Strategies to evaluate outcomes in long-COVID-19 and post-COVID survivors

SARS-CoV-2 infection can impact the physical, cognitive, mental health of patients, especially in those recovered in intensive care units. Moreover, it was proved that the effects of the virus may persist for weeks or months. The term long-COVID or post-COVID syndrome is commonly used for indicating a variety of physical and psychological symptoms that continue after the resolution of the acute phase. This narrative review is aimed at providing an updated overview of the impact of physical, cognitive, and psychological health disorders in COVID-19 survivors, by summarizing the data already published in literature in the last year. Studies cited were found through PubMed searches. We also presented an overview of the post-COVID-19 health consequences on three important aspects: nutritional status, neurological disorders, and physical health. Moreover, to activate a correct health planning policy, a multidisciplinary approach for addressing the post- COVID-19 issue, has been proposed. Finally, the involvement of health professionals is necessary even after the pandemic, to reduce expected post-pandemic psychosocial responses and mental health disorders.


Introduction
Clinical manifestations of COVID-19 vary from asymptomatic forms to self-limiting conditions, up to severe manifestations featuring respiratory and multi-organ involvement [1][2][3][4][5][6]. Epidemiological data reveal that up to 20% of COVID-19 patients progress to a severe condition that requires hospitalization [7]. Among those who are hospitalized, up to one-quarter need intensive care unit (ICU) admission, making them more vulnerable to secondary pneumonia, cardiac injury, sepsis, kidney injury, and neurologic disorders [8].
The term 'Long COVID' or 'Post-COVID' is commonly used to describe an array of signs and symptoms that are present after acute COVID-19. The UK's National Institute for Health and Care Excellence described the Long COVID as "ongoing symptomatic COVID-19" (symptoms between 4 and 12 weeks) and "Post-COVID syndrome" when symptoms lasting longer than 12 weeks [9]. Recently the Long COVID has been recognized by the World Health Organization (WHO) as an international healthcare concern and an "emergency-use" ICD code has been issued [10]. The study of the long-term outcome of patients discharged from ICU revealed significant disabilities, collectively known as post-intensive care syndrome (PICS) [2], affecting physical, cognitive, and psychological health. PICS includes symptoms like generalized weakness, memory disturbances, poor Open Access *Correspondence: s.bimonte@istitutotumori.na.it 2 Division of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori Fondazione G. Pascale, 80131 Naples, Italy Full list of author information is available at the end of the article

The post-COVID syndrome
The Post-COVID Syndrome includes persistent symptoms related to residual inflammation, organ damage, non-specific effects from the hospitalization post-intensive care syndrome, social isolation, or impact on preexisting health conditions [18][19][20].
Post-COVID syndrome could be due to various mechanisms such as post-ICU syndrome, post-viral fatigue syndrome, permanent organ damage, or others [21]. Even if Long COVID was initially thought to be limited to survivors of hospital care and to those admitted to the ICU, it is now evident that most cases are described even in those who were not hospitalized or who did not immediately seek medical care [22][23][24].
The most frequent alterations include headache, dizziness, balance and coordination disorders, difficulty in attention, concentration, and memory, as well as chronic fatigue, insomnia, changes in taste and smell, depression, and anxiety. These physical, psychological, and neurocognitive symptoms are close to those present in post-traumatic stress disorder (PTSD) [25,26].
Several studies observed persistent symptoms and unexpected substantial organ dysfunction after SARS-CoV-2 infection in an increasing number of patients after recovering from their initial illness [27][28][29].
Data from a prospective cohort study on 270 COVID-19 survivors confirmed a post-COVID-19 syndrome in half of the patients experiencing symptoms such as fatigue and respiratory (dyspnea) or neurological complaints, 10-14 weeks after disease onset [30,31] showed that 76% of hospitalized COVID-19 survivors reported at least one symptom that persisted, with fatigue or muscle weakness being the most frequently reported symptom, 6 months after illness onset.
Among ICU COVID-19 survivors several patients face impairments regarding their cognitive and mental health or physical function far beyond their hospital discharge [32].
Data collected among symptomatic adults tested in outpatient settings (patients with mild COVID-19 without hospitalization) reported that 94% experienced one or more symptoms (cough 43%, fatigue 35%, or shortness of breath 29%) after infection onset, resulting in prolonged illness [28]. Persistent symptoms (such as anosmia/ageusia, dyspnea, or asthenia) have been reported in twothirds of patients with non-critical COVID-19 [30]. The ongoing COVID-19 pandemic and the occurrence of Post-COVID syndrome has highlighted the PICS issue and the complex rehabilitation needs for people with severe illness and long ICU stays as well as for COVID-19 survivors that have not been hospitalized. The persistence of various symptoms in Long-COVID patients is a major health issue worldwide. Monitoring and treatment of patients with post-COVID syndrome are necessary to ensure rehabilitation and recovery of general functions. These findings support the need for a multidisciplinary approach to the care of this vulnerable population and to conduct research studies during 1-2 years of follow-up, as is currently happening in the UK and USA [31,33,34] (see Table 1).

Potential tools to evaluate outcomes in long-COVID and post-COVID patients: our proposal
Cognitive, physical, and psychological dysfunction reported by COVID19 patients can have profound effects on the HR-QoL [32].
We proposed a multimodal process as well as the sequence of several aspects of the health-related quality of life (HRQoL) contributing to the impact of the disease on cognitive, physical, and nutritional outcomes by considering the set of the following tools: 1. The Short Form Health Survey 36 (SF-36), which is a short questionnaire (36 items) that evaluates eight dimensions: physical functioning (10 items), social functioning (2 items), limitations due to physical problems (4 items), limitations due to emotional problems (3 items), mental health (5 items), energy/vitality (4 items), pain (2 items) and perception of general health (6 items) [35]. The SF-36 investigates the health changes of an individual compared to the previous year. As the tool evaluates the state of health in general, it is suitable for studies in the general population and transversal or longitudinal investigations on specific diseases, and treatments. Due to its characteristic of a general questionnaire, it needs to be accompanied by specific questionnaires when studying patient populations. 2. The Barthel Index, developed to measure improvements in individuals with a chronic disability who underwent rehabilitation programs, is commonly used in post-ARDS patients [36].

The Psychological General Well-Being Index
(PGWBI) is designed for providing an index for measuring subjective well-being or suffering. It is composed of 22 items to assess anxiety, depression, positive well-being, self-control, general health, and vitality [37]. 4. The EuroQoL [38]. It represents the attempt to develop a standardized, general tool for describing and evaluating HRQoL regardless of the specific disease. It is a questionnaire consisting of five dimensions and an analog self-assessment scale. 5. The Pittsburgh Sleep Quality Index (PSQI), for assessing sleep quality [39]. 6. The Mini-Mental Test investigates the neurocognitive and functional state through simple targeted questions as well as small graphical tasks. It explores different domains of brain function, such as orientation, memory, attention and calculation, the ability to recall certain acquisitions, language, etc. [40]. 7. The Brief Pain Inventory (BPI) rapidly assesses the severity of pain and its impact on functioning [41]. 8. PTSS-14 (Post Traumatic Stress Syndrome 14 items) is a screening instrument to identify the patients who developed the Syndrome [42]. 9. HADS (Hospital Anxiety and Depression Scale) to evaluate the level of depression and anxiety of the patients discharged at home [43]. 10. MNA (Mini Nutritional Assessment) a nutritional educational program to assess nutritional status in patients in healthcare settings, appears ideal for patients with COVID -19, alongside a clinical and Para clinical evaluation [44,45].
(1) Neurological disorders Accumulated pieces of evidence highlighted that SARS-CoV-2 affected the nervous system [46][47][48]. In patients with a severe form of the disease, neurological manifestations were more evident. As reported by Mao et al. [46], neurologic manifestations affected or the central nervous system (CNS) (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), or the peripheral nervous system (PNS) (nerve pain and impairment of vision, test, and smell) or the skeletal muscular apparatus (injury). Among CNS alterations, the acute cerebrovascular disease was more evident in older patients and with severe infection and included cerebral hemorrhage and ischemic stroke diagnosed by clinical symptoms and head CT. Carfi et al. [3] demonstrated that worsened quality of life was observed in 44.1% of patients, and 87.4% reported persistence of at least 1 symptom, particularly fatigue and dyspnoea. The pathologic mechanism underlying the CNS invasion of SARS-CoV-2 is presumably like that of other respiratory viruses. Specifically, SARS-COV-2 can invade the CNS through the hematogenous or retrograde neuronal route. Since SARS-CoV-2 infects a large part of the world's population, understanding the potential neurologic implications of COVID-19 will help clinicians to identify and intervene in neurologic morbidity during and after the pandemic.
(2) Physical health Patients who have undergone intensive care after discharge may experience a post-intensive care syndrome (PICS) characterized by physical, mental, cognitive [1], and nutritional problems [49]. The impact of ICU on physical function can impair daily activities, involving the neuromuscular, cardio-respiratory, and skeletal systems: these individuals very often report inability to return to work, musculoskeletal weakness and difficulty walking, impaired lung and respiratory function [50][51][52][53].
Most of the complications due to COVID-19 described were related to hospitalized patients and therefore not associated with patients who received home care. Few studies have evaluated the presence of complications in patients positive for SARS-Cov-2 who did not require hospital care but were still positive for SARS-Cov-2. In a population-based cohort study in Denmark, it was found that the risk of severe complications after COVID-19 in non-hospitalized patients about 6 months after the infection is very low, but these still have a higher risk for venous thrombotic events than people without disease and negative for SARS-Cov-2 [54]. There are currently no other studies evaluating the long-term effects of the virus in non-hospitalized patients beyond six months of infection.
(3) Nutritional status Previous studies have highlighted the poor nutritional status of patients upon admission and during their stay in intensive care. The greater propensity for malnutrition and wasting is more visible in these critically ill patients, due to their developed metabolic disorders [49]. Nutritional status has long been considered an important factor that can influence the outcome of various infectious diseases, including viral pneumonia caused by SARS-CoV2 (COVID-19) [55,56]. In COVID-19 patients, an altered nutritional status characterized by malnutrition and loss of body weight can be found and due to various causes [57,58], including dyspnoea, anorexia, dysphagia, nausea, vomiting, diarrhea, increased energy requirements [59] advanced age, frailty, comorbidity [57] and prolonged hospital stay in ICU [58]. Currently, there are no specific dietary guidelines for post-COVID-19 patients with PICS disorders. However, several aspects could be considered to improve the impairments of cognitive functions. Eating habits can affect cognitive abilities [60]: unbalanced diets can have an overall negative impact on cognitive and mental health [61][62][63], negatively affecting the ability to reason, attention, and memory [61,62,64] and promote dementia and depression [65][66][67][68]. Greater adherence to a diet that includes healthy foods such as vegetables, fruits, seafood, lean meats, and whole grains, reduces the likelihood of suffering from depression or anxiety [69][70][71]. Nutrients such as vitamins (B1, B6, B12, B9, C, E, D), polyphenols, ω-3 fatty acids, minerals (iron, zinc, selenium), and foods with a  [72,73], and positively influence cognitive function [68,[74][75][76][77][78][79][80][81][82][83][84]. In this regard, several studies have reported that greater adherence to the Mediterranean diet was associated with an improvement in cognitive function and a reduced risk of cognitive impairment [83,[85][86][87][88][89]. It would be useful to monitor body composition, using methods such as bio impedance-analysis (BIA) or plicometry, and the nutritional status using the MNA [44,45], to offer the most adequate nutritional support that contributes to reduce physical and cognitive complications both in post-hospitalization and in the long term.

Conclusions
The Sars-Cov-2 is an invisible enemy that makes us feel constantly under threat, it can infect people at any time, and this can generate different responses in subjects: anxiety, depression, panic, sleep, concentration disorders, and fatigue. All normal and legitimate reactions, however, must be contained to try to limit the effects, allowing us to better face the emergency we are experiencing. COVID-19 survivors, after clinical recovery, may have neurocognitive damage that should not be underestimated, and the extent and duration of which is not yet known. As we reported, also the COVID-19 survivors (without hospitalization), reported the post-COVID-19 syndrome. The most frequent alterations found are headache, balance and coordination disorders, difficulty in attention, insomnia, changes in taste and smell, depression, anxiety, physical and nutritional dysfunctions. The isolation, the hospitalization, the drama of the health emergency could have been decisive in the onset of some of these symptoms. Overall, the impact of post-COVID-19 syndrome should be considered as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Thus, preventive interventional approaches mitigating social impact should be considered as an integral part of the response to the crisis during pandemics. Moreover, the involvement of specific health professional figures is needed even after the pandemic, to manage and care for an increased number of patients (Fig. 1).