COVID-19 sequelae: Clinical features and research progress

Na Li, Zhe Wang, Yun-Li Bao, Hai-Ru Tang, Jun Huang, Xiao-Hui Yu, Jiu-Cong Zhang

1. Department of Gastroenterology, the 940 Hospital of Joint Service Support Forces of the Chinese People's Liberation Army, Lanzhou 730050, China

2. The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730000, China

Keywords:SARS-CoV-2 COVID-19 Sequela Clinical features Research progress

The novel coronavirus pneumonia (Corona Virus Disease 2019,COVID-19) caused by the novel coronavirus (SARS-CoV-2) has caused extremely serious harm to human life and health since the outbreak at the end of 2019. As of April 24, 2022, more than 500 million confirmed cases and more than 6 million deaths have been reported worldwide [1]. As the number of people cured of COVID-19 continues to increase, the appearance of long-term persistent symptoms has become another focus of experts from various countries following the acute infection period. Previous studies have shown that patients with Severe Acute Respiratory Syndrome(SARS) and Middle East Respiratory Syndrome (MERS) generally have persistent symptoms of related systems after being cured [2],while SARS-CoV-2 is associated with SARS-CoV and MERSCoV belong to the Coronaviridae family and the genus Coronavirus β, and have similar viral structures [3], especially sharing specific binding receptors with SARS-CoV,Angiotensin-convertingenzyme 2(ACE2) [4], thereby playing a pathogenic role. Therefore, scholars at home and abroad are closely following up patients who have recovered from COVID-19, and sequelae involving respiratory,circulatory, nervous, and digestive systems have been observed [5-8].The most common symptoms include fatigue, muscle weakness,and difficulty sleeping, depression, dyspnea and so on[9], which seriously affect people's normal work and daily life.

1. Pathophysiology

As a new member of the coronavirus family and the genus β of coronaviruses [10], the single-stranded positive-stranded RNA genome of SARS-CoV-2 can encode four important structural proteins, namely, spinosin surface protein (S protein), nucleocapsid protein (N protein), matrix protein (M protein), and small envelope protein (E protein). Among them, spinosin S, which is encapsulated on the surface of the viral envelope E protein, is a key structure that determines viral invasion into the host cell and contains two subunits, S1 and S2. S1 subunit contains the Receptorbindingdomain (RBD), which is responsible for binding to the host receptor, and S2 subunit promotes membrane fusion between the virus and the host cell [4]. Stinger protein S enters cells by binding to ACE2 receptors specific to the surface of target cells[11], and eventually attacks a variety of target cells expressing ACE2, including vascular endothelium, heart, gastrointestinal tract, and kidney, in addition to the most prominent alveolar cells[12]. Meanwhile, damaged target cells such as alveoli release large amounts of viral and pro-inflammatory factors, which further activate the immune system and release cytokines, causing cytokine storm [13,14], thus further aggravating the disease and causing acute respiratory distress syndrome (ARDS) [15] or even multiorgan dysfunction syndrome (MODS) [16].

2. Covid-19 Sequelae

Because SARS-CoV-2 can damage the body through a variety of mechanisms, its sequelae can involve many human systems.According to the research [17], the main sequelae of covid-19 patients within 14 days to 3 months after discharge include persistent fatigue,dyspnea, decline in quality of life, myocarditis, olfactory and taste dysfunction, etc. A large cohort study of 1733 patients with COVID-19 discharged from Wuhan Jinyintan hospital showed that [9], 76%of the recovered patients had at least one persistent symptom six months after acute infection, mainly including fatigue or muscle weakness (63%), sleep difficulties (26%) and anxiety or depression(23%). In addition, the severity of the disease during acute infection was related to the occurrence of persistent symptoms. This is similar to another 7-month follow-up of 3762 patients from 56 countries [18].Another domestic research group [19] conducted telephone follow-up on 2433 patients in Wuhan. 1095 patients (45.0%) reported at least one discomfort symptom one year after sars-cov-2 infection. Fatigue,sweating, chest tightness, anxiety and myalgia were the most common. At the same time, it was proposed that old age, women and acute severe infection were the risk factors for sequelae. For patients who have undergone intensive care treatment during acute infection,they are more likely to have new symptoms such as fatigue, dyspnea and psychological cognitive impairment after discharge. 60% of severe patients are unable to work normally due to the persistence of sequelae after discharge. Women and old age are also risk factors[20]. In order to better manage the persistent symptoms of COVID-19 pneumonia, international guidelines have put forward [21], defining the covid-19 whose symptoms and signs last for 4-12 weeks as"Ongoing Symptomatic COVID-19", and defining the long-term persistent symptoms and signs as "Post-Covid-19 Syndrome (PCS),which refers to the symptoms and signs that occur during or after sars-cov-2 infection. The duration was more than 12 weeks and could not be attributed to other diagnoses. Studies have found that about a quarter of discharged patients are still positive for sarscov-2 nucleic acid in nasopharyngeal swabs, while some subjects are positive for more than 3 months [22]. For the cause of persistent injury of covid-19 related affected organs, in addition to the direct attack of sars-cov-2 on the body, the disorder of immune system and inflammatory response caused by acute infection may be the pathophysiological basis of long-term sequelae [23]. Studies on major inflammatory indicators such as neutrophils and C-reactive protein show that low-grade inflammatory response can persist after patients are discharged from hospital, resulting in oxidative stress and tissue damage [24]. In addition, the long-term mental health status of covid-19 rehabilitated patients was evaluated. The results showed that the patients had obvious mental health problems such as post-traumatic stress disorder (PTSD), anxiety, depression and insomnia. The related reasons may include gender, age, social stability, economic status, social isolation and fear of infection [25].

3. Clinical Characteristics of COVID-19 Sequelae

3.1 Pulmonary System

Since the lung is the organ most affected by covid-19 [15], a large number of studies have shown that persistent dyspnea is one of the most common persistent symptoms in discharged patients [17].Pulmonary function was measured in 110 non-critical patients.The results showed that patients had varying degrees of impaired pulmonary diffusion function at discharge [26]. Three months after discharge, about 55.7% of patients left chest CT abnormalities,mainly manifested as ground glass shadow (44.1%), while 44.3%of patients had abnormal lung function, mainly manifested as impaired lung diffusion capacity (34.8%) [27], and these lung injuries still accounted for a large proportion in the follow-up of 6 months[9]. For critically ill and critically ill patients, they are more prone to sustained impairment of pulmonary function after discharge[28,29]. Therefore, it is necessary to carry out more long-term and close follow-up for patients diagnosed as critically ill and critically ill during acute infection, so as to help them with rehabilitation treatment as soon as possible. A research team conducted continuous follow-up of 83 severe patients who did not need mechanical ventilation during hospitalization for 3, 6, 9 and 12 months after discharge, and evaluated their pulmonary function, motor ability and chest high-resolution CT (HRCT). The results showed that the degree of dyspnea and motor ability of most rehabilitated patients improved over time. However, at 12 months of follow-up.There are still 33% of patients with impaired pulmonary carbon monoxide diffusion volume (DLCO) (＜ 80% predicted value), and 24% of patients with abnormal chest HRCT. Women are a high-risk factor for persistent pulmonary diffusion dysfunction [30]. A follow-up study in Germany divided 180 patients into non-hospitalized and hospitalized groups without oxygen inhalation, low flow oxygen inhalation, high flow oxygen inhalation, invasive mechanical ventilation and extracorporeal membrane oxygenation (ECMO)treatment according to the severity of the disease in the acute infection period. The results showed that the severity of the disease in the acute infection period was significantly related to the impairment of pulmonary function, chest CT and respiratory symptoms in the follow-up period of 1 year [31]. These findings indicate that a large proportion of patients with COVID-19 have long-term abnormalities in imaging and pulmonary function after discharge. What deserves special attention is that a recent follow-up study observed 71 medical staff who had been infected with SARS for 15 years. The results show that some patients still have varying degrees of pulmonary CT and pulmonary dysfunction [32]. It is speculated that the lung injury of covid-19 rehabilitated patients may also last for a long time. It is very necessary to carry out relevant lung function rehabilitation training to improve their lung function while maintaining close follow-up. Consensus and guidelines have been published in many countries, proposing to take pulmonary rehabilitation measures after discharge as soon as possible for covid-19 patients [33]. For example,the pulmonary rehabilitation (PR) program [34] is a core part of the management of patients with chronic respiratory diseases. Through multidisciplinary and personalized respiratory physiotherapy,endurance training, daily life training, psychological support and other comprehensive measures, it can significantly improve the pulmonary function, exercise ability and quality of life of covid-19 patients [35], It has been proved to be effective, feasible and safe to improve the respiratory sequelae of covid-19 patients with different severity grades [33].

3.2 Cardiovascular Sequelae

Studies have shown that people with underlying cardiovascular disease are closely related to adverse disease outcomes of covid-19 [36]. At the same time, the attack of sars-cov-2, cytokine storm,ischemia and hypoxia and other direct and indirect mechanisms lead to the injury of cardiomyocytes and vascular endothelial cells, resulting in a series of complications of circulatory system in the acute infection period, mainly including hypertension, acute myocardial injury, myocarditis, arrhythmia and so on [9,37]. Among them, myocardial injury is significantly related to the fatal outcome in the acute infection period in the hospital [38]. Studies have shown that cardiovascular symptoms can last until discharge, and new cardiovascular diseases may occur at the same time. A cohort study in Wuhan showed that 3 months after discharge, 13% of convalescent patients with covid-19 had obvious cardiovascular symptoms,including rapid heart rate and newly diagnosed hypertension [39].A follow-up of 139 medical staff who had suffered from covid-19 showed that 11 weeks after discharge, 41.7% of the recovered patients had at least one symptom related to the cardiovascular system, mainly chest pain and dyspnea, 49.6% of the participants had abnormal ECG, and 60.4% of the recovered patients had abnormal cardiac magnetic resonance imaging (CMR), A total of 30.9% of the participants met the criteria of pericarditis and / or myocarditis[40]. CMR is a non-invasive reference standard for cardiac function and tissue characterization injury. For patients with confirmed or suspected active covid-19 and clinical evidence of myocardial injury, CMR can provide important information about the etiology and severity of myocardial injury [41], and can play an important role in the follow-up detection of cardiovascular sequelae of covid-19 discharged patients. A cohort study in Germany followed 100 rehabilitated patients for 3 months after discharge. CMR test showed that 78% of rehabilitated patients had heart involvement, mainly myocarditis (60%) [42]. The results of CMR follow-up in 64 patients with mild home rehabilitation showed that 71% of the participants were detected to have heart damage [43]. DanielE. Clark et al. [44]conducted a case-control study on covid-19 rehabilitated soldiers,including 50 soldier cases and 50 healthy soldiers. The results showed that 94% of soldier cases had cardiovascular symptoms in the later stage of rehabilitation. Further, four soldier cases diagnosed with myocarditis were followed up for long-term CMR, and one soldier still showed abnormal CMR and persistent active myocarditis at the follow-up of 7 months. Because persistent myocardial involvement such as myocarditis will cause adverse consequences such as sudden cardiac death during medium and high-intensity sports, some researchers followed up competitive athletes who had suffered from covid-19 in the past. The results showed that 46% of athletes found late gadolinium enhancement (LGE) through CMR test, of which 15% met the CMR diagnostic criteria of myocarditis[45]. These results have attracted the attention of exercise cardiologists and put forward relevant condition evaluation and exercise recovery plan [46]. In addition, it was observed in SARS convalescent patients that the treatment with high-dose steroids in the acute stage in hospital can cause long-term lipid metabolism disorder, which is related to the occurrence of cardiovascular sequelae [47]. In patients with covid-19 acute infection, patients with progressive deterioration of the condition need to be given glucocorticoid treatment as appropriate. Whether it will lead to the occurrence of hormone treatment-related sequelae needs to be closely monitored for a long time. Previous studies have confirmed that hospitalized pneumonia caused by various reasons is a risk factor for cardiovascular disease after hospital, and the risk of cardiovascular disease can be increased by 2-8 times within one month after discharge, even 10 years after discharge [48]. Based on the above phenomena, long-term follow-up of covid-19 rehabilitation patients is very important.

3.3 Neurologic Complications

Previous studies have confirmed that ACE2 can be expressed not only in vascular endothelium, but also in glial cells and neurons [49].Therefore, sars-cov-2 can trigger a series of neurological symptoms,mainly including taste disorder, olfactory disorder, headache,dizziness and so on through the mechanism of damaging brain circulation, neural tissue and its secondary systemic inflammatory response [50]. Olfactory and gustatory disorders are typical symptoms of covid-19. The study found that more than 50% of patients had olfactory or gustatory disorders 4 weeks after the acute phase [51],and some patients (11.7%) lasted until 1 year after infection [52]. In addition, studies have found that there are sensory disorders such as hearing loss and tinnitus in cured patients [53].

Headache is another persistent symptom of covid-19 nervous system. Up to 91% of rehabilitated patients have intermittent headache, which lasts for more than 28 days [54]. A follow-up study from Spain showed that [55], 74.6% of patients had headache symptoms during hospitalization, some with significant loss of smell, and a quarter of patients had migraine like severe pain attacks,which was similar to the results of the latest study with a continuous follow-up of 3 months [56]. Notably, these studies also found that more than 50% of patients with persistent headache had no previous history of recurrent headache at 6-week and 3-month follow-up.In addition, studies have shown that there is a correlation between persistent headache and olfactory or taste dysfunction, which may be related to the high inflammatory state caused by sars-cov-2 and the mechanism of virus invading peripheral nerve endings and damaging trigeminal nerve vascular endothelium [56].

The neurophilic nature of sars-cov-2 is also manifested in nerve inflammation and demyelination caused by invading the nervous system. Case reports show that [57], previously healthy men developed leg pain and foot sensory loss 53 days after the diagnosis of covid-19, and then gradually involved limbs, face and respiratory muscles. Cerebrospinal fluid and nerve conduction tests support the diagnosis of Guillain Barre syndrome (GBS). A female patient developed signs such as fatigue, intermittent tingling, numbness and blurred vision 3 weeks after covid-19 infection. Brain magnetic resonance imaging (MRI) showed demyelinating changes. After excluding other causes, she was finally diagnosed as multiple sclerosis caused by covid-19 [58].

Patients with short-term cognitive impairment and memory impairment were mainly shown in the study [59-61]. Studies have shown that the level of biomarkers of central nerve injury such as plasma neurotrophic factor increases abnormally in the acute stage of infection, and gradually returns to the normal level after 6 months of follow-up. However, neurological symptoms such as fatigue, brain fog and cognitive changes persist [62]. Therefore, it is reasonable to suspect that the neurological sequelae caused by covid-19 may not be accompanied by sustained central nervous system injury. Further comprehensive and long-term follow-up of the nervous system is needed to clarify the relevant mechanism of its sequelae.

3.4 Psychiatric Complications

It is reported that covid-19 rehabilitated patients have many mental and psychological symptoms, mainly PTSD, anxiety, depression,insomnia, etc. [25], which is similar to the previous reports of mental and psychological symptoms after the SARS and mers epidemics[63,64]. The early follow-up results of one month after the diagnosis of covid-19 showed that mental and psychological symptoms were common, including anxiety (42%), insomnia (40%), depression(31%), PTSD (28%) and obsessive-compulsive symptoms (20%)[65]. When covid-19 patients were discharged 6 months later, they still had fatigue or myasthenia (63%), sleep difficulties (26%),anxiety or depression (23%), among which the severity of women and acute infectious diseases were risk factors for persistent psychopsychological symptoms [9]. The latest follow-up report shows that the mental and psychological symptoms of some patients can last until 16 months after discharge [66]. Previous studies on the sequelae of SARS patients found that mental health diseases and chronic fatigue continued for 4 years and still affected more than 40% of rehabilitated patients [63]. Therefore, the mental health assessment of covid-19 rehabilitation population needs to be carried out for a long time.

Covid-19 related psychosocial disorders involve many reasons.Biological factors such as immune regulation disorder and cytokine storm caused by sars-cov-2 [65], as well as psychosocial factors such as women, old age, economic pressure, social isolation and fear of disease jointly promote the occurrence and development of psychosocial disorders in rehabilitated patients, seriously affect the quality of life of rehabilitated patients, and have an impact on social development. In addition, previous history of mental illness may be an independent risk factor for covid-19 [67]. Studies have shown that some convalescent patients with covid-19 have a "moderate risk of suicide" [68], while within one year after infection with sarscov-2, 27.60% of patients need psychotropic drugs to alleviate their psychological diseases [69]. Therefore, it is necessary to carry out early primary prevention for people with existing mental diseases and identified risk factors, and evaluate the mental health status of rehabilitated patients as soon as possible, so as to actively take effective psychological intervention measures to alleviate the psychological and mental pressure of rehabilitated people and promote their comprehensive rehabilitation [70].

3.5 Gastrointestinal System

A large number of early studies have confirmed that covid-19 patients are accompanied by gastrointestinal symptoms such as loss of appetite, diarrhea and vomiting during acute infection. At the same time, sars-cov-2rna can be detected in the feces of covid-19 patients [71-74]. Studies have reported that one month after the diagnosis of covid-19, the overall incidence of gastrointestinal diseases is 6%, mainly including abdominal pain, loss of appetite,diarrhea and vomiting [75]. At 90 days after infection, up to 44% of patients with gastrointestinal symptoms were characterized by loss of appetite (24%), nausea (18%), gastric acid reflux (18%) and diarrhea(15%) [76]. At 6 months of follow-up, gastrointestinal symptoms can still be observed, mainly including loss of appetite (8%), diarrhea or vomiting (5%) [9]. The long-term persistence of gastrointestinal symptoms in covid-19 patients may be related to the long-term existence of sars-cov-2 in the gastrointestinal tract. Some studies have shown that after the detection results of sars-cov-2 RNA in respiratory tract turn negative, the detection results of viral RNA in feces can still be positive, indicating that when sars-cov-2 is cleared in respiratory tract, it can persist in gastrointestinal tract, with an average duration of 28 days and up to 47 days in some patients [72].In addition, the "gut lung axis" formed by the bidirectional action of respiratory tract infection and intestinal microbial environment can lead to the change of intestinal microenvironment in respiratory tract infection caused by coronavirus and influenza virus [77]. As the target organ of sars-cov-2, studies have confirmed that sars-cov-2 infection can lead to the change of intestinal flora, the increase of opportunistic pathogenic bacteria and the decrease of intestinal beneficial microorganisms during acute hospitalization. Even after the virus nucleic acid detection in nasopharyngeal swabs and fecal samples turns negative and respiratory tract symptoms disappear,the imbalance of intestinal flora still persists [78]. Therefore, the long-term effect of covid-19 on gastrointestinal system needs to be comprehensively and deeply studied in order to better understand the occurrence and development mechanism of gastrointestinal persistent symptoms, so as to guide patients' rehabilitation more scientifically.

3.6 Others

Acute kidney injury (AKI) is a common complication of covid-19 during acute infection. The incidence of AKI in covid-19 patients during hospitalization is very high, which is significantly related to in-hospital death, while the renal function of a large number of patients cannot be recovered at discharge [79-81]. However, some studies have found that the renal function damage caused by covid-19 has not reached the diagnostic criteria of AKI, and the renal function indexes of patients who originally need renal replacement therapy (RRT) are stable during hospitalization. Therefore, it is proposed that covid-19 will not cause AKI or can not aggravate the chronic renal injury of covid-19 patients [82]. Therefore, larger studies are necessary to clarify the correlation between covid-19 and renal impairment. For AKI patients who need RRT treatment during hospitalization for acute infection, 41% can stop RRT treatment when their renal function improves at discharge, while 8% need to continue RRT treatment [83]. In addition, following up patients with covid-19 for 6 months, it was observed that 13% of patients had decreased glomerular filtration rate (EGFR) (＜ 90ml / min /1.73m2), and these patients had normal renal function and had never had acute renal injury in the acute phase [9]. Therefore, it is necessary to closely monitor the renal function of covid-19 rehabilitated people with acute renal injury and new renal insufficiency after discharge,so as to take appropriate prevention and treatment measures in time to improve their renal function, so as to reduce the long-term burden of the disease.

Sars-cov-2 can be associated with pancreas β Cell specific ACE2 receptors combine to damage islet cells, leading to new onset hyperglycemia, diabetes or induced diabetes ketoacidosis (DKA),while diabetes is a clear risk factor for covid-19 severity and adverse outcomes [84,85]. The blood glucose of diabetes patients caused by covid-19 was monitored. During the follow-up of 14 weeks, it was observed that the blood glucose of the patients was significantly improved, but oral hypoglycemic drugs were still needed to maintain the stability of blood glucose [86]. In addition, sars-cov-2 can also affect thyroid function. In thyroid tissue, the combination of sarscov-2 and ACE2, abnormal immune response and cytokine storm can cause thyroid tissue damage. At the same time, it can also affect hypothalamic pituitary thyroid axis, resulting in thyroid dysfunction diseases such as subacute thyroiditis, Graves disease and Hashimoto thyroiditis [87]. The case report of sars-cov-2 infection related subacute thyroiditis showed that after active treatment, two patients were still diagnosed with subclinical hypothyroidism at 6 weeks of follow-up [88].

Male reproductive system is the target organ of sars-cov-2. Studies have shown that there are reproductive system dysfunction such as testicular pain, orchitis and epididymitis in covid-19 patients[89,90]. A study from Switzerland showed that the number of motile sperm in young soldiers who recovered from covid-19 decreased significantly during short-term follow-up [91]. Although some studies have found the presence of sars-cov-2 virus particles in male semen samples [92], the results are not accurate. The long-term impact of covid-19 in male rehabilitated patients is not clear. Whether sarscov-2 will affect male reproductive function and whether there is sexual transmission need long-term follow-up monitoring.

Persistent skin problems afflict covid-19 rehabilitated people. Hair loss is one of the most common long-term persistent symptoms in covid-19 rehabilitation patients. About 25% of follow-up patients have hair loss, which lasts for more than 6 months [9,93]. In addition,skin lesions associated with covid-19 also include urticaria, measles like rash, chilblain, etc., with a duration ranging from 2 to 70 days[94].

Covid-19 related sequelae are more likely to occur in the elderly over 65 years old. 83% of elderly rehabilitation patients have at least one persistent symptom three months after the diagnosis of covid-19.The main symptoms include fatigue (53.1%), dyspnea (51.5%), joint pain (22.2%) and cough (16.7%) [95]. Covid-19 persistent symptoms are also common in children and adolescents, but the incidence is lower than that in the elderly. A 3-month follow-up of adolescent and child patients found that about 50% of participants saw at least one persistent symptom, fatigue (38%) was still the most common symptom, in addition to loss of taste or smell (16%), headache(15%), sensory impairment (11%), cognitive impairment (10%), etc.[96].

4. Conclusions and Future Directions

Since the outbreak of novel coronavirus pneumonia, it has coexisted with humans for nearly three years. At present, the longterm persistent symptoms of patients with novel coronavirus pneumonia and the related mechanisms of their occurrence and development have not been completely clear. It is still unknown whether the rehabilitation group will have new long-term sequelae in the future. Therefore, more comprehensive and close follow-up of the convalescent population of novel coronavirus pneumonia is the focus of medical work in the future. With the increasing number of cured patients, the emergence of related sequelae has had a serious impact on people's work and life, caused a heavy disease burden,and seriously hindered the development of society. Therefore, there is an urgent need for multidisciplinary intervention to establish a personalized treatment and rehabilitation system for different groups such as age, gender, occupation, economic level and region, so as to promote the comprehensive rehabilitation of sequelae groups.