Clinical and Functional Outcomes of COVID-19 Survivors After Hospitalization

Coronavirus disease 2019 (COVID-19) causes various clinical manifestations during acute infection and at the post-acute phase with persistent symptoms called long COVID. It occurs in mild and moderate to severe cases which require hospitalization. In patients needing hospitalization, especially intensive care unit admission, the risk of long COVID increases. Many hospitalized patients exhibited more symptoms in 60 days after the illness than non-hospitalized patients. This review aimed to identify the clinical and functional outcomes in COVID-19 survivors after hospitalization. The articles in the PubMed database published in 2019-2021 were reviewed and found 20 be eligible. The clinical outcomes were the appearance or persistence of general and multi-organ symptoms, nutritional disorders, and decreased lung function. The functional outcomes found were decreased muscle strength, physical, psychological, and cognitive functions, increased disability and dependencies, as well as decreased vocational status and quality of life. The incidence of each outcome could not be determined due to the variety of methods used to examine and present outcomes. To conclude, COVID-19 causes long-term clinical and functional outcomes that need to be identified to prevent and manage long-term physical and functional disorders.


Introduction
Coronavirus disease 2019 (COVID-19) causes various clinical manifestations. The World Health Organi zation classifies the severity of this disease into mild, moderate, severe, and critical. 1 The severity of the disease increases the need for hospitalization, intensive care unit (ICU) admission, and even mortality. 2 People with a comorbid for COVID-19 have a higher risk for more severe disease. 3 In addition to causing various symptoms during acute infection, COVID-19 has longterm effects on survivors. This condition is called postacute sequelae of COVID-19 or long COVID-19 (LC). The LC is a patient with signs and symptoms that persist for about 4-12 weeks or appear after the acute phase (≥12 weeks). 4 Clinical outcomes (CO) and functional outcomes (FO) of COVID-19 survivors can be affected. A review by Hayes, et al., 5 found over 100 persistent symptoms after COVID-19 infection. Reported symptoms include cardiovascular, pulmonary, respira to ry, fatigue, pain-related symptoms, generalized infection symptoms, psychological disorders, cognitive impairment, sensory disturbances, skin problems, and impaired function. 5 A previous study have shown that LC not only occurs in patients with moderate to severe cases which require hospitalization but also in mild cases. 6 However, the risk of post-intensive care syndrome (PICS) was increased in patients needing hospitalization, especially ICU admission. 7 One systematic review found that a large proportion of hospitalized patients exhibited one or more symptoms of LC at 60 days after the illness compared to non-hospitalized patients. 8 Thus, this review study aimed to identify the CO and FO in COVID-19 survivors after hospitalization to give the knowledge or to develop a rehabilitation program for COVID-19 survivors.

Method
Articles were searched in the PubMed database with keywords ('functional' OR 'clinical') AND ('status' OR 'outcome') AND ('severe' OR 'critical') AND ('COVID-19') AND ('survivor') for the period from September 2021 to October 2021. The article type was an original article published from December 2019 to October 2021. Inclusion criteria were original articles with the study subjects of COVID-19 survivors after being discharged from the hospital, written in English, and freely access i -ble in pdf or HTML format.
The identical articles were identified first, then reviewed based on title, abstract, and keywords. Data taken were the author(s), study design, total subject, outcome assessment period, CO, and FO. Data were synthesized narratively and displayed as a table and text. The CO synthesized was based on symptoms, physical examination, laboratory, and imaging findings, while FO was determined based on functional impairment, disability, and quality of life.

Results
A total of 1,053 articles based on keywords searched and 40 articles matched with eligibility criteria. After reading the full text, 27 articles explaining both CO and FO were found. The study types were a prospective cohort (n = 20), a retrospective cohort (n = 5), an ambidirectional cohort (n = 1), and a cross-sectional (n = 1) study. Twenty prospective cohort studies were analyzed as a final result. The Preferred Reporting Items for Systema tic Reviews and Meta-Analyses (PRISMA) flowchart for a systemic review ( Figure 1) was used to explain the results. The result summary is presented in Table 1.

Discussion
Most studies were conducted in the first few months of 2020. During this period, COVID-19 was known to be caused by the original variant of severe acute res piratory system coronavirus 2 (SARS-CoV-2) with various clinical and functional outcomes.

Clinical Outcomes of COVID-19 The Appearance or Persistence of General Symptoms
The most common symptoms reported by COVID-19 survivors after one month to one year after being discharged from the hospital were shortness of breath and fatigue. The presence of persistent symptoms in COVID-19 survivors is caused by several mechanisms, including the presence of SARS-CoV-2 and a persistent inflammatory response in various tissues, reactivation of neurotrophic pathogens when immune dysregulation occurs, interactions of viruses with the microbiome or virome of the host cell, blood coagulation problems, dysfunction of vagal nerve signaling, abnormal cell metabolism, the presence of primitive immune cell activity, and molecular mimicry leading to autoimmunity between pathogens and host cells. [29][30] The Appearance or Persistence of Multi-organ Symptoms Angiotensin-converting enzyme 2 (ACE2), employed by SARS-CoV-2 as a receptor to enter human cells, is abundant in lung epithelial cells, especially in the alveoli. However, ACE2 is also widespread in various organs,  such as the heart, intestines, and kidneys. 31 Therefore, the virus can persist and damage various organs, resulting in other manifestations, both during the acute phase and after the patient recovers. Autoimmunity is also known to cause inflammation and damage in various organs. 29 One study found an abnormal estimated glomerular filtration rate. 20 Acute kidney failure is one of the complications due to COVID-19, which has a prevalence of 17%, of which 77% have severe COVID-19, and 5% of the total patients require renal replacement therapy. 32 In addition to the kidneys, abnormal results were found in cardiovascular organs, gastrointestinal, and neuro lo gical tissue. 32

Decreased Lung Function
Various studies carried out pulmonary function tests on COVID-19 survivors. They found that ventilation was impaired through a decrease in forced vital capacity and forced expiratory volume in one second, a decrease in total lung capacity, and a decrease in diffusion capacity. 10,12,14-17,22-26 COVID-19 survivors needed a long period to recover due to lung fibrosis and other morphological changes fully. The recovery rate is affected by the severity level, which is affected in turn by gender, obesity, and the presence of comorbidities. 14 Predomi nant impair ment of lung function is a restrictive pattern with  27 189 Fatigue and weakness, myalgia and arthralgia, sleep dis-Neurocognitive impairments orders, respiratory disorders, sensory alterations, gastrointestinal symptoms, movement impairments Bertolucci, et al. 28 39 Dysphagia, peripheral nervous system impairment

Nutritional Disorders
Nutrition-related problems that arise in COVID-19 survivors, especially severe degrees of disease, are caused by other related manifestations. 33 Difficulty of swallowing and weakness can make it difficult for the patient to eat. This condition is exacerbated by reduced appetite, resulting in muscle wasting. 33 In the end, survivors report ed a weight loss of >5% of their pre-illness body weight. 34 In other survivors, the diagnosis of mal nu trition was established. Moderate to severe mal nutri tion is the most common diagnosis. 35

Functional Outcomes of COVID-19 Decreased Muscle Strength
Decreased muscle strength may occur due to chronic skeletal muscle damage by SARS-CoV-2. 36 In addition, muscle weakness can be the result of immobility that occurs during hospitalization. 37 Prolonged ICU stay or mechanical ventilation used increased the occurrence of ICU-related muscle weakness. 20,22 Decreased Physical Performance The 6MWT was the most frequently used method to determine decreased exercise capacity and increased exertional desaturation post-COVID-19. 10,12,[14][15][16][17]22,25 Wong, et al., described that in patients who had exertional desaturation or hypoxemia (reduced SpO2 ≥4%), 45% had walking distance less than the lower limit of normal on the 6-minute walking distance, and 100% had DLCO less than the lower limit of normal. 38 These results suggest that desaturation during exercise is associat ed with pulmonary vascularity. 38

Psychological Disorder
Anxiety and depression were the most frequently reported psychological disorders in COVID-19 survivors, especially those requiring hospitalization. 39 Mental health disorders occur due to direct neuro-invasion by viruses that cause nerve cell damage or due to immune activation that causes an inflammatory response, especially in the brain. 39 In addition, having to undergo isolation makes it difficult to meet family and the inability to carry out normal activities, as well as guilt toward those closest to them because they have increased the risk of exposure to disease, all of which become stressors for the emergence of symptoms of anxiety and depression. 40

Cognitive Impairment
Not all literature describes methods for assessing the presence of cognitive impairment. However, in some literature that explains this, the Montreal Cognitive Assessment method was found to be the most widely used method to assess cognitive impairment. Similar to psychological disorders, cognitive impairment is also caused by damage to neurological function and the immune system. 32,39 In addition, patients undergoing treatment in hospitals do not receive stimulation and cognitive reorientation due to limited interactions be tween humans. 40 Cognitive symptoms that arise post-COVID-19 include difficulty thinking and concentrating (brain fog), decreased memory, and difficulty carrying out executive functions. 37 Any disturbances in physical, mental health, and cognitive functions cause post-intensive care syndrome, seen in individuals who have had treatment in an intensive care unit. 7

Increased Disability and Dependency
Physical impairments that arise are related to the treatment given in the acute phase. 40 The more severe the severity of the disease, the more complex the treatment given in the hospital. Severe disease increases the likelihood of mechanical ventilation, sedation, and neuromuscular blockade associated with prolonged immobilization. 40 Subsequent immobilization causes muscle and joint contractures, making it difficult for the patient to move. These disabilities make survivors dependent on carrying out daily activities. The Short Physical Performance Battery test method can be used to measure mobility ability through walking speed, Functional Ambulatory Category for walking/ambulation ability, and Barthel Index to determine individual dependence in daily activities. 40 Decreased Vocational Status COVID-19 infection caused a significant reduction in return to workability. 13,15,20,22,26 Several studies found that 50% to 87.5% of COVID-19 survivors did not return to their previous work or activity. 13,15,20 One study found that 43% of COVID-19 survivors felt too ill to work. 26 Among survivors who returned to work, many experienced a reduction of work capacity. 22,26

Conclusion
The CO identified in several studies is the appearance or persistence of general symptoms, multi-organ symptoms, decreased lung function, and nutritional disorders, while the FO includes decreased muscle strength and physical performance, psychological or cognitive disorders, increased disability or dependency, as well as decreased vocational status and HRQoL. With various methods used to examine the CO and FO of COVID-19 survivors after hospitalization and not all literature being equipped with a percentage of each outcome, the authors could not determine the incidence of each outcome. Further studies need to elucidate the incidence and differential outcomes associated with each variant of SARS-CoV-2 and their specific mechanisms. After knowing these outcomes, medical personnel are expected to be able to assess the CO and FO of COVID-19 patients to be used as a basis for carrying out rehabili tation management. Good cooperation between medical per son nel and survivors is needed to improve the HRQoL and prevent persistent anatomical and phy siological damage to the body.

Ethics Approval and Consent to Participate
Not applicable.