biomedicines Review Long COVID-19 Syndrome: A Comprehensive Review of Its Effect on Various Organ Systems and Recommendation on Rehabilitation Plans Zhipeng Yan 1,*,† , Ming Yang 2,† and Ching-Lung Lai 1,* 1 Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong 999077, China 2 Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China; [email protected] * Correspondence: [email protected] (Z.Y.); [email protected] (C.-L.L.) † These authors have contributed equally to this work. Abstract: The majority of people infected with SARS-CoV-2 fully recovered within a few weeks. How- ever, a considerable number of patients of different ages still suffer from long-lasting problems similar to the multi-organ damage in its acute phase of infection, or experience symptoms continuously for a longer term after the recovery. The severity of the primary infection seems not to be associated with the possibility and severity of long-term symptoms. Various unresolved symptoms have been reported in COVID-19 survivors months after hospital discharge. Long COVID-19 Syndrome refers to survivors 4 months after initial symptoms onset. It is important to understand the systemic effects of Long COVID-19 Syndrome, its presentations, and the need for rehabilitations to restore functional recovery in survivors. Government, healthcare workers, and survivor groups should collaborate to Citation: Yan, Z.; Yang, M.; Lai, C.-L. establish a self-sustaining system to facilitate follow-up and rehabilitations, with prioritization of Long COVID-19 Syndrome: A resources to more severely Long COVID-19 Syndrome survivors. This review looks into the systemic Comprehensive Review of Its Effect effects of Long COVID-19 Syndrome in various aspects: respiratory, cardiovascular, hematological, on Various Organ Systems and renal, gastrointestinal, neurological, and metabolic effects of Long COVID-19 Syndromes. Recom- Recommendation on Rehabilitation mendations for follow-up and rehabilitations details have been explored to cope with the tremendous Plans. Biomedicines 2021, 9, 966. Long COVID-19 Syndrome patients. https://doi.org/10.3390/ biomedicines9080966 Keywords: Long COVID-19 Syndrome; Post COVID-19 Syndrome; rehabilitations; recovery Academic Editors: Mauro Maniscalco and Pasquale Ambrosino Received: 1 July 2021 1. Introduction Accepted: 3 August 2021 Ever since the first case of COVID-19 reported in early December 2019 in China, the Published: 5 August 2021 incidence has been rising drastically. As of 11 May 2021, the total number of recorded infections is over 157 million, with over 3.2 million deaths [1,2]. Though a majority of Publisher’s Note: MDPI stays neutral patients recovered from COVID-19 infections, over 70%-of-survivors were reported to have with regard to jurisdictional claims in impairments in one or more organs 4 months after initial symptoms [3]. They are termed published maps and institutional affil- “long haulers” [4], or patients living with “Chronic COVID syndrome”, “post-COVID-19 iations. syndrome”, or “postacute-COVID19 [5,6]. Extensive symptoms have been reported by convalescent patients, such as chronic cough, chest tightness, shortness of breath, cognitive dysfunction, and extreme fatigue, in Long COVID-19 Syndrome [7]. Long COVID-19 Syndrome is an umbrella term, including post-acute COVID-19 and Copyright: © 2021 by the authors. post-COVID-19 syndrome, depending on the duration after the acute onset of symptoms Licensee MDPI, Basel, Switzerland. (Figure1). Postacute-COVID-19 is defined as ongoing symptomatic COVID-19 for people This article is an open access article who still have symptoms 4 and 12 weeks after the onset of acute symptoms, while post- distributed under the terms and COVID-19-syndrome is for people who still have symptoms for more than 12 weeks conditions of the Creative Commons after onset of acute symptoms according to the UK NICE guidelines [7]. In a systematic Attribution (CC BY) license (https:// review and meta-analysis looking into the long-term effect of COVID-19, the five most creativecommons.org/licenses/by/ common symptoms are fatigue (58%), headache (44%), attention disorder (27%), hair loss 4.0/). Biomedicines 2021, 9, 966. https://doi.org/10.3390/biomedicines9080966 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 966 2 of 19 (25%), and dyspnea (24%) [8]. These symptoms may take months to resolve, even among non-hospitalized persons with mild illness course in the acute phase [9]. Figure 1. The timeline of Post-acute COVID-19 syndrome is defined as 4 to 12 weeks between initial confirmation of SARS-CoV-2 infection, while Post-COVID-19 syndrome is defined as 12 weeks after initial infection. The underlying progression/persistence of symptoms is associated with initial virus elimination recovery and angiotensin-converting enzyme 2 (ACE2)-associated system damage. Despite the commencement of global COVID-19 vaccination programs [10], the infec- tion rate remains high at the time of writing. This may imply we will have to live with COVID-19 for a significant period of time before there is herd immunity. It is important to understand the long-term effects of COVID-19 infection and manage its possible long-term complications in recovered COVID-19 patients to facilitate follow-up treatments. COVID-19 is caused by SARS-CoV-2 infection. SARS-CoV-2 uses the angiotensin- converting-enzyme 2 (ACE2) receptor to enter the cell through binding with spike-like protein (S-protein) [11,12], though some other receptors may also be involved. ACE2, therefore, plays a vital role in the pathogenesis of COVID-19. ACE2 is widely expressed in different body tissues, including the lung, heart, liver, kidney, and gastrointestinal system [13]. Thus, multi-organ injuries are observed in COVID-19, such as acute respiratory distress syndrome, acute myocardial injury, acute kidney injury, and acute liver injury. Survivors of severe COVID-19 are also found to be with multi-organ impairments after discharge [5]. Recovered COVID-19 patients are defined as previously infected patients with SARS- COV-2 negative testing by polymerase-chain-reaction (PCR) on 2 consecutive occasions separated by at least 24 h and without clinical symptoms at the time of discharge [14]. 2. The Effects of Long COVID-19 Syndrome on Various Systems At the time of writing, limited research has been published on this topic. Reports of survivors of SARS-CoV-1 and MERS-CoV infection showed persistent symptoms or underlying organ injury despite “recovery” [15–17]. This happens similarly in COVID-19 patients. A recent study showed that the increased risk of Long COVID-19 Syndrome was independent of age and existence of pre-existing medical conditions [18]. This review aims to look into the long-term effects of COVID-19 infection on respiratory, cardiovascular, neurological, and metabolic system of recovered COVID-19 patients (Table1 and Figure2), and to make recommendations on the management of Long COVID-19 patients. Biomedicines 2021, 9, 966 3 of 19 Table 1. Long COVID-19 Syndrome on various systems: an evidence-based summary. Possible Systems Main Diagnosis Features Prognosis References Mechanisms Extensive bilateral diffuse alveolar damage with cellular SARS-CoV-2 spike S1 domain protein Pulmonary function deficit 6 months fibromyxoid exudates; Acute respiratory distress binding to ACE2 receptor; Post Acute after infection; extensive diffuse Respiratory system desquamation of pneumocytes [19–30] syndrome (ARDS) Respiratory Distress Syndrome fibrosis with impairment; Long-term in-situ and hyaline membrane diffuse alveolar damage thrombosis formations; diffusion impairment and pulmonary fibrosis. Endothelitis; Micro-thrombosis, Majority (81%) of the COVID-19 Capillary damage; myocarditis patients survived the hypercoagulability; Increased target-to-blood pool Cytokine storm and macrophage activating acute episode; ongoing subclinical Cardiovascular system microangiopathy; ratio; capillary disturbance; [31–35] syndrome-caused endothelial dysfunction. myocarditis may evolve into thromboembolism; myocarditis; impaired oxygen diffusion. myocardial dysfunction and sudden atrial fibrillation; cardiac death. supraventricular tachycardia Elevated convalescent D-dimer Prognostic biomarkers for monitoring and C-reactive protein levels; clinical progression of Long Haematological system Thromboembolism N/A [36–38] persistently increased biomarkers COVID-19 patients need to of inflammation. be investigated Acute kidney injury; renal Declined glomerular filtration High abundance pf ACE2 expression Significant risks of mortality Urinary system [39–42] failure; rate (eGFR); kidney infarction in kidneys. and morbidity Bowel diffuse damage; The liver enzymes remained Gastrointestinal impairment and Enterocytes desquamation, Rich in ACE2 and furin expression; persistently elevated 14 days after dysfunction; hepatitic and edema, small bowel dilation, fecal-oral transmission; plasma cells and Digestive system discharge, while the liver functions in [43–49] cholestatic liver injury; lymphocytes infiltration and lymphocytic infiltrations into lamina majority survivors normalized pancreatic injury mesenteric nodes hemorrhage propria of intestinal tissues. 2 months after hospital discharge and necrosis. Blood vessel damage, impaired oxygen Over 40% survivors without prior supply, viral infiltration into the central psychiatric conditions lived with Mood changes; cognitive nervous system and inflammatory depression within 90