

"TOVID" (Telephony Or Videophony for Isolated elDerly) provided the same aim. Compared to video calls, telephone calls proved easier to handle independently and were used more frequently among the elderly in hospitals, long-term care, and nursing homes. Both modalities were equally satisfying overall, though video calls were even more favored by the nursing home and long-term care residents when given help with establishing the call [210] .

There is also the need for social workers to be trained in practices involving the elderly regarding subjects that were highlighted in times of COVID-19, namely ageism, loneliness, the use of technology, and the required collaborative practice between those of different professions [211] .

COVID-19 can severely affect immune regulation [6, 27, 29, 30, 34, , as it involves multiple organs [30, 224, 225, [234] [235] [236] [237] [238] [239] [240] , namely the central nervous system [241] [242] [243] . During the pandemic, health polices at both national and international levels [244, 245] and related social consequences have changed almost every aspect of our lives, leading to feelings of anxiety, loneliness, isolation [52], and stress [246] . Altogether, the pandemic of COVID-19 has become a live enemy to our IMMERS [152] . The present review concluded that the adverse effects of isolation could be mitigated through health behaviors. Armed with the capacity to utilize the suggested methods, we can aim for a robust immune system and fight this battle [247] , which has persisted for a year now [248] . Pro-sensing biomaterials are of emerging interest that can accelerate the early immune responses [243] , while testing the clinical efficacy of a variety of ancient and modern therapies that selectively modulate inflammation remains under investigation [249] [250] [251] [252] .

DeclarationsEthics approval and consent to participate 

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The authors declare that they have co conflicts of interest.

There is no funding for the present study.

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Effects of inflammation on social processes and implications for health

Social regulation of inflammation related gene expression in the multi-ethnic study of atherosclerosis

Loneliness and acute stress reactivity: A systematic review of psychophysiological studies

Synergistic relationships among stress, depression, and troubled relationships: insights from psychoneuroimmunology

Loneliness promotes inflammation during acute stress

The association between loneliness, social isolation and inflammation: A systematic review and meta-analysis

Loneliness and stress-related inflammatory and neuroendocrine responses in older men and women

Effectiveness of LISTEN on loneliness, neuroimmunological stress response, psychosocial functioning, quality of life, and physical health measures of chronic illness

Loneliness in middle age and biomarkers of systemic inflammation: Findings from Midlife in the United States

Loneliness in healthy young adults predicts inflammatory responsiveness to a mild immune challenge in vivo

Social networks and inflammatory markers in the Framingham Heart Study

Longitudinal analysis of loneliness and inflammation at older ages: English longitudinal study of ageing

Loneliness and neuroendocrine, cardiovascular, and inflammatory stress responses in middle-aged men and women

Loneliness, Depression, and Inflammation: Evidence from the Multi-Ethnic Study of Atherosclerosis

Transcriptional modulation of the developing immune system by early life social adversity

Psyche and immunity. A selected literature study of psychoneuroimmunology in healthy persons

Stress, loneliness, and changes in herpesvirus latency

Loneliness predicts pain, depression, and fatigue: understanding the role of immune dysregulation

Threats to Belonging, Immune Function, and Eating Behavior: an Examination of Sex and Gender Differences

Cytokine dysregulation associated with exam stress in healthy medical students

Exploring the emotions of patients undergoing therapy for hepatitis C

Community-Driven Health Priorities for Healthy Aging With HIV

Mechanisms for the Negative Effects of Internalized HIV-Related Stigma on Antiretroviral Therapy Adherence in Women: The Mediating Roles of Social Isolation and Depression

Psychosocial Well-Being and HIV-Related Immune Health Outcomes among HIV-Positive Older Adults: Support for a Biopsychosocial Model of HIV Stigma and Health

Social stigma in the time of coronavirus disease 2019

Loneliness and COVID-19 preventive behaviours among Japanese adults

Psychosocial modifiers of immunocompetence in medical students

Loneliness in old age

A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling

Transcriptional control of monocyte gene expression in post-traumatic stress disorder

Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis

Exploring Relationships Among Peripheral Amyloid Beta, Tau, Cytokines, Cognitive Function, and Psychosomatic Symptoms in Breast Cancer Survivors

Coping with being cooped up: Social distancing during COVID-19 among 60+ in the United States

Balanced diet is a major casualty in COVID-19

Nutritional strategies to counter stress to the immune system in athletes, with special reference to football

Self-quarantine and weight gain related risk factors during the COVID-19 pandemic

Eating disorders in times of the COVID-19 pandemic-Results from an online survey of patients with anorexia nervosa

COVID-19 Pandemic Brings a Sedentary Lifestyle in Young Adults: A Cross-Sectional and Longitudinal Study

Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms

Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic

Cardiorespiratory fitness and the metabolic syndrome: Roles of inflammation and abdominal obesity

Insomnia during COVID-19 pandemic and lockdown: Prevalence, severity, and associated risk factors in French population

COVID-19 related loneliness and sleep problems in older adults: Worries and resilience as potential moderators

Insomnia during the COVID-19 pandemic in a Greek population

Do lonely days invade the nights? Potential social modulation of sleep efficiency

Sick and tired: Does sleep have a vital role in the immune system?

Sleep Pattern Changes in Nursing Students during the COVID-19 Lockdown

Psychological Outcomes Associated with Stay-at-Home Orders and the Perceived Impact of COVID-19 on Daily Life

Determining depression and related factors in a society affected by COVID-19 pandemic

Social Isolation and Psychological Distress Among Older Adults Related to COVID-19: A Narrative Review of Remotely-Delivered Interventions and Recommendations

COVID-19: Preliminary Data on the Impact of Social Distancing on Loneliness and Mental Health

Changes in Physical Activity and Sedentary Behavior in Response to COVID-19 and Their Associations with Mental Health in 3052 US Adults

From stress to inflammation and major depressive disorder: a social signal transduction theory of depression

Impact on mental health by "Living in Isolation and Quarantine" during COVID-19 pandemic

Infodemic and Fake News in Spain during the COVID-19 Pandemic

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

COVID-19 and the role of chronic inflammation in patients with obesity

The Immunoemotional Regulatory System

The immune system: a target for functional foods?

Nutritional recommendation for COVID-19

Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet

Challenges of Maintaining Optimal Nutrition Status in COVID-19 Patients in Intensive Care Settings

The anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin-mediated T lymphocyte homing

Role of vitamin d in boosting immunity against covid-19

Vitamin D regulation of the renin-angiotensin system

An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men

Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers

Vitamin D Levels and COVID-19 Susceptibility: Is there any Correlation? Med Drug Discov, 2020

Knowledge and awareness on natural dietary immunoboosters to combat covid 19-a survey

Melatonin restores neutrophil functions and prevents apoptosis amid dysfunctional glutathione redox system

Functional Foods and Lifestyle Approaches for Diabetes Prevention and Management

Aptamers: an emerging class of bioaffinity ligands in bioactive peptide applications

Immunity-Boosting Spices and the Novel Coronavirus

Can concomitant use of zinc and curcumin with other immunity-boosting nutraceuticals be the arsenal against COVID-19?

Fight COVID-19 depression with immunity booster: Curcumin for psychoneuroimmunomodulation

The effects of allium sativum on immunity within the scope of COVID-19 infection

Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease: Running title: Propolis against SARS-CoV-2 infection and COVID-19

Ramadan intermittent fasting and immunity: An important topic in the era of COVID-19

Interleukin-6, C-reactive protein and biochemical parameters during prolonged intermittent fasting

Obesity and inflammation: Effects of short-term fasting on IL6 and relationship to diurnal cortisol

Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma

Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

The effect of fasting or calorie restriction on autophagy induction: A review of the literature

Intermittent fasting, a possible priming tool for host defense against SARS-CoV-2 infection: Crosstalk among calorie restriction, autophagy and immune response

Antiviral Functional Foods and Exercise Lifestyle Prevention of Coronavirus

The immunological case for staying active during the COVID-19 pandemic

The anti-inflammatory effects of exercise in the syndromic thread of diabetes and autoimmunity

Can exercise affect immune function to increase susceptibility to infection?

Coronavirus disease (COVID-19): The need to maintain regular physical activity while taking precautions

ACSM's guidelines for exercise testing and prescription

Does High Cardiorespiratory Fitness Confer Some Protection Against Proinflammatory Responses After Infection by SARS-CoV-2? Obesity (Silver Spring)

National Sleep Foundation's updated sleep duration recommendations: final report. Sleep Health

Impact of lock-down on mental health and tips to overcome

Mental health and psychosocial considerations during the COVID-19 outbreak

How the COVID-19 pandemic is focusing attention on loneliness and social isolation

Stress resilience during the coronavirus pandemic

A Look Back and a Path Forward: Poetry's Healing Power during the Pandemic

COVID-19 and spontaneous singing to decrease loneliness, improve cohesion, and mental well-being: An Italian experience

Puppy love in the time of Corona: Dog ownership protects against loneliness for those living alone during the COVID-19 lockdown

Telemedicine: opportunities and developments in Member States: report on the second global survey on eHealth

Telehealth for global emergencies: Implications for coronavirus disease 2019 (COVID-19)

COVID-19 and telemedicine: Immediate action required for maintaining healthcare providers well-being

The empirical foundations of telemedicine interventions for chronic disease management

Recommendations and management of hyperglycaemia in pregnancy during COVID-19 pandemic in Italy

Protocol for a partially nested randomised controlled trial to evaluate the effectiveness of the scleroderma patient-centered intervention network COVID-19 home-isolation activities together (SPIN-CHAT) program to reduce anxiety among at-risk scleroderma patients

Telepsychiatry and other cutting edge technologies in Covid-19 pandemic: bridging the distance in mental health assistance

Adaptation of evidence-based suicide prevention strategies during and after the COVID-19 pandemic

Strategies to Promote Social Connections Among Older Adults During 'Social Distancing' Restrictions

Can social isolation caused by physical distance in people with psychosis be overcome through a Phone Pal? Eur Psychiatry

Adaptations of an outpatient Dialectical Behavioral Therapy during the COVID-19 pandemic and consequences of the confinement on patients with borderline personality disorder

Characteristics of COVID-19 infection in Beijing

Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections

COVID-19-Related Loneliness and Psychiatric Symptoms Among Older Adults: The Buffering Role of Subjective Age

Combating Heightened Social Isolation of Nursing Home Elders: The Telephone Outreach in the COVID-19 Outbreak Program

Communication Technology Preferences of Hospitalized and Institutionalized Frail Older Adults During COVID-19 Confinement: Cross-Sectional Survey Study

COVID-19 Pandemic: Workforce Implications for Gerontological Social Work

Impact of SARS-CoV-2 Pandemic on Patients with Primary Immunodeficiency

SARS-CoV-2-A Tough Opponent for the Immune System

Challenges for management of immune thrombocytopenia during COVID-19 pandemic

Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran

Lymphopenia in COVID-19: Therapeutic opportunities

Occurrence of acute coronary syndrome, pulmonary thromboembolism, and cerebrovascular event in COVID-19

Immune-epidemiological parameters of the novel coronavirus -a perspective

Kawasaki Disease and Multisystem Inflammatory Syndrome in Children with COVID-19

The immune system and COVID-19: Friend or foe?

Anosmia: a missing link in the neuroimmunology of coronavirus disease 2019 (COVID-19)

Genetic predisposition models to COVID-19 infection

Death due to COVID-19 in an Infant with Combined Immunodeficiencies

Cutaneous lesions and COVID-19: Cystic painful lesion in a case with positive SARS-CoV-2

Adrenal insufficiency in coronavirus disease 2019: a case report

Dysregulation of the Immune Response in COVID-19

Case Report: Death due to COVID-19 in Three Brothers

Human coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 in children

Primary Immunodeficiency Diseases in COVID-19 Pandemic: A Predisposing or Protective Factor?

COVID-19 affects healthy pediatricians more than pediatric patients

Interindividual immunogenic variants: Susceptibility to coronavirus, respiratory syncytial virus and influenza virus

Role of Toll-like receptors in the pathogenesis of COVID-19

Cytokine release syndrome: inhibition of pro-inflammatory cytokines as a solution for reducing COVID-19 mortality

Cardiovascular diseases burden in COVID-19: Systematic review and metaanalysis

Acute Cardiac Injury in COVID-19: A Systematic Review and Meta-analysis

Central Nervous System Involvement in COVID-19

SARS-CoV-2: A comprehensive review from pathogenicity of the virus to clinical consequences

The Overlap between Genetic Susceptibility to COVID-19 and Skin Diseases

Death due to COVID-19 in a patient with diabetes, epilepsy, and gout comorbidities. Clin Case Rep

The role of angiotensin-converting enzyme 2 in COVID-19 induced lung injury

Neurological manifestations as the predictors of severity and mortality in hospitalized individuals with COVID-19: a multicenter prospective clinical study

COVID-19 infection and stroke risk

Biosensing surfaces and therapeutic biomaterials for the central nervous system in COVID-19

Health Care Policies and COVID-19 Prevalence: Is There Any Association?

COVID-19 in Iran: Forecasting Pandemic Using Deep Learning

The prevalence of post-traumatic stress disorder related symptoms in Coronavirus outbreaks: A systematic-review and meta-analysis

COVID-19 pandemic is not the time of trial and error

With Risk of Reinfection, Is COVID-19 Here to Stay?

Immune checkpoint inhibition in COVID-19: risks and benefits

SARS-CoV-2: From the pathogenesis to potential anti-viral treatments

Phytopharmaceuticals mediated Furin and TMPRSS2 receptor blocking: can it be a potential therapeutic option for Covid-19?

Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients

Not applicable

 These negative effects on immunity can be mitigated by moderate physical activity, adequate nutrition and better quality of sleep.  Telemedicine can provide access to medical professionals and ease the coping process for people in need of constant health care during lockdown and social distancing.