iii. Acute respiratory distress syndrome (ARDS), mechanical ventilation, and associated cognitive decline: Although the exact ratio of COVID-19 patients developing severe disease and requiring hospitalization or intensive care unit (ICU) admission varies extensively, there is undoubtedly a noticeable proportion that progresses to life-threatening conditions [83]. Preliminary studies from China investigating data of more than 70 thousand patients suggested that around 19% of patients with COVID-19 develop severe or critical disease, most likely necessitating hospitalization [84]. A survey of 17 studies examining statistics of hospitalized COVID-19 patients from different regions found that one-third of all hospitalized and threequarters of all ICU-admitted patients develop ARDS [83]. Cognitive impairment following ARDS of variable etiology is widely reported and reviewed [85]. Although severe inflammation, hemodynamic instability, and hypoxia have been indicted, the exact mechanism causing it is unknown. However, a review of studies has shown that cognitive impairment post-ARDS has a high incidence and ranges from 70–100% at hospital discharge, to 46–80% at one year after discharge, to 20% at five years after discharge [85]. In addition, an observational study in France described several ICU-admitted COVID-19 patients with complaints of ARDS developing encephalopathy manifesting as confusion and agitation [31]. According to Tzotzos et al., of the COVID-19 ICU-admitted patients who develop ARDS, more than 80% must receive mechanical ventilation [83]. Mechanical ventilation, regardless of ARDS, is associated with cognitive decline and reduced quality of life in the long run [86]. Since mechanical ventilation inextricably leads to the administration of sedatives, it is essential to note delirium and other cognitive consequences that may accompany, both in the short and long term [87]. The likelihood of a systemic inflammation playing a significant role in the development of cognitive loss compared to direct viral damage is underscored by the sparse evidence of the virus being found in the CSF [16]. Furthermore, instead of being two entirely independent processes, the neurotropism of SARS-CoV-2 and the widespread parallel inflammation may also operate in conjunction [7] and collectively lead to direct and indirect neuronal damage with cognitive deficits. Lastly, it is crucial to not trivialize non-specific but potentially key elements in developing cognitive sequelae, namely COVID-19 complications such as ARDS and subsequent mechanical ventilation [11].

#### *4.3. The Psychosocial Strain of the Pandemic and Associated Lockdowns*

i. Psychological stressors: While countries battle their second or third waves, confinement due to lockdowns and the fear of one or one's loved ones contracting

COVID-19 are just some of the reasons that continue to cause an unprecedented psychological burden on people across the world [12,88]. With psychological conditions such as anxiety and depression now being recorded globally, cognitive consequences can be reasonably expected as a unique symptomatic presentation [89]. A systematic review remarked that some studies had shown the prevalence of post-traumatic stress disorder (PTSD) ranging from 7% to as high as 53.8% during the pandemic [90]. Moreover, this psychological disorder has been correlated with diminishing cognitive function, especially in the elderly [91], showing how 'Cognitive COVID' is possibly related to an individual's psychological state.

ii. Social isolation and government-mandated lockdowns: An article published in late 2020 had reviewed the available evidence and stipulated that social distancing/isolation and lack of human interaction may have a detrimental effect on a person's cognition [92]. Echoing these findings, a study conducted in Italy during May 2020 investigated the effects of psychological stressors as a result of isolation in the form of national lockdown as a mitigation technique on the global cognitive function of the public [93]. Findings suggested cognitive function such as barring memory deteriorated during lockdowns. Furthermore, with a greater prevalence of anxiety, depression, and other mental health changes, a significant deleterious impact on cognitive function(s) was noted in those who had lesser social interactions [93].

Further research needs to correlate lockdowns and various psychosocial factors of the pandemic with cognitive ability to gather experimental evidence. Consequently, the findings may aid in ascertaining if this psychological burden is responsible for the reason why COVID-19 survivors may develop cognitive sequelae following their recovery. Likewise, any significant conclusions may also illustrate if psychosocial distress in the wake of lockdowns increases an individual's risk of being affected and the severity by which they are affected due to other causal factors outlined in this text earlier.

#### **5. COVID-19 Vaccination, Autoimmunity, and Cognitive Impairment**

The vaccine roll-out for COVID-19 began recently, but nearly 3.57 billion doses have been administered worldwide already [1]. Various vaccines were approved by the World Health Organization (WHO) for emergency use but all of them fall under three major subtypes: messenger RNA (mRNA), viral vector, and inactivated whole-virus [94]. As the pace of vaccine administration increases, more data is surfacing regarding post-vaccination adverse events. Neurocognitive symptoms following vaccinations COVID-19 vaccinations are rare but emerging case reports require due attention to accurately evaluate the pathophysiology and risk-factors carefully and accurately.

Two cases of encephalopathy within one week following inoculation via an mRNA vaccine were reported in patients with no prior neuropsychiatric history [95]. Furthermore, an 89-year-old patient developed delirium after a first dose of an mRNA vaccine [96]. The mRNA in the vaccines encodes antigen S-2B, which includes SARS-CoV-2 spike glycoprotein. The spike glycoprotein during a viral infection initiates a cascade of inflammatory reactions after attaching to ACE2 receptor, leading to COVID-19 encephalopathy [95]. Authors hypothesize that cells translating this vaccine mRNA may produce the same glycoprotein and in turn mimic the encephalopathy caused by an active viral infection [95]. Furthermore, acquired immunity via anti-spike antibodies linking to spike protein of SARS-CoV has been known to boost inflammation by activating macrophages [80]. A similar mechanism following development of anti-spike antibodies against SARS-CoV-2 after administration of mRNA vaccines may lead to widespread inflammation, macrophage activation, and development of neurological symptoms [80,95,96].

An interesting case is of an adult, who recovered from COVID-19 6 weeks ago, developing MIS following a second dose of an inactivated virus vaccine [97]. Features of shock and cardiac dysfunction were present in the patient along with elevated inflammatory markers, indicating MIS. The authors postulate that the vaccine may have accentuated their

body's immune response which was 'already primed' following SARS-CoV-2 infection and therefore led to an uninhibited inflammatory condition in the body [97].

Some authors have warned against the use of certain immunogenic proteins of SARS-CoV-2 in vaccines that are homologous to the human immune system [98]. With most of SARS-CoV-2's immunogenic epitopes matching human proteins, there is a reasonable risk that vaccines containing these epitopes will lead to autoimmunity [98]. Excessive inflammation, creation of autoantibodies, and a series of biochemical processes due to autoimmunity may lead to neuroinflammation, damage to neuronal integrity and cognitive impairment [99]. Using Alzheimer's Disease as a parallel in mouse models, a temporal association between increasing autoimmunity and declining cognitive competence was found [100], highlighting the damaging effect accelerated autoimmunity may have on brain function.

#### **6. Discussion**

We have identified three major areas of discussion when debating on causality of cognitive symptoms occurring during and after a SARS-CoV-2 infection. The direct neurotropism of SARS-CoV-2 is largely based on information available for SARS-CoV. Several hypotheses on mechanisms of direct neurotropism have been outlined, such as infiltration of virus-laden immune cells, hematogenous spread through CVOs or breaks in BBB, and retrograde neuronal transmission through invasion of the olfactory system. Furthermore, non-specific systemic inflammation which also manifest as multisystemic inflammatory syndrome (MIS) due to a 'cytokine storm' reported in COVID patients predisposes them to vascular injuries, leading to neuroinflammation. As mentioned earlier, treatment methods such as intubation to treat ARDS can also lead to cognitive symptoms. Lastly, a neuropsychiatric vantage point allows us to underscore the importance of prevailing psychological stressors and their effect on a person's cognitive ability.

For the first time, to our knowledge, in this text we have also reviewed case studies of cognitive impairment and adverse-events following COVID-19 vaccinations, especially the mRNA subtype. We have discussed the occurrence of a heightened immune response to spike glycoprotein encoded by the mRNA in the vaccine which leads to a condition similar to COVID-19 encephalopathy. By discussing the potential occurrence of autoimmunity following inoculation, we have identified the risk of using viral epitopes that are homologous to proteins in the human immune system.

Furthermore, despite the varying prevalence and presentations of cognitive deficits, due to the sheer scale of the pandemic, with global cases crossing 173 million [1], any proportion will result in substantial implications on health systems and a massive influx of patients with cognitive complaints. Therefore, with more significant evidence through research, greater awareness regarding the probable emergence of 'Cognitive COVID' in some patients is required—both for the public, early seeking medical care, and healthcare workers, for readiness and early detection.

As described above, the varying levels of cognitive impairment will require a thorough evaluation, planned follow-ups, and in-patient management if required. Consequently, facilities and institutions should allocate adequate resources and enable their healthcare workers via training to effectively respond to those COVID-19 survivors at high risk for developing cognitive sequelae [6].

Additionally, the therapeutic significance of understanding and ascertaining the etiology of 'Cognitive COVID', particularly on a cellular level, is manifold. There are available interventions that may mitigate the negative impact of high inflammation levels with a potential cytokine storm, including cytokine antagonists and other anti-inflammatory modulators [64]. Importantly, due to the requirement of physical distancing to avoid transmission of SARS-CoV-2, telemedicine for diagnosis and cognitive rehabilitation is an exciting and promising avenue to be utilized [101]. Moreover, as a psychosocial burden and mental health disorders are possible causal elements, telepsychiatry services can play a crucial role in preventing cognitive impairments [102].

#### **7. Conclusions, Limitations and Way Forward**

Cognitive COVID is an oft-ignored aspect of the pandemic, but with greater attention now being paid to the non-respiratory and long-term cognitive consequences of COVID, it is vital to collect further evidence regarding the prevalence, presentation, correlations, and causality of these events. Furthermore, the potentially long-term nature of these deficits and their devastating effect on quality of life, especially the elderly, makes it more pressing to review our current approach in early identification, management, and rehabilitation of patients exhibiting cognitive symptoms [6]. In this article, we have highlighted the probable causality of Cognitive COVID by reviewing the available hypotheses, case reports, and clinical data that has been published after the pandemic started and used previous coronaviruses as a basis to form a parallel to the novel coronavirus 2019.

Due to the relative recency of the pandemic and unavailability of coherent data, it is extremely challenging to reach a plausible conclusion regarding the intricate interplay of causal factors. Criteria to determine causality such as the Bradford-Hill criteria [103] are difficult to apply on the causal factors. The lack of consistent data available from different regions across the world and various methods of measuring inflammation or cognitive deficits disallow direct comparison. The biological plausibility criterion of Bradford-Hill criteria, however, has been discussed at depth in the text to decipher neurological and inflammatory mechanisms that lead to clinical symptoms. Another criterion of analogy can be extrapolated to use of available data from SARS-CoV and MERS-CoV to predict SARS-CoV-2's effect on the brain. We are also limited by a lack of research conducted into different variants of SARS-CoV-2 and their effect on cognition.

The way forward is to develop a standardized protocol for neurocognitive assessment of COVID-19 patients, especially at times of discharge from hospitalization and end of medical interventions such as intubation. These steps will mitigate the threat posed by 'Cognitive COVID' and will undoubtedly decrease the burden on already overwhelmed healthcare systems.

Moving forward, greater attention should be paid to cognitive impairment during and after COVID-19 and vaccination. With the emergence of new strains of COVID-19, such as the Delta and the Lambda variant [104], the variation in prevalence of cognitive manifestations of the viral infection needs to be ascertained. Therefore, it is imperative to collect empirical data from multiple demographics in order to attain uniform clinical and biochemical information regarding causality and risk-factors in developing cognitive impairments.

**Author Contributions:** Conceptualization, I.U.; methodology, H.A.A. and A.A.; formal analysis, H.A.A.; data curation, M.N.D. and M.A.; writing—original draft preparation, H.A.A., M.D.G., A.A. and M.A.; writing—review and editing, S.S. and D.D.B.; visualization, I.U. and D.D.B.; supervision, I.U. and D.D.B.; project administration, I.U. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** No new data were created or analyzed in this study. Data sharing does not apply to this article.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

## *Review* **Impact of COVID-19 on Neuropsychiatric Disorders**

**Niloufar Zia 1, Parsa Ravanfar 2, Sepideh Allahdadian 3 and Mehdi Ghasemi 4,\***

**Abstract:** Since the Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many studies have shown that besides common COVID-19 symptoms, patients may develop various neuropsychiatric conditions including anxiety, mood disorders, psychosis, neurodegenerative diseases (e.g., dementia), insomnia, and even substance abuse disorders. COVID-19 can also worsen the patients underlying neuropsychiatric and neurodevelopmental conditions during or after the system phase of disease. In this review, we discuss the impact of SARS-CoV-2 infection on development or status of neuropsychiatric conditions during or following COVID-19.

**Keywords:** coronavirus disease 2019 (COVID-19); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); neuropsychiatry; neurodegenerative diseases; neurodevelopmental diseases

#### **1. Introduction**

In December 2019, a novel Coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China. Soon after it became an epidemic throughout the world. SARS-CoV-2 has some spikes on its surface which are the membrane-anchored tiners consisting of receptor binding s1 and membrane-fusion s2 segment. The Cov name originated from these spikes. S1 segment consists of the receptor binding domain (RBD) that causes pathogenicity and infects the host cell via binding to the angiotensin-converting receptor-2 (ACE-2) on all tissues [1,2]. RBD has greater affinity for ACE-2 on cells of the ileum, kidney, heart, brain, lung, and vasculatures. It is responsible for the different manifestations it has, including respiratory disease and mild pneumonia; its usual symptoms include fever, shortness of breath, cough, and fatigue [3]. Besides systemic manifestation, accumulating reports indicate that patients with COVID-19 may develop a variety of neuropsychiatric conditions during or after COVID-19 (Figure 1) [4–7]. SARS-CoV-2 infection may also affect the patients' current neuropsychiatric conditions in various ways. Given the high burden of neuropsychiatric conditions on society besides COVID-19 itself, in this review, we will discuss the impact of SARS-CoV-2 infection on new-onset and current neuropsychiatric conditions in patients with COVID-19.

**Citation:** Zia, N.; Ravanfar, P.; Allahdadian, S.; Ghasemi, M. Impact of COVID-19 on Neuropsychiatric Disorders. *J. Clin. Med.* **2022**, *11*, 5213. https://doi.org/10.3390/ jcm11175213

Academic Editor: Alfonso Troisi

Received: 6 August 2022 Accepted: 2 September 2022 Published: 3 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Figure 1.** Neuropsychiatric manifestations and possible underlying mechanisms after SARS-CoV-2 infection. ACE2, angiotensin-converting enzyme 2; AD, Alzheimer's disease; BBB, blood-brain barrier; IL-6, interleukin-6; LRRK2, leucine-rich repeat kinase 2; PD, Parkinson's disease; TNF-α, tumor necrosis factor-α.

#### **2. Neuropsychiatric Complications of COVID-19**

Acute neuropsychiatric presentations and potentially long-term complications have been reported in people infected with COVID-19 as well as those who recovered from it [5]. In a large study using the TriNetX Analytics Network (a federated network recording anonymized data from electronic health records in 62 healthcare organizations, primarily in the United States [US]) and including 62,354 patients with confirmed diagnosis of COVID-19 [8], it was shown that COVID-19 was associated with increased incidence of a first psychiatric diagnosis in the following 14 to 90 days compared with six other health events (i.e., influenza, other respiratory tract infections, skin infection, cholelithiasis, urolithiasis, and a large bone fracture). The hazard ratios were greatest for anxiety disorders, insomnia, and dementia. The incidence of any psychiatric diagnosis in the 14 to 90 days after COVID-19 diagnosis was 18.1%, with 5.8% having a first diagnosis (e.g., first diagnosis of dementia 1.6% in patients older than 65 years) [8,9]. There is a wide range of underlying etiologic factors both within and beyond the CNS that lead to neuropsychiatric sequelae (Figure 1) [7].

In two large sample retrospective studies of 40,469 patients who recovered from COVID-19 in the TriNetX database, diagnosis of anxiety (and related disorders) and mood disorders was established in 4.6% and 3.8%, respectively, on or within one month after diagnosis of COVID-19 [6] (Table 1). Another retrospective study on 44,779 COVID-19 patients without previous psychiatric illness in the TriNetX Analytics Network revealed that the rate of all diagnoses of psychiatric disorders (i.e., including relapses) was higher within 14 to 90 days after COVID-19 diagnosis than after control health events (i.e., influenza, other respiratory tract infections, skin infection, cholelithiasis, urolithiasis, and a large

bone fracture) [9]. The most common psychiatric diagnosis after COVID-19 diagnosis was anxiety disorder (12.8%, 95% confidence interval [CI] 12.4–13.3), followed by mood disorders (9.9%, 9.5–10.3). The probability of a first diagnosis of mood disorder within 14 to 90 days after COVID-19 diagnosis was 2% (95% CI 1.7–2.4), with depressive episode as the most common first diagnosis of mood disorder (1.7%, 95% CI 1.4–2.1) [9]. In another retrospective cohort study on 236,379 survivors of COVID-19 in the TriNetX Analytics Network, estimated incidences for first-time anxiety disorders in the following 6 months in the whole cohort and those admitted to intensive care unit (ICU) were 17.39% (95% CI 17.04–17.74) and 19.15% (95% CI 17.90–20.48), respectively [8]. Moreover, the estimated incidences for first-time mood disorders in the following 6 months in this study were 4.22% (95% CI 3.99–4.47) and 5.82% (95% CI 4.86–6.97) [8]. The prevalence of self-reported symptoms of depression and anxiety was much higher. Studies using self-report tools have suggested a markedly greater frequency of depressed mood (29.2%), anxiety, and post-traumatic anxiety symptoms (20.8–96.2%) in different countries including China and Italy [10–13] (Table 1).

There are multiple factors that contribute to the development of mood and anxiety disorders associated with COVID-19. These factors can be categorized into three domains: contextual factors and life stressors, disease-related reduction in quality of life such as fatigue and breathlessness, and biological factors impacting the brain such as neuro-immunological phenomena. Based on the evidence provided by Taquet et al., this higher occurrence of first-time mood and anxiety disorders cannot be solely attributed to the contextual factors such as economic and social adversities/challenges/stressors associated with COVID-19. Here, we focus on the disease-related pathophysiological mechanisms that may account for the occurrence of these psychiatric manifestations. The association between COVID-19 and depression and anxiety can be due to neurotropism of the virus, or the immunological reactions of the body such as cytokine storm [18]. In a study by Mazza et al. in Italy, there was a significant association between systemic immune-inflammation index (SII) with measures of anxiety and depression [12]. COVID-19 has been characterized by an exaggerated inflammatory response known as a "cytokine storm", and inflammatory cytokines have been associated with depression [19]. Conversely, the presence of a previous diagnosis of mood disorder is associated with higher mortality rates after prolonged hospitalization [20].

First-time psychosis may also occur among patients with COVID-19 as assessed in the TriNetX Analytics Network as well as systematic reviews of case reports and case series from different regions worldwide [8,9,21]. Although there has been shown a low probability of being newly diagnosed with a psychotic disorder in the 14 to 90 days after COVID-19 diagnosis (0.1%, 95% CI 0.08–0.2), broadly similar to the probability after control health events [9], the estimated incidences of psychotic disorders within 6 months after COVID-19 was higher by 1.40% (95% CI 1.30–1.51). It was even more increased in those patients initially admitted to the ICU due to COVID-19 (2.77%, 95% CI 2.31–3.33) [8]. A more recent systematic review of case reports and case series of 57 patients with COVID-19 (collected from six electronic databases including PubMed, Scopus, Web of Science, PsycInfo, PsycArticles, and CINAHL) also reported that the mean age for onset of psychotic symptoms (predominantly delusions and hallucinations) was the early 40s (men: 43.4 and women: 40.3), more than two thirds (~69%) of patients did not have any prior psychiatric disorders [21]. Only 26.3% of patients presented with moderate-severe COVID-19-related disease and complications. Overall, psychotic symptoms resolved markedly in 63.2% of cases after treatment with antipsychotics, benzodiazepines, valproic acid, and electroconvulsive treatment [21]. COVID-19-related new-onset psychosis and mania have been also reported in children and adolescents, even in those with asymptomatic COVID-19 infections as described in some case reports in the U.S. [22].

New onset dementia and cognitive dysfunction can occur in relation with COVID-19 [8,9,16,23]. A retrospective analysis of 50 patients with COVID-19 in the U.S. found cognitive impairment in 26% of cases [23]. Another study on 153 COVID-19 cases in the United Kingdom (UK) also showed that overall, 23 (15.3%) patients developed neuropsychiatric disorders related to COVID-19, among which 10 (43%) patients had newonset psychosis, 6 (26%) had a neurocognitive (dementia-like) syndrome, and 4 (17%) had an affective disorder [16]. Further larger cohort studies showed that the estimated incidence of dementia during the first 14 to 90 days after a diagnosis of COVID-19 is 0.44% (95% CI 0.33–0.60); which was higher in those patients older than 65 years (1.6%,

95% CI 1.2–2.1), with a hazard ratio (HR) between 1.89 and 3.18 [9]. The estimated incidence of new dementia in the following 6 months was even higher by 0.67% (95% CI 0.59–0.75) and again with an increased rate in those patients initially admitted to ICU due to COVID-19 (1.74%, 95% CI 1.31–2.30) or in those who had encephalopathy by 4.72% (3.80–5.85) [8].

Both short-term (i.e., within 14 to 90 days) and 6-month onset of other neuropsychiatric conditions, such as insomnia and substance use disorder, may rise in the COVID-19 population as assessed in the TriNetX Analytics Network [8,9]. A post-discharge evaluation of 120 COVID-19 patients in France after an average of 110.9 days following admission showed that the most frequently reported persistent symptoms were fatigue (55%), dyspnea (42%), loss of memory (34%), difficulty in concentration (28%), and sleep disorders (30.8%) [24]. The probability of a first diagnosis of insomnia in the 14 to 90 days after COVID-19 diagnosis was further shown to be 1.9% (95% CI 1.6–2.2), more common than after controlled health events (HRs 1.85–3.29), in agreement with predictions that circadian disturbances will follow COVID-19 infection [9,25]. Close to 60% of the insomnia diagnoses were not accompanied by a concurrent diagnosis of an anxiety disorder [9]. The estimated incidence of first insomnia within 6 months post-COVID-19 was 2.53% (95% CI 2.37–2.71) [8]. The estimated incidence of new substance use disorder within 6 months following COVID-19 was 1.92% (95% CI 1.77–2.07) [8]. Overall, the above data indicate that COVID-19 is followed by remarkable rates of long-term neuropsychiatric diagnoses.

#### **3. Impact of COVID-19 on Neuropsychiatric Disorders**

The COVID-19 virus infection and the impact of the virus on society causes several different sequels and comorbidities in physical and mental health [26]. Infection with COVID-19 may cause the worsening of neuropsychiatric disorders and/or the development of neuropsychiatric disorders [26,27]. In addition, the societal consequences of the pandemic (i.e., isolation and quarantine) have caused the worsening and development of neuropsychiatric disorders [26]. Examples of relevant neuropsychiatric disorders in the context of COVID-19 include depression, anxiety, delirium, mood compulsivity, cognitive impairment, and obsessive-compulsive symptoms [26,28]. There are a variety of mechanisms that likely cause the worsening of the development of neuropsychiatric disorders in the context of COVID-19 infection and the ongoing pandemic [26].

Recent research examining the impact of COVID-19 infection on mental health functioning suggests that the virus causes an inflammation of the CNS which, in turn, may stress mental health processes and functioning through cytokine secretion [26]. Other research suggests that COVID-19 increases the risk of or exacerbates neuropsychiatric disorders via hypoxemia, which is common among individuals infected with COVID-19 [29,30]. Moreover, other research identifies additional ways by which COVID-19 infection and the pandemic negatively impact mental health (e.g., isolation, changes in social support, economic stressors) [26].

Individuals with pre-existing neuropsychiatric disorders and symptoms are likely at greater risk of poor mental health outcomes in the context of COVID-19 [26,31]. Indeed, the worldwide virus appears to affect people differently based on their baseline psychiatric functioning. As such, individuals with mood disorders, anxiety disorders, and psychotic disorders, may have a different baseline of psychiatric functioning and could be at higher risk of developing neuropsychiatric disorders or experiencing a worsening of neuropsychiatric symptoms following COVID-19 infection, as assessed in different studies and regions including the U.S. and Brazil [8,9,26,31,32].

Individuals with neuropsychiatric disorders demonstrate different and worse symptoms and functioning as compared to their counterparts in the context of the ongoing COVID-19 pandemic [26,33]. Specifically, individuals with pre-existing mood and anxiety disorders report increased stress and fear of pollution in the current pandemic [31]. In addition, these symptoms reached clinically significant or concerning levels. Among individuals with a pre-existing neuropsychiatric disorder who contracted COVID-19, many experienced an exacerbation of mental health symptoms [26,31,34,35]. Specifically, individuals may have experienced serious neuropsychiatric complications, including delirium, cognitive impairment, significant mood alterations, or even psychosis [26,31,32]. Indeed, even among people without pre-existing neuropsychiatric disorders, delirium occurs in most individuals who contract COVID-19 [26,36].

#### *3.1. Anxiety Disorders*

Individuals with anxiety disorders are at risk of poorer outcomes in the context of the COVID-19 pandemic [34]. Using an online subject pool from the U.S. and Canada, researchers found that individuals with anxiety-related disorders experienced higher stress as well as greater fear, socioeconomic consequences, xenophobia, and traumatic stress as compared to individuals with mood disorders and individuals without clinically significant mental health concerns in the context of the COVID-19 pandemic [34]. As such, individuals with anxiety disorders are at greater risk of certain poor outcomes even as compared to individuals with mood disorders in the context of the ongoing COVID-19 pandemic [34]. Regarding mechanisms behind the relationship between anxiety disorders and poor outcomes, individuals with anxiety disorders were more likely to engage in effortful isolation and ineffective coping strategies [34]. Perhaps these behaviors, in combination with other associated behaviors, increased the risk of certain poor outcomes for individuals with anxiety disorders as opposed to their counterparts [34]. The increased risk of poor outcomes across several domains (i.e., psychological or economic) among individuals with anxiety disorders in the context of the COVID-19 pandemic cannot be ignored. There is a need for research, intervention, and policy to address the increased risk and poor outcomes among this population.

#### *3.2. Mood Disorders*

Based on a recent meta-analysis, individuals with a pre-existing mood disorder have a significantly higher chance of hospitalization and death as compared to those without a pre-existing mood disorder following COVID-19 infection [37]. These meta-analytic results highlight the vulnerability of individuals with pre-existing mood disorders for poor health outcomes in the context of contracting COVID-19. As such, researchers and policymakers should consider those with pre-existing mood disorders when creating policy regarding vaccinations and other relevant public health decisions [37]. Mood disorders may confer a greater risk of susceptibility to COVID-19 for a variety of reasons. Individuals with pre-existing mood disorders experience increased psychological stress during the COVID-19 pandemic, which was further associated with maladaptive life and behavioral changes [34,38]. Certain mood disorders are associated with a greater risk of poor outcomes. For instance, a study in Australia demonstrated that specifically men with bipolar disorder are the most at-risk group among individuals with mood disorders regarding risk of depression and financial concerns [38]. As such, it is important to consider how individuals with pre-existing mood disorders may be at risk of certain poor health and psychological outcomes in the context of the ongoing COVID-19 pandemic.

#### *3.3. Neurodevelopmental Disorders*

Neurodevelopmental disorders typically emerge during early-to-middle childhood and may result in functional impairment and/or limitations regarding neuropsychological, cognitive, and adaptive development. Examples of neurodevelopmental disorders include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disabilities, and specific learning disabilities [39].

Unfortunately, children with neurodevelopmental disorders (e.g., ASD and ADHD) are at higher risk of poor mental health and difficulties with functioning than their counterparts in the context of the COVID-19 pandemic, as evidenced by a cross-sectional parent-reported study in the UK [40]. Indeed, children with neurodevelopmental disorders experienced an increase in emotional difficulties and conduct problems as well as a decrease in prosocial behaviors during the pandemic [40]. Depression and anxiety among children and their parents with ASD have increased as reported by studies in different countries such as the US and Switzerland [41,42]. Among children with neurodevelopmental disorders studied in the UK, female children with ASD experienced the highest emotional symptoms [40]. The severity of neurodevelopmental symptoms increased during the course of the pandemic among children and adolescents in the U.S. [43]. In addition, a recent study on 238 adolescents (ages 15–17 years) from two sites in the Southeastern and Midwestern U.S. showed that associated behavioral considerations, including opposition/defiance and impulsivity, also increased during the pandemic [44]. The stressors and increased symptomatology of children with neurodevelopmental disorders also impacted parents; indeed, parents of children with neurodevelopmental disorders reported worse mental health than their counterparts during the pandemic in the UK [40].

Research has provided potential mechanisms or avenues by which individuals with neurodevelopmental disorders experienced worse outcomes in the context of the pandemic. Specifically, individuals with neurodevelopmental disorders experienced closures in or abrupt disruption of their health services [45], which likely caused decreases in physical and mental health [46,47]. The lack of access to physical exercise during lockdown and quarantine(s) may have been particularly detrimental to individuals with neurodevelopmental disorders as exercise may be used to regulate several symptoms of neurodevelopmental disorders [46]. Researchers have also postulated that boredom and associated decreases in motivation have engendered rises in depression and poor outcomes among children and young people with neurodevelopmental disorders [48]. In addition, changes in remote and hybrid schools were associated with increased dropout rates from school among children and young adults with ADHD in the U.S. [43].

Certain aspects of the ongoing pandemic may have increased risk of poor outcomes among children with ASD specifically. Indeed, individuals with ASD may have certain vulnerabilities that were exacerbated by the pandemic [48]. Quarantine and isolation policies in response to the pandemic caused severe disruption to the routines and services typically accessed by people with ASD [49]. In some cases, individuals with ASD lost complete access to services partially because individuals with ASD were not considered a marginalized population [20]. In addition, the evaluation of individuals with suspected ASD was also interrupted and services and diagnoses were delayed [20]. As such, individuals with ASD and individuals yet to be diagnosed with ASD experienced specific stressors that likely impeded effective intervention and support services. As a result, the research described above regarding poor outcomes among individuals with ASD and their families is not surprising.

Although initial research indicates that the negative impact of quarantine and lockdown on mental and physical health does not appear to be long-lasting among children and young people with neurodevelopmental disorders, longitudinal research has not yet been conducted to examine the long-lasting impact of COVID-19 on individuals with neurodevelopmental disorders [44].

#### *3.4. Psychotic Disorders*

Psychotic disorders are characterized by cognitive and perceptual dysfunction, usually hallucinations or delusions [50]. Psychotic disorders may be accompanied by mood disturbances and can be caused by [50]. In the U.S., between 0.25% and 0.64% of the population is diagnosed with a psychotic disorder [51]. However, over the course of the pandemic, the incidence of psychotic disorders and symptoms has risen [51]. Moreover, the risk of psychosis among individuals with COVID-19 is higher than the average population, with between 0.9% and 4% of individuals with COVID-19 experiencing psychosis [51].

As among individuals with neurodevelopmental disorders, services and supports for individuals with psychotic disorders were severely disrupted over the course of the pandemic. In addition, because of the symptoms and vulnerabilities associated with psychotic disorders, this population is highly vulnerable to the changes in routine and access to care caused by the COVID-19 pandemic [51]. Individuals with psychotic disorders may

have experienced disruptions in their access to medication and face-to-face services [51–54]. These changes and barriers to services caused significant decompensation among many individuals with psychotic disorders and were also associated with increased paranoia and anxiety [51,52]. Decompensation refers to a significant deterioration in psychological functioning and an increase in severity of symptoms that is not typical [51]. Because of the transition to telehealth and phone services, providers may not have been able to accurately track and identify patients' decompensation over the course of the pandemic [51]. As such, individuals with psychotic disorders may have been uniquely at risk for experiencing worsening symptoms without proper support or intervention [51].

A single-center retrospective and observational study in Spain found that SARS-CoV-2 infection has also increased risk of and severity of psychosis symptoms [55]. Indeed, psychosis (e.g., delusions) has emerged among individuals with no history of these symptoms following infection with the virus [55]. However, it is unclear to what extent psychosis following infection with COVID-19 is caused by the virus itself versus the medications used by health providers to treat the virus [55]. Certain researchers posit that COVID-19 causes inflammation in the central nervous system, which then causes individuals to experience psychosis [55]. Regardless of the exact cause, individuals with COVID-19 are at increased risk of experiencing psychosis, even those without a prior history [55]. More research studies are needed to understand the cause of psychosis among individuals with COVID-19 as well as assessment and intervention strategies.

#### *3.5. Cognitive Disorders*

Cognitive disorders are overall characterized by executive function impairment and are associated with difficulties with organization, regulation, and perception [56]. Individuals with cognitive disorders may experience difficulties with processing speed, reasoning, decision-making, awareness, attention, learning, impulsivity, memory, or language [56]. More than 16 million individuals in the United States are currently diagnosed with a cognitive disorder [57].

Individuals with cognitive disorders are at significantly higher risk of contracting the virus given baseline difficulties with executive functioning [54]. Indeed, because individuals with cognitive disorders may struggle to care for themselves, it may be harder for them to adhere to safety standards regarding isolation, social distancing, and quarantine [58]. As part of this concern, individuals with cognitive disorders may live in collective housing or treatment units and the functioning of these structures has been severely impacted by the pandemic. As such, it is highly likely the functioning of individuals within these communities has also been severely affected. In addition, such facilities for individuals with cognitive disorders may allow the virus to spread easily across patients and staff putting individuals with cognitive disorders at even higher risk of contracting the virus [59]. If infected with COVID-19, individuals with cognitive disorders may also have worse outcomes, especially if their access to caregivers or supervision is limited in the context of ongoing social distancing and quarantine policy [58,60]. Research is needed to identify and develop standards for communal living facilities for individuals with cognitive disorders that prioritizes the delivery of services and the safety of patients.

Intellectual disabilities are a subset of cognitive disorders. Unfortunately, the health and well-being of individuals with cognitive disorders has been negatively impacted by the ongoing pandemic. Specifically, research indicates that mental health and physical activity have significantly decreased among children and young adults with both physical and intellectual disabilities [47]. Decreases in physical activity were due to quarantine and isolation policies as well as the closing of community centers and exercise facilities [47]. Among parents of children with intellectual disabilities, 90% reported worsening mood and increased behavioral problems among their children [47]. Although this study identified the potential for the development of solutions to the problems and barriers experienced by individuals with intellectual disabilities, no such solutions have been systematically implemented [47]. Thus, both research and advocacy are needed to address the problems and outcomes among individuals with intellectual disabilities over the course of the ongoing pandemic.

#### *3.6. Neurodegenerative Disorders*

Studies have revealed that ACE-2 is also expressed on neurons, glial cells, epithelial cells of blood-brain barrier (BBB), as well as oligodendrocytes. Interestingly a high concentration of substantia nigra may help the virus to enter, which itself may be the cause of reported neuropsychiatric sequelae of the infection [61]. Varieties of neurological symptoms including headache, ageusia, anosmia, and different forms of neurodegenerative disorders have been reported as consequences of SARS-CoV-2 infection [62]. Inflammation as a consequence of viral entry to the brain can cause oxidative damage and apoptosis of the cells in the brain, which has been reported as a cause of neurodegeneration and neurodegenerative disease [63]. Alzheimer's disease (AD) and Parkinson's disease (PD) are two neurodegenerative disorders reported to be caused by prolonged inflammation in patients infected by SARS-CoV-2 as a possible postinfectious manifestation. Inflammatory processes are also involved in other neurodegenerative disorders such as progressive supranuclear palsy syndrome (PSPS) [64], corticobasal syndrome (CBS) [64], and multiple system atrophy-parkinsonian type (MSA-P) [65]. COVID-19 has been reported to affect the international classification of functioning, disability, and health functioning in patients with MSA [66]. Accumulating evidence also suggests that SARS-CoV-2 infection can induce neurodegenerative disorders [67].

In view of the above, SARS-CoV-2-induced reactive oxygen species (ROS) caused by oxidative damage has been reported to cause accumulation of the amyloid beta (Aβ) proteins which itself is involved in the pathogenesis of AD. In addition, increased tau level as a result of neuroinflammation followed by viral entry to the brain has been reported as another possible cause of cognitive impairment within patients of SARS-CoV-2 [67,68]. COVID-19 incidence and complications are increased in patients with AD and related dementia. Patients with AD or related dementias have a cognitive impairment which causes difficulty understanding and remembering the recommendations. This disease is also more associated with other comorbidities such as cardiovascular disease, which may be another reason for high mortality of COVID-19 in these patients (90%) [69,70]. It has been also reported that APOE4 isoform of AD which causes a decreased amount of APO has increased the risk for COVID-19 infection and progression [71].

Several possible pathogeneses have been reported as a cause of PD in COVID-19 patients. Vulnerability of the basal ganglia and dopamine-rich region as well as the neuroinflammation caused by SARS-CoV-2 has been reported as a possible cause of failure of dopamine synthesis in COVID-19 patients [67]. Moreover, DJ1 and Leucine-rich repeat kinase 2 (LRRK2), key proteins in dopamine regulation and oxidative reaction, can be affected by SARS-CoV-2, resulting in dopamine dysregulation and inflammation in substantia nigra and α-synuclein aggregation [67,72].

Apart from the effect of COVID-19 on patients' access to different medical and psychological care, decreased physical activity and family support [73] and different neuropsychiatric outcomes have been reported that may be due to dopamine depletion in PD patients as a neurotransmitter to help with adoption to different changes in healthy individuals, which is lacking in PD patients. Anxiety and stress may remain and become chronic due to lack of adaptation as a result of dopamine depletion [74]. There are three different hypotheses about the effect of COVID-19-induced stress in PD patients. Stress can interfere with the levodopa effect and reduce it [75]. In addition, chronic stress has been revealed to decrease the dopamine activity within the rodent's ventral tegmentum compared to healthy controls and has been reported as a cause of neurodegeneration in PD and AD [76]. Emotional stress as a trigger for freezing gait has been reported as well [77]. One important aspect of COVID-19 infection is dehydration, diarrhea, fever and decrease in water intake which may be another important aspect to consider when adjusting the medication dosage. However, COVID-19 infection has been reported as a trigger for worsening of PD motor

and nonmotor symptoms. Although, the patients with higher age and duration of illness had been reported to have more mortality risk compared to the participants with younger age and shorter disease duration [73,78], worsening of motor and non-motor symptoms, such as rigidity, tremor, fatigue, pain, and concentration, has not been related to disease duration or severity [79]. In view of the above, it can be concluded that COVID-19 can cause different effects on PD via decreasing dopamine secretion, neurodegeneration, and can be a trigger for the developing or worsening of symptoms in PD and AD.

#### **4. Conclusions**

Since the COVID-19 pandemic, accumulating lines of evidence have revealed that besides common clinical manifestations, SARS-CoV-2 infection is associated with development or worsening of a variety of neuropsychiatric conditions. These can occur during or shortly after the onset of COVID-19. However, more recent longitudinal studies have revealed that COVID-19 increases the estimated risk of developing or worsening of neuropsychiatric conditions, such as mood, anxiety, psychotic disorders, dementia, insomnia, or even substance abuse disorders, after 6 months following COVID-19. These data indicate that close and long-term neuropsychiatric and cognitive monitoring of patients with COVID-19 are critical in order to diagnose these sequels and take appropriate therapeutic approaches as early as possible, and eventually improve patients' and their families quality of life.

Although SARS-CoV-2 infection itself can be associated with the above-mentioned neuropsychiatric sequela, one should not overlook the multiple factors that contribute to the development or worsening of neuropsychiatric conditions during the COVID-19 pandemic. Overall, we can categorize these into three major domains: (i) the pandemic's burden on the society acting as psycho-socio-economic stressors (e.g., deterioration of economic state, lockdown or quarantine, disruption of health care provision, and loss of job or family members due to COVID-19), (ii) disease-related reduction in quality of life (e.g., fatigue and breathlessness), and (iii) the impact of infection itself on brain function. These factors separately or in combination with each other may play critical roles in development or exacerbation of neuropsychiatric conditions during the pandemic. For instance, a population-based longitudinal study on 16,910 participants in the UK revealed an independent association between COVID-19 and increased risk of economic vulnerability among participants, measured by both household income sufficiency and sickness absence from work [80]. The economic recession resulting from the COVID-19 pandemic has adversely affected many people's mental health and created new barriers for people already suffering from mental illness [81]. This is not only limited to COVID-19 pandemic, as such negative impacts on mental health and neuropsychiatric conditions have been seen in other global or regional shocks including wars [82–84], natural disasters [85,86], or other disease outbreaks, e.g., with Ebola [87,88], Zika virus [89], Middle East respiratory syndrome coronavirus (MERS) [90,91], and severe acute respiratory syndrome coronavirus (SARS-CoV) [90]. Social isolation due to lockdown or quarantine may have been particularly detrimental to individuals with neuropsychiatric and neurodevelopmental disorders, as social interaction and exercise may be used to regulate several symptoms of these disorders [46,92]. Data from an online questionnaire from 55,589 participants from 40 countries during the COVID-19 pandemic have revealed that lockdown significantly increases anxiety and depression at every degree of lockdown intensity, especially in combination with the presence of prior mental health issue [92]. This emphasizes the need for a proactive intervention to protect mental health of the general population but more specifically of vulnerable groups [92].

Almost over 2.5 years have passed since the COVID-19 pandemic; and as our knowledge about different neuropsychiatric manifestations directly or indirectly related to COVID-19 is improving, it overall highlights the critical need for global preparedness in the mental health sector during outbreaks of such infectious diseases. Important steps and innovations have been taken over the last 2 years to enable better service delivery to the affected populations. For instance, use of telemedicine and electronic prescriptions

have become pivotal tools to be implemented globally [93]. This could be an essential element of continuity of care, especially during the lockdown or quarantine period. The promotion and empowerment of community-based mental health services especially in low-and-middle-income countries can also decrease the present treatment gap even during infectious disease outbreaks [94]. The development of global or local guidelines or consensus recommendations for such neuropsychiatric issues during or after the outbreak seems to be another effective way in reducing such psychiatric and mental health complications [94].

In the end, with an improvement of our knowledge about the pathophysiology of SARS-CoV-2 in brain dysfunction and neuropsychiatric conditions as well as the development of mediations targeting the infection itself or its related pathologic molecular signaling pathways, we may improve or even prevent the development of such neuropsychiatric manifestations. For instance, due to the presence of immune dysfunction and cytokine storm in COVID-19 patients, anti-inflammatory, immunomodulatory, or immunosuppressive medications have been tested or even in animal models of SARS-CoV-2 infections with variable benefits [95,96]. Vaccination has also created a new epoch in improving survival rate and acute critical illness related to COVID-19 [97]. Notably, a large retrospective cohort of 9479 individuals who developed COVID-19 despite SARS-CoV-2 vaccination, well-matched to controls, found that vaccination protected against severe acute illness, stroke, seizures, and psychotic disorders after breakthrough COVID-19 as assessed within 6 months post-vaccination. However, it may not protect from fatigue and other post-COVID-19 behavioral and cognitive symptoms [98]. Overall, research in this area is advancing. For instance, some studies have found an association between low neurotrophic factors and COVID-19-related neuropsychiatric complications [99]; thus, neurotrophic drugs such as cerebrolysin may serve as a potential therapeutic approach to improve neuropsychiatric manifestations of COVID-19 [100]. Clearly, more research studies and clinical trials are needed in this regard.

**Author Contributions:** N.Z., P.R., S.A. and M.G. conceived and designed the review, outlined the performed rigorous literature search, designed the table and figure, and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** M.G. is supported by a clinical research training scholarship in ALS funded by The ALS Association and The American Brain Foundation, in collaboration with the American Academy of Neurology as well as NIH-funded Wellstone fellowship training grant (NIH 5P50HD060848-15) for research on FSHD.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

MDPI St. Alban-Anlage 66 4052 Basel Switzerland Tel. +41 61 683 77 34 Fax +41 61 302 89 18 www.mdpi.com

*Journal of Clinical Medicine* Editorial Office E-mail<EMAIL_ADDRESS>www.mdpi.com/journal/jcm

MDPI St. Alban-Anlage 66 4052 Basel Switzerland

Tel: +41 61 683 77 34

www.mdpi.com ISBN 978-3-0365-7194-2


**3. Implementing autism-specific screening**

Both the Social Security Act [40] and the Individuals with Disabilities Education Improvement Act [41] reaffirm the mandate for PCPs to play a central role in the identification of develop‐ mental disabilities. Between birth and 2nd birthday, children are recommended to participate in a sequence of 11 preventive pediatric healthcare visits (i.e., well-child visits). In the context of these visits, healthcare professionals have a unique opportunity to develop a long-term, trusting relationship with the children and their families. Parents expect that healthcare professionals take an interest in their child's development and behavior, competently identify strengths and weaknesses, and are able to help them access available community resources, if necessary [6].

#### **3.1. Limitations of developmental surveillance**

Developmental surveillance is defined as a "flexible, longitudinal, continuous, and cumulative process whereby knowledgeable healthcare professionals identify children who may have developmental problems" ([5] p. 407). Surveillance includes eliciting and attending to the parents' concerns, maintaining a developmental history, making accurate and informed observations of the child, identifying the presence of risk and protective factors, and docu‐ menting the process and findings. According to the AAP recommendations on developmental surveillance and screening [5], healthcare professionals are recommended to implement developmental screening during all well-child visits. At the same time, this policy statement also asserts that developmental surveillance by itself is insufficient for detecting developmen‐ tal concerns in a large number of children. Instead, the AAP recommends using a combination of developmental surveillance and formal screening tests. Research has shown that healthcare professionals who rely solely on clinical judgment are much less accurate in estimating developmental status than professionals who implement formal screening tests [42, 43]. That is, the clinical impressions of healthcare professionals tend to have excellent specificity (i.e., if children are identified, concerns tend to be valid). At the same time, their sensitivity in detection developmental delays is quite poor, leading to many un-identified children and revealing significant difficulties in detecting less obvious delays. For example, Hix-Small and colleagues [44] conducted a study where global developmental delays (at 12 and 24 months) were identified based on both, clinical impressions and a formal screening test (Ages and Stages Questionnaire, ASQ;[45, 46]). Results revealed that 48% of children with true develop‐ mental delays would have been missed if only clinical impressions were used. Similarly, in a study that aimed to identify toddlers with ASD, Robins [47] screened a total of 4,797 children, identifying 21 children who were later diagnosed with ASD. Of those 21 children, only 4 were previously red-flagged by the child's pediatrician.

### **3.2. Recommended and implemented screening practices**

surveys indicate 34% of parents reported some familiarity with the LSAE campaign. Significant changes in target parent behaviors were detected in that more parents knew of the behaviors likely to be associated with ASD, the best time to get help for ASD, and the developmentalmilestones their childshouldbe reaching[38].Similarly, substantiallymore healthcare professionals believe that they have the resources necessary to educate parents about monitoring child development, and fewer advocated a 'wait and see' approach,

Both the Social Security Act [40] and the Individuals with Disabilities Education Improvement Act [41] reaffirm the mandate for PCPs to play a central role in the identification of develop‐ mental disabilities. Between birth and 2nd birthday, children are recommended to participate in a sequence of 11 preventive pediatric healthcare visits (i.e., well-child visits). In the context of these visits, healthcare professionals have a unique opportunity to develop a long-term, trusting relationship with the children and their families. Parents expect that healthcare professionals take an interest in their child's development and behavior, competently identify strengths and weaknesses, and are able to help them access available community resources, if

Developmental surveillance is defined as a "flexible, longitudinal, continuous, and cumulative process whereby knowledgeable healthcare professionals identify children who may have developmental problems" ([5] p. 407). Surveillance includes eliciting and attending to the parents' concerns, maintaining a developmental history, making accurate and informed observations of the child, identifying the presence of risk and protective factors, and docu‐ menting the process and findings. According to the AAP recommendations on developmental surveillance and screening [5], healthcare professionals are recommended to implement developmental screening during all well-child visits. At the same time, this policy statement also asserts that developmental surveillance by itself is insufficient for detecting developmen‐ tal concerns in a large number of children. Instead, the AAP recommends using a combination of developmental surveillance and formal screening tests. Research has shown that healthcare professionals who rely solely on clinical judgment are much less accurate in estimating developmental status than professionals who implement formal screening tests [42, 43]. That is, the clinical impressions of healthcare professionals tend to have excellent specificity (i.e., if children are identified, concerns tend to be valid). At the same time, their sensitivity in detection developmental delays is quite poor, leading to many un-identified children and revealing significant difficulties in detecting less obvious delays. For example, Hix-Small and colleagues [44] conducted a study where global developmental delays (at 12 and 24 months) were identified based on both, clinical impressions and a formal screening test (Ages and Stages Questionnaire, ASQ;[45, 46]). Results revealed that 48% of children with true develop‐ mental delays would have been missed if only clinical impressions were used. Similarly, in a

indicating that the marketing campaign was effective [39].

**3. Implementing autism-specific screening**

8 Recent Advances in Autism Spectrum Disorders - Volume I

**3.1. Limitations of developmental surveillance**

necessary [6].

The use of general developmental screening instruments has been recommended by the AAP since 2001 [48]. Current recommendations for identifying children with developmental disabilities (not specifically ASD) suggest population-wide screening at 9, 18, and 30 months [5]. Empirical information on the extent to which these recommendations have been imple‐ mented is limited. Two national surveys of AAP members completed in 2002 and 2009 indicate that implementation has been slow [49, 50]. When asked about their screening practices, only 23.0% (2002) and 47.7% (2009) of physicians reported that they 'always' or 'almost always' administer a formal screening tool. Since many healthcare professionals may administer standard screening tools in a non-standard manner (e.g., by asking some but not other items) or only administer these tools to patients considered 'high risk', these numbers likely overes‐ timate true implementation [51]. Researchers who asked parents to report on the screening practices of their healthcare professionals found that less than 27% of parents of children between 10 to 35 months recalled completing a developmental screening questionnaire within the last 12 months [52]. Only two survey-based studies have evaluated the implementation of ASD-specific screening instruments. In a 2004 survey of 255 pediatricians licensed in Maryland and Delaware, dosReis and colleagues reported that only 8% of the respondents screened for ASD [53]. In a 2007 survey of 51 pediatricians licensed in Alabama and Mississippi, Gillis reported that 28% reported using ASD-specific screening instruments [54]. Importantly, only one pediatrician reported routine screening for ASD at 18- or 24-months, suggesting that many healthcare professionals administer ASD-specific screening tests only to children who are considered 'high risk'.

#### *3.2.1. Barriers to successful screening in the primary care setting*

Well-child visits are often the only routine, formalized, and longitudinal contact a child has with a healthcare professional and thus is an ideal place to implement population-wide screening. Given this widely acknowledged responsibility, it is striking that many practices do not implement developmental and ASD-specific screening measures as recommended by the AAP. In the following we will consider several key barriers that interfere with healthcare professionals' ability to implement effective screening practices.

**1.** Parental compliance with the preventive pediatric healthcare schedule

The Medical Expenditure Panel Survey provides nationally representative information on preventive care for children between 0 and 5 years of age [55]. Results indicate that the average compliance ratio is 71.3% (*SD* = 1.4%), indicating that on average, parents attend about 3 out of 4 AAP recommended well-child visits. In addition, findings reveal large variation in wellchild visit attendance based on the families' socioeconomic status, access to resources, and geography. That is, the compliance ratio was significantly below average if the child was without health insurance (*M* = 52.5%, *SD* = 3.8), lived below the poverty level (*M* = 62.8%, *SD* = 2.4), lived with a single parent (*M* = 65.5%, *SD* = 2.7), was Hispanic or Black (*M* = 64.5%, *SD* = 2.1, or *M* = 64.7%, *SD* = 2.9, respectively), or had parents without a high-school degree (*M* = 60.8%, *SD* = 3.1). Moreover, in terms of geography, the compliance ratio ranged between 90.9% (*SD* = 5.0) in New England and 51.3% (*SD* = 3.4) in the West South Central Census division. To account for this variability in parental compliance with the preventive pediatric care schedule, practices may be able to screen about 30% more children by flexibly administering screening measures during sick-visits, when necessary [56].

tion can be dramatically reduced by administering the follow-up interview (3:1); (3) even though the sensitivity of the M-CHAT has not been evaluated, comparisons to prevalence esti‐ mates of ASD suggest that the M-CHAT is likely to miss a considerable number of children [7]. Assuming current prevalence estimates (1:88), the sample reported by Roberts [47] likely in‐ cluded about 55 children with ASD. Even after considering participant attrition as a factor (i.e., families who did not complete the follow-up interview or diagnostic evaluations), the number of children with ASD actually identified by the researchers (*n* = 21) is considerably lower than

Promoting Early Identification of Autism in the Primary Care Setting: Bridging the Gap Between What We Know and

What We Do

11

http://dx.doi.org/10.5772/53715

The extent to which limited parent literacy interferes with the implementation of broad-band developmental and ASD-specific screening measures has not been investigated. However, da‐ ta presented by Davis and colleagues suggest that limited parental literacy has the potential to pose significant obstacles, particularly in the context of practices that primarily serve indigent or immigrant communities [60, 61]. Based on a convenience sample of 396 parents from one large medical center (i.e., Louisiana State University Medical Center, Shreveport, LA), 11% and 16% of parents showed a reading level below 4th and 7th grade, respectively. Limited parental literacy may be an important factor in explaining missing data problems, reported across many population-based screening studies. For example, Hix-Small and colleagues reported that only about 54% of the administered screening questionnaires were completed and re‐

The successful implementation of effective screening practices requires more than educational opportunities for individual staff members. Instead, what is needed is a context that supports organizational restructuring [51, 62]. That is, practices need to develop, evaluate, and refine office-wide implementation systems that divide responsibilities among staff members at multiple levels. For example, the screening instrument may be distributed by a member of the front desk staff, scored by a nurse, reviewed with the family by a provider, and possible referrals may be coordinated by a social worker. Developing such an office-wide implemen‐ tation system requires an 'internal champion' to lead the charge, a process for collecting data to monitor progress, and a seamless integration with the clinics' electronic medical record system. In order to be sustainable, the implementation system also needs to be sufficiently robust to be workable in the context of busy periods (e.g., the onset of the winter viral season)

Research suggests that traditional methods of education, including printed educational materials and didactic, lecture-based continuing medical education (CME) sessions, have little to no effect on the behavior of healthcare professionals [63, 64]. During recent years, several alternative approaches to the traditional CME format have been suggested. These approaches include specialized modules on ASD that are included as part of pediatric residency training programs (e.g., CDC Autism Case Training) [65, 66], and academic detailing where a focused

would be expected.

turned [44].

and staff turnover.

**4.** Limited parent literacy

**5.** Need for practice-wide system change

*3.2.2. Novel approaches to support autism-specific screening practices*

**2.** Competing priorities, time, and reimbursement constraints

During the last decade, the AAP [5, 6, 57] has published three separate statements on the early detection of developmental-behavioral problems. Recommended screenings include: (1) screening for maternal postpartum depression (in the first year), (2) broad-band developmen‐ tal screening (at 9, 18, and 24/30 months), (3) ASD-specific screening (at 18 and 24 months), (4) social-emotional screening (contingent upon abnormal developmental or ASD screeners), (5) kindergarten readiness screening (at 4 years), and (6) mental health/psychological function screening (age 5 years and thereafter). Implementing such a dense screening schedule in the context of short well-child visits filled with competing priorities (e.g., vaccinations, medical surveillance), and limited reimbursement options is often noted as a key challenge by health‐ care professionals [53].

**3.** Availability of high-quality screening instruments

Given that screening tools are being developed, revised, and evaluated on an ongoing basis, the AAP practice guidelines do not recommend any particular ASD-specific screening instru‐ ment [6]. Instead, the AAP guidelines include a review of several potential measures, leaving it up to the healthcare professional to select an instrument that fits the particular needs of their practice. To date, the ASD-specific screening measure that has been adopted most widely in primary care settings is the Modified Checklist for Autism in Toddlers (M-CHAT; [47, 58, 59]. The M-CHAT is a 23-item yes/no parent report screener for ASD. Screening positive (i.e., "fail‐ ing") is defined as failing any three items, or any two of six critical items. Failed items are re‐ viewed with a follow-up interview, typically administered by phone a few weeks after the screener is completed. Most of the research evaluating the efficacy of this measure has focused on the positive predictive value (PPV), defined as the number of true positive cases divided by number of cases that screened positive. Robins reported on the screening results of 4,797 tod‐ dlers (screened during their 15-, 18-, or 24-month well-child visits) [47]. The numbers of tod‐ dlers who failed the M-CHAT questionnaire, failed the M-CHAT follow-up interview, and were eventually diagnosed with ASD, were 466, 61, and 21, respectively. Thus, if the results of the follow-up interview were considered, the M-CHAT revealed a PPV of.57. However, with‐ out the follow-up interview, the PPV of the M-CHAT was as low as.06. These estimates are consistent with data reported by Kleinman and colleagues [59], who reported PPVs of.65 and. 11, depending on whether the follow-up interview was or was not considered. Based on these findings, at least three conclusions seem warranted: (1) without administering the follow-up interview, the M-CHAT is likely to over-identify children by a factor of 17:1; (2) over-identifica‐ tion can be dramatically reduced by administering the follow-up interview (3:1); (3) even though the sensitivity of the M-CHAT has not been evaluated, comparisons to prevalence esti‐ mates of ASD suggest that the M-CHAT is likely to miss a considerable number of children [7]. Assuming current prevalence estimates (1:88), the sample reported by Roberts [47] likely in‐ cluded about 55 children with ASD. Even after considering participant attrition as a factor (i.e., families who did not complete the follow-up interview or diagnostic evaluations), the number of children with ASD actually identified by the researchers (*n* = 21) is considerably lower than would be expected.

**4.** Limited parent literacy

without health insurance (*M* = 52.5%, *SD* = 3.8), lived below the poverty level (*M* = 62.8%, *SD* = 2.4), lived with a single parent (*M* = 65.5%, *SD* = 2.7), was Hispanic or Black (*M* = 64.5%, *SD* = 2.1, or *M* = 64.7%, *SD* = 2.9, respectively), or had parents without a high-school degree (*M* = 60.8%, *SD* = 3.1). Moreover, in terms of geography, the compliance ratio ranged between 90.9% (*SD* = 5.0) in New England and 51.3% (*SD* = 3.4) in the West South Central Census division. To account for this variability in parental compliance with the preventive pediatric care schedule, practices may be able to screen about 30% more children by flexibly administering screening

During the last decade, the AAP [5, 6, 57] has published three separate statements on the early detection of developmental-behavioral problems. Recommended screenings include: (1) screening for maternal postpartum depression (in the first year), (2) broad-band developmen‐ tal screening (at 9, 18, and 24/30 months), (3) ASD-specific screening (at 18 and 24 months), (4) social-emotional screening (contingent upon abnormal developmental or ASD screeners), (5) kindergarten readiness screening (at 4 years), and (6) mental health/psychological function screening (age 5 years and thereafter). Implementing such a dense screening schedule in the context of short well-child visits filled with competing priorities (e.g., vaccinations, medical surveillance), and limited reimbursement options is often noted as a key challenge by health‐

Given that screening tools are being developed, revised, and evaluated on an ongoing basis, the AAP practice guidelines do not recommend any particular ASD-specific screening instru‐ ment [6]. Instead, the AAP guidelines include a review of several potential measures, leaving it up to the healthcare professional to select an instrument that fits the particular needs of their practice. To date, the ASD-specific screening measure that has been adopted most widely in primary care settings is the Modified Checklist for Autism in Toddlers (M-CHAT; [47, 58, 59]. The M-CHAT is a 23-item yes/no parent report screener for ASD. Screening positive (i.e., "fail‐ ing") is defined as failing any three items, or any two of six critical items. Failed items are re‐ viewed with a follow-up interview, typically administered by phone a few weeks after the screener is completed. Most of the research evaluating the efficacy of this measure has focused on the positive predictive value (PPV), defined as the number of true positive cases divided by number of cases that screened positive. Robins reported on the screening results of 4,797 tod‐ dlers (screened during their 15-, 18-, or 24-month well-child visits) [47]. The numbers of tod‐ dlers who failed the M-CHAT questionnaire, failed the M-CHAT follow-up interview, and were eventually diagnosed with ASD, were 466, 61, and 21, respectively. Thus, if the results of the follow-up interview were considered, the M-CHAT revealed a PPV of.57. However, with‐ out the follow-up interview, the PPV of the M-CHAT was as low as.06. These estimates are consistent with data reported by Kleinman and colleagues [59], who reported PPVs of.65 and. 11, depending on whether the follow-up interview was or was not considered. Based on these findings, at least three conclusions seem warranted: (1) without administering the follow-up interview, the M-CHAT is likely to over-identify children by a factor of 17:1; (2) over-identifica‐

measures during sick-visits, when necessary [56].

10 Recent Advances in Autism Spectrum Disorders - Volume I

**3.** Availability of high-quality screening instruments

care professionals [53].

**2.** Competing priorities, time, and reimbursement constraints

The extent to which limited parent literacy interferes with the implementation of broad-band developmental and ASD-specific screening measures has not been investigated. However, da‐ ta presented by Davis and colleagues suggest that limited parental literacy has the potential to pose significant obstacles, particularly in the context of practices that primarily serve indigent or immigrant communities [60, 61]. Based on a convenience sample of 396 parents from one large medical center (i.e., Louisiana State University Medical Center, Shreveport, LA), 11% and 16% of parents showed a reading level below 4th and 7th grade, respectively. Limited parental literacy may be an important factor in explaining missing data problems, reported across many population-based screening studies. For example, Hix-Small and colleagues reported that only about 54% of the administered screening questionnaires were completed and re‐ turned [44].

**5.** Need for practice-wide system change

The successful implementation of effective screening practices requires more than educational opportunities for individual staff members. Instead, what is needed is a context that supports organizational restructuring [51, 62]. That is, practices need to develop, evaluate, and refine office-wide implementation systems that divide responsibilities among staff members at multiple levels. For example, the screening instrument may be distributed by a member of the front desk staff, scored by a nurse, reviewed with the family by a provider, and possible referrals may be coordinated by a social worker. Developing such an office-wide implemen‐ tation system requires an 'internal champion' to lead the charge, a process for collecting data to monitor progress, and a seamless integration with the clinics' electronic medical record system. In order to be sustainable, the implementation system also needs to be sufficiently robust to be workable in the context of busy periods (e.g., the onset of the winter viral season) and staff turnover.

#### *3.2.2. Novel approaches to support autism-specific screening practices*

Research suggests that traditional methods of education, including printed educational materials and didactic, lecture-based continuing medical education (CME) sessions, have little to no effect on the behavior of healthcare professionals [63, 64]. During recent years, several alternative approaches to the traditional CME format have been suggested. These approaches include specialized modules on ASD that are included as part of pediatric residency training programs (e.g., CDC Autism Case Training) [65, 66], and academic detailing where a focused training session on early identification of ASD is presented to the entire office staff of individual practices [67]. In the following section, we will describe a third approach that has been used widely to improve the delivery of high-quality healthcare, although it has yet to be imple‐ mented with a focus on improving early detection of children with ASD.

knowledge with practical voices from peers. In between the Learning Sessions, teams engage in Action Periods during which they implement change in a cyclical fashion: a) teams develop a PLAN to implement change, b) they DO the work to implement the chance, c) they STUDY their progress by measuring clinical behaviors, and d) they ACT upon the results by refining

Promoting Early Identification of Autism in the Primary Care Setting: Bridging the Gap Between What We Know and

What We Do

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http://dx.doi.org/10.5772/53715

When multiple risk factors are present (e.g., the child has a family history of ASD, the child's parents or other family members are concerned about behaviors related to ASD, the child's pediatrician notes concerns about ASD, or the child fails an ASD-specific screener), the AAP clinical practice guidelines recommend that the child's PCP simultaneously (1) provides parental education on ASD, (2) refers the child for a comprehensive ASD evaluation, (3) refers the child for an audiology evaluation, (4) refers the child to Early Intervention or Early Childhood Education Services, and (5) schedules a targeted follow-up visit within one month [6]. Accomplishing all five actions simultaneously is considered crucial to avoid costly delays.

Little is currently known about how parents experience autism-specific screening, parent education, and referrals provided by the child's PCP in accordance with the AAP clinical practice guidelines. By definition, these interactions between PCP and parent precede a formal ASD diagnosis. Thus, PCPs typically communicate a certain level of uncertainty about the child's ASD diagnosis, emphasizing that the child is considered to be at 'high risk for ASD', and focusing on the need for a comprehensive evaluation to 'rule out ASD'. Even at this tentative level, communicating concerns about ASD requires initiating or engaging parents in a difficult conversation. For some parents, this conversation confirms suspicions that lay dormant for various amounts of time. For other parents, it comes out of nowhere and confronts them with concerns they had not previously contemplated. In either case, parents might not yet be emotionally ready to consider the possibility that their child has autism. Parents often feel responsible for their child's behavior or delays, feel guilty about not noticing or acting upon these concerns more promptly, and fear the stigma all too often associated with devel‐

When prompted to reflect upon the time when their child was first diagnosed, many parents of older individuals with ASD express significant levels of discontentment, in some cases resentment and anger [72, 73]. In part, these strong emotions stem from the fact that most families experience significant delays between the time when they first note concerns [73], the time when they choose to share these concerns with their child's physician [9, 74], the time when their child is first evaluated [11], and the time when the ASD diagnosis is first given [7, 11]. On average, parents report seeing four to five doctors before an ASD diagnosis is made, which occurs on average at age of four or five years [7, 11, 72, 73]. Parental perceptions of delay in diagnosis due to 'watchful waiting' are associated with (1) lower satisfaction with the diagnostic process, (2) lower satisfaction with the help physicians offer after the diagnosis, and

(3) lower parental confidence in the physician's ability to help [72, 73, 75].

their approach (Plan-Do-Study-Act cycles of learning).

opmental disabilities.

**4. Communicating concerns about autism to parents**

#### The Breakthrough Series Collaborative Model

The Breakthrough Series Collaborative Model (BSCM) has been developed by the Institute of Healthcare Improvement (IHI, www.ihi.org) [68], and used successfully to improve the delivery of preventive services by pediatric practices [69], follow-up to newborn hearing screening [70], and child mental health service use [71]. In this model, several healthcare provider teams partner with external experts to overcome specific barriers that impede the delivery of high-quality care within their organization. Figure 2 presents the key elements of a Breakthrough Series model.

**Figure 2.** Breakthrough Series Model

The breakthrough series starts with the selection of a specific topic that is considered ripe for improvement. Even though data on the efficacy of learning collaboratives to increase early identification of ASD has not been published to date, we suggest that this would be a very appropriate topic, (1) because of the high prevalence rates of ASD, and (2) because the existing knowledge in this area is sound but not widely used. Once the topic is selected, a faculty team is assembled that combines expertise in the subject area as well as an improvement advisor who coaches teams on improvement methods. Organizations elect to join the collaborative through an application process, appointing multi-disciplinary teams within the organization (a champion's committee). The multi-disciplinary teams from all organizations are then brought together for Learning Sessions that combine the exchange of formal academic knowledge with practical voices from peers. In between the Learning Sessions, teams engage in Action Periods during which they implement change in a cyclical fashion: a) teams develop a PLAN to implement change, b) they DO the work to implement the chance, c) they STUDY their progress by measuring clinical behaviors, and d) they ACT upon the results by refining their approach (Plan-Do-Study-Act cycles of learning).


**3.1 Nanosecond laser fluorescence spectrometer**

A homemade laser fluorimeter (Fig. 3) has been built for the experiments. The fluorimeter consist of a laser source, optical elements for light conversion, a fiber-optic cable, a cuvette and an optical multichannel analyser.

Fig. 3. Nanosecond laser fluorescence spectrometer scheme (for details see text). The letters H, V and C denote the horizontal, vertical and circular light polarization.


**4. Discussion**

In the present study, we showed that CCT could dose-dependently exert an antiadipogenic effect by decreasing lipid accumulation, a hallmark of antiobesity action. Our results showed that 5 μM CCT, but not 1 μM CCT, added at the early stage of cell differentiation reduced lipid accumulation. CCT exhibited the same efficacy as genistein in reducing intracellular fat. However, this result did not allow discriminating whether this decrease was the result of a lower generation of lipid droplets and, hence, a lower lipid load or if it was a cytotoxic effect of CCT on adipocytes via cell death, leading to a reduction in adipocyte mass and intracellular fat. To rule this out, lipid droplet metrics and cell viability were evaluated, with no differences observed in either analysis in the presence or absence of CCT.

Thus, we also investigated the effects of CCT on the expression of essential adipogenesis-related transcription factors involved in coordinating the adipogenic process. We analyzed the effect of CCT on the expression of early (*C*/*EBP*β and *C*/*EBP*δ) and late (*C*/*EBP*α and *PPAR*γ) genes which play key roles in adipogenesis. In this context, regulating the expression of these factors can modulate the differentiation capacity of adipocytes [43].

Typically, the mRNA levels of *C*/*EBP*β and *C*/*EBP*δ increase during early differentiation, subsequently declining after the removal of adipogenic cocktail (AC), at which point the levels of *C*/*EBP*α and *PPAR*γ increase [44,45]. It is known that *C*/*EBP*β and *C*/*EBP*δ promote adipogenesis, at least in part, by inducing *C*/*EBP*α and *PPAR*γ.

Interestingly, our results, at the ID time-point, indicate that adipocyte differentiation in the presence of the highest concentration of CCT led to a decrease in *C*/*EBP*β mRNA levels, while those of C/EBPδ were not affected. However, at the FD time-point of differentiation, both tested concentrations of CCT diminished *C*/*EBP*α mRNA levels, while those of *PPAR*γ remained unchanged.

The antiadipogenic effect of 5 μM is in line with reports showing that a knockdown of *C*/*EBP*β inhibited adipocyte differentiation in 3T3-L1 preadipocytes [45]; however, in our work, CCT did not affect *C*/*EBP*δ expression. It is possible that an unaltered *C*/*EBP*δ expression can compensate for the decrease in C/EBPβ at the early stages of differentiation [46], thus playing a role in the induction of *PPAR*γ expression. Most carotenoids inhibit the adipogenic process via the repression of *PPAR*γ [47,48]; however, CCT did not alter *PPAR*γ mRNA levels at the FD time-point. In this sense, as mentioned in Section 1, CCT is unlike β-carotene and other carotenoids, potentially exerting its effects via another mechanism [49]. On this note, it is known that β-carotene added during the differentiation of NIH 3T3-L1 preadipocytes reduced the triacylglycerol content, as well as the number and size of lipid droplets, compared with control differentiated cells by diminishing *PPAR*γ expression [50]. On the other hand, Gul T et al. [51] reported that crocins at a concentration of 30 μM (treatment for 48 h) were able to diminish intracellular fat in 3T3-L1 cells, albeit producing a decrease in viability. PPARγ is not only crucial for adipogenesis but is also required for the maintenance of differentiated adipocytes [52]. It is known that knockdown of *PPAR*γ compromises adipose tissue function, accompanied by insulin resistance, inflammation, angiogenesis, and fibrosis [53]. Thus, it appears that, by not altering *PPAR*γ mRNA levels, CCT guarantees the culmination of the preadipocyte differentiation.

The decrease in *C*/*EBP*β mRNA level seems to be CCT-dose-dependent, in contrast to that of *C*/*EBP*α. This suggests that CCT is an efficient carotenoid in that it selectively downregulates *C*/*EBP*α mRNA levels with no change in *PPAR*γ expression. It has been reported that mice adipocytes in which the *C*/*EBP*α gene was disrupted showed defects in lipid accumulation [54]. Furthermore, various bioactive compounds reduce lipid accumulation in adipocytes by downregulating the expression of *C*/*EBP*α [55]. In line with these observations, the inhibition of *C*/*EBP*α reported herein could be involved in the decrease in intracellular fat caused by CCT during the induction of differentiation.

Taking our findings into consideration, further research should be conducted in this regard to determine the exact mechanism of CCT in combination with other standard therapeutic approaches applied to the obese population. This could contribute to the development of new strategies to improve the treatment of obesity.

Through our study, we have broadened the knowledge related to the health properties of CCT isolated from saffron as an antiadipogenic compound. Our research provides evidence that CCT efficiently reduces lipid accumulation in adipocytes, presumably via downregulation of *C*/*EBP*α expression. We can conclude that CCT is more potent than genistein in reducing lipid accumulation, with a similar effect produced at a lower concentration. It has been reported that genistein has a therapeutic effect on obesity [56], whereas several studies showed that its administration may be effective for adipocyte differentiation [57]. Thus, CCT's greater efficacy than genistein suggests that this natural compound is a potential candidate to be included in dietary therapies aimed at reverting adipose tissue accumulation in obesity.

**Author Contributions:** Conceptualization, S.L.; methodology, N.M.-L., A.B.-B., S.L., M.V. and E.J.-O.; validation, E.J.-O., A.B.-B. and S.L.; formal analysis, S.L.; investigation, S.L., E.J.-O., A.B.-B., E.N. and M.B.; resources, S.L., E.N., G.L.A., N.M.-L. and A.B.-B.; data curation, S.L. and E.J.-O.; writing—original draft preparation, S.L.; writing—review and editing, E.N., A.B.-B. and S.L.; visualization, S.L.; supervision, S.L.; project administration, S.L. All authors read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** We acknowledge the administrative and technical support of Maria Carmen Cifuentes. **ConflictsofInterest:**Theauthorsdeclarenoconflict of interest.


**3. The kind and characteristics of sorbents**

It is well known that alkali sorbents such as CaO, CaCO3, Ca(OH)2, NaOH, Na2CO3, NaHCO3, KOH, MgO, Mg(OH)2, dolomites, and dolomite limestones(CaCO3/MgCO3) are used to remove SO2 and acid gases in the flue gas cleaning processes (Kunio et al., 1994; Jonas et al., 1984; Jung et al., 2000). Under these sorbents, calcium-based alkali sorbents are the most widely used to remove SO2. Because calcium-based sorbents have good reactivity toward acidic gases and lower cost compared to other sodium-based alkali adsorbent.

The sorbent should be selected in consideration of the most important factors, hygroscopicity and price. Sodium-based sorbents have better removal efficiency of pollutant gases but is more expensive than calcium-based sorbents. While calcium-based sorbents exhibit hygroscopicity, but sodium-based sorbents deliquescency. In Table 2, various sorbents frequently used in flue-gas desulfurization processes are compared and the physical properties of the sorbents are also described as a part of basic research to understand whether they are utilized in flue-gas desulfurization processes. In addition, in Table 3 the molecular weight, specific gravity, density, decomposition temperature, melting point, particle size, solubility, and maleficence of the sorbents frequently used in flue-gas desulfurization processes are presented.

**2.2.3 Application to waste water treatment (nitrogen, phosphorous, heavy metals, pH**

Recycling of waste oyster shells has much limitation in environmental engineering. First, the quantity of waste oyster shells is too much to be recycled in environmental engineering. Second, a plan to retreat the waste oyster shells contaminated after adsorption of heavy metals should be prepared above all. Third, recycling of waste oyster shells would require removal of impurities through proper processing and treatment through a calcination process, which decreases the economic feasibility. Fourth, the repeated use lowers the

It is well known that alkali sorbents such as CaO, CaCO3, Ca(OH)2, NaOH, Na2CO3, NaHCO3, KOH, MgO, Mg(OH)2, dolomites, and dolomite limestones(CaCO3/MgCO3) are used to remove SO2 and acid gases in the flue gas cleaning processes (Kunio et al., 1994; Jonas et al., 1984; Jung et al., 2000). Under these sorbents, calcium-based alkali sorbents are the most widely used to remove SO2. Because calcium-based sorbents have good reactivity toward acidic gases and lower cost compared to other sodium-based alkali adsorbent.

The sorbent should be selected in consideration of the most important factors, hygroscopicity and price. Sodium-based sorbents have better removal efficiency of pollutant gases but is more expensive than calcium-based sorbents. While calcium-based sorbents exhibit hygroscopicity, but sodium-based sorbents deliquescency. In Table 2, various sorbents frequently used in flue-gas desulfurization processes are compared and the physical properties of the sorbents are also described as a part of basic research to understand whether they are utilized in flue-gas desulfurization processes. In addition, in Table 3 the molecular weight, specific gravity, density, decomposition temperature, melting point, particle size, solubility, and maleficence of the sorbents frequently used in flue-gas

**2.2.4 Improvement of sludge dehydration capacity (digested sludge etc.)**

mixture reduces the required dehydration time.

**2.2.5 Others (calcination, red tide, coagulation, fertilizer, etc.)**

**neutralization, etc.)**

prepared.

**2.3 Recycling limitation**

efficiency below commercial products.

desulfurization processes are presented.

**3. The kind and characteristics of sorbents**

Table 2. Characteristics of selected sorbents.

Table 3. Characteristics of sorbents in FGD process.


Preface

Pulmonary thromboembolism has appeared as a frequent complication in COVID-19 infection. As such, this book discusses the diagnosis of pulmonary thromboembolism in patients with and without COVID-19. Chapters address such topics as clinical symptoms of the disorder, biochemical and radiological findings in patients with pulmonary thromboembolism, and the modern approach to therapy.

The book is a useful resource for the general population of doctors, particularly internists, pulmonologists, and infectious disease specialists.

> **Jelena Stojšić, MD Ph.D.** University Clinical Centre of Serbia, Belgrade, Serbia

### **Chapter 1**