Archives of Academic Emergency Medicine. 2023; 11(1): e28 REV I EW ART I C L E Late Complications of COVID-19; An Umbrella Review on Current Systematic Reviews SeyedAhmad SeyedAlinaghi1, AmirBehzad Bagheri2, Armin Razi3, Paniz Mojdeganlou4, Hengameh Mojdeganlou5, Amir Masoud Afsah6, Arian Afzalian3, Parinaz Paranjkhoo7, Ramin Shahidi8, Pegah Mirzapour1, Zahra Pashaei1, Mohammad Amin Habibi9, Parmida Shahbazi10, Sahar Nooralioghli Parikhani3, Narjes Sadat Farizani Gohari11, Yusuf Popoola12, Esmaeil Mehraeen13∗, Daniel Hackett14 1. Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran. 2. Interdisciplinary Consortium on Advanced Motion Performance, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. 3. School of medicine, Tehran University of Medical Sciences, Tehran, Iran. 4. Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. 6. Department of Radiology, School of Medicine, University of California, San Diego (UCSD), California, USA. 7. Turpanjian College of Health Sciences, American University of Armenia, Yerevan 0019, Armenia. 8. School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran. 9. Clinical Research Development Center, Qom University of Medical Sciences, Qom, Iran. 10.Orthopedic Department, Orthopedic Surgery Research Center (OSRC), Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. 11.School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. 12.Health Information Management Unit, Department of Computer Science, Adeleke University, Ede, Nigeria. 13.Department of Health Information Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran. 14.Physical Activity, Lifestyle, Ageing and Wellbeing Faculty Research Group, School of Health Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. Received: January 2023; Accepted: February 2023; Published online: 12 March 2023 Abstract: Introduction: Several clinical manifestations have been discovered for COVID-19 since the emergence of SARS-CoV-2, which can be classified into early, medium, and long-term complications. However, late complications can be present after recovery from acute COVID-19 illness. The present study aims to comprehensively review the available evidence of late complications related to COVID-19. Methods: A search was conducted, using keywords, through electronic databases, which included Scopus, Web of Science, PubMed, and Embase up to August 29, 2022. Study selection was performed according to a strict inclusion and exclusion criteria. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist was followed, and studies were appraised using the National Institute of Health (NIH) quality assessment and risk of bias tool. Results: In total, 50 studies were included, and nine distinct COVID-19 late complication categories were identified. A review of these studies revealed that neurologic and psychiatric (n=41), respiratory (n=27), musculoskeletal and rheumatologic (n=22), cardiovascular (n=9), and hepatic and gastrointestinal (n=6) complications were the most prevalent complications of long COVID-19. Conclusion: Almost all human body systems are affected by late complications of COVID-19 with different severity and prevalence. Fatigue and some other neuropsychiatric symptoms are the most common late complications among long COVID-19 patients. Respiratory symptoms including dyspnea (during exercise), cough, and chest tightness were the next most prevalent long-term complications of COVID-19. Since these complications are persistent and late, being aware of the signs and symptoms is essential for the healthcare providers and patients. Keywords: COVID-19; SARS-CoV-2; Post-Acute COVID-19 Syndrome; Patient Outcome Assessment Cite this article as: SeyedAlinaghi SA, Bagheri AB, Razi A, Mojdeganlou P, Mojdeganlou H, et al. Late Complications of COVID-19; An Um- brella Review on Current Systematic Reviews. Arch Acad Emerg Med. 2023; 11(1): e28. https://doi.org/10.22037/aaem.v11i1.1907. ∗Corresponding Author: Esmaeil Mehraeen, Department of Health Infor- mation Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index SA. SeyedAlinaghi et al. 2 1. Introduction In relation to the groundbreaking emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in late December 2019, several concepts were presented regarding the clinical aspects of COVID-19 caused by SARS-CoV-2 (1, 2). SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) receptors to invade the host cells (3). Due to the widespread expression of ACE2 in human organs, COVID-19 can present with different clinical manifestations, including pneumonia, myocarditis, cardiac infarction, kidney injuries, neurologic manifestations, gastrointestinal disorders, etc. (4). SARS- CoV-2 is still spreading worldwide, and growing evidence re- ports the de novo manifestations of COVID-19. The dura- tion of symptoms of COVID-19 is not fully understood and the complications of COVID-19 present in different timelines and can be categorized into early (5), medium (6), and late (7) manifestations after COVID-19 infection. Manifestations and clinical and para-clinical indicators remaining different from healthy baseline level days to months after COVID-19 infection are considered post-COVID-19 complications (8). According to National Institute for Health and Care Excel- lence (NICE), post-COVID-19 infection is characterized by manifestations that are sustained for more than 12 weeks af- ter COVID-19 infection, and other diagnoses cannot be made for such complications (9). Although the majority of complications arise from the onset of COVID-19, a body of evidence reported the late compli- cations related to COVID-19, which are present in the sur- vivors of COVID-19 several weeks to months after the elim- ination of SARS-CoV-2, which can be attributed to the indi- rect damage of organs. Some pathways, including immune dysregulation, coagulopathy, and endothelial damage are in- troduced for late complications of COVID-19 (10). Conse- quently, it was shown that almost all human body systems are affected by COVID-19 and can show late complications. However, the percentage, severity, and duration of such late manifestations are different. Additionally, late complications are associated with an abnormal level of some laboratory pa- rameters such as inflammatory and anti-inflammatory pa- rameters that can indicate organ dysfunction (11, 12). Several systematic reviews and meta-analyses documented the late complications of COVID-19, including a broad range of organ injuries. In this umbrella review, we sought to pro- vide comprehensive evidence on the late complications of COVID-19 to improve the clinical insight of physicians and Postal Code: 5681761351, Tel: +98-45-32426801, Fax: +98-45-32422305, E-mail: es.mehraeen@gmail.com, ORCID: https://orcid.org/0000-0003-4108-2973. summarize the post-COVID-19 complications and highlight the importance of follow-up in patients with COVID-19. 2. Methods In this study we comprehensively reviewed current system- atic review studies about late and long-term complications of COVID-19. To optimize validity and authenticity, we utilized items of the Preferred Reporting Items for Systematic Re- views and Meta-Analyses (PRISMA) checklist. Studies were appraised using the National Institute of Health (NIH) qual- ity assessment and risk of bias tool. 2.1. Data sources An extensive search of four online databases was performed, which included Web of Science, PubMed, Scopus, and Em- base. Articles were restricted to English language and the search was conducted up to August 29, 2022. The following is the search strategy we have used on PubMed database, whereas search strategies for other databases are provided in Supple- mental material 1. ("COVID-19" [mesh] OR "SARS-CoV-2" [mesh] OR COVID- 19 [tiab] OR SARS-CoV-2 [tiab] OR coronavirus disease 2019 [tiab] OR severe acute respiratory syndrome coronavirus 2 [tiab]) AND (Long-Term Outcome*[tiab] OR Long-Term complication*[tiab] OR Late complication*[tiab] OR Chronic complication*[tiab] OR Long-term effect*[tiab] OR Long- Term Impact*[tiab] OR Consequence*[tiab] OR Sequelae [tiab] OR Long COVID [tiab] OR Sequel [tiab] OR post-acute COVID syndrome [tiab] OR long-COVID [tiab] OR post-acute COVID19 syndrome [tiab]) AND (Systematic review [tiab] OR meta-analysis [tiab]). Besides searching through databases, several Journals were searched in a manual search. 2.2. Study selection To improve the study selection process, a two-step method was employed. Two researchers screened articles with regard to titles and abstracts. The second step involved screening of full texts that were potentially eligible. Articles that met the inclusion/ exclusion criteria were advanced to the next step of data extraction. In other words, articles were included if they had a systematic review nature, were peer-reviewed, and assessed long-term complications of COVID-19. On the other hand, studies were excluded if they were non-human research studies, lacking the required data, duplications, nar- rative reviews, umbrella reviews, abstracts with deficient full texts, preprint articles, editorial letters, conference abstracts, case series, and case reports. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 3 Archives of Academic Emergency Medicine. 2023; 11(1): e28 2.3. Data extraction Four researchers were involved in extraction of data from ar- ticles that met the eligibility criteria. A preformatted spread- sheet was used to gather the extracted data. Potential com- plications of long COVID-19 were categorized into the fol- lowing nine groups: cardiovascular, renal, hepatic and gas- trointestinal, respiratory, neurologic and psychiatric, mus- culoskeletal and rheumatologic, stroke, ocular, thrombosis, and embolism. Information concerning late complication assessment methods, late complication onset, and time of recovery from sequelae was also extracted. Any duplicates were removed, and the accuracy of the extracted data was checked. 2.4. Quality and bias risk assessment The quality and authenticity of the selected articles, as stated before, were evaluated by conforming to the PRISMA check- list. We also addressed bias risk by utilizing National Institute of Health (NIH) questionnaire for quality assessment. Table 1 illustrates the application of this tool to our study. Each study was assessed and rated by two independent researchers. Last two columns show their ratings of individual papers. Details of this questionnaire are available at the bottom of this table. 3. Results The database search yielded 727 potential studies (after re- moving duplicates), and following the screening and quality control according to NIH quality assessment tool (Table 1), a total of 50 articles met the inclusion criteria (Figure 1). The included studies were carried out in an extensive range of countries including USA (n=9), UK (n=8), Italy (n=4), Canada (n=3), China (n=3), Australia (n=2), Germany (n=2), Ireland (n=2), Saudi Arabia (n=2), Spain (n=2), and Switzer- land (n=2). The following countries were each subject to one study: Brazil, Denmark, India, Indonesia, Iran, Iraq, Mexico, Pakistan, South Africa, and UAE. In total 1,833 studies were included in our enrolled sys- tematic reviews, and they had included a total of 5,425,998 COVID-19 patients. Two studies were conducted on children (103,212 children and adolescent COVID-19 patients), and the remaining 48 papers were carried out on adults. In re- gard to level of evidence, 19 studies were meta-analyses and had quantitative synthesis while, the remaining 31 studies were systematic reviews, two of which were conducted in- volving case-reports and case-series and 29 studies had in- cluded case-control, cross-sectional, and cohort studies in their qualitative synthesis. Review of included studies demonstrated that neurologic and psychiatric (n=41), respiratory (n=27), musculoskeletal and rheumatologic (n=22), cardiovascular (n=9), and hep- atic and gastrointestinal (n=6) complications were the most prevalent complications of long COVID-19. Moreover, renal, ocular, and stroke sequelae were also reported by a few stud- ies (n=2 for each sequela). There was one study that reported thrombosis or embolism as a complication of long COVID- 19. Finally, the onset of complications ranged between 10 days up to 13 months. The thorough details of included stud- ies are provided in Table 2. 4. Discussion Almost all human body systems are affected by late com- plications of COVID-19 with different severities and preva- lences. This systematic umbrella review found that late com- plications of long COVID-19 infection could be classified into nine groups. A discussion of each of these groups is covered below. Neurologic and Psychiatric It seems that late neurologic and psychiatric manifestations of the COVID-19 infection are the main and most prevalent features of this disease, and fatigue is the most prevalent symptom in long-COVID patients. Premraj L et al., (13) re- viewed 18 studies and more than 10000 COVID-19 patients. They concluded that some late COVID-19 manifestations may last for more than 3 months after infection. These symp- toms include psychiatric symptoms such as fatigue, cogni- tive impairment (memory problems, attention deficit), and sleep disorders. These symptoms and others like depression, post-traumatic stress disorder (PTSD), anxiety, anger, fear, dizziness, and mood change were reported in most studies (7, 13-46). However, COVID-19 severity in the acute phase of the infection was not correlated with increased symptoms in the post-acute phase of COVID-19 (47). There was some evidence inferring that identification of the long-term psy- chological consequences during the pandemic is critical to ensuring proper care provision (18, 48). Neurologic manifestations like headache, myelitis, neu- ropathies, paresthesia, parkinsonism, cogwheel rigidity (49), optic neuritis, altered smell, olfactory dysfunction (anosmia, ageusia), encephalitis (50), epilepsy, Bell’s palsy, and my- oclonus were also reported in some studies. Guillain-Barre syndrome was the most prevalent neurological condition of long COVID-19 reported in the study by Ahmed JO et al. (50). Headache was also one of the common symptoms of long COVID-19 during the first six months after recovery in the study by Fernández-de-las-Peñas, César et al. (51). Respiratory The lung is the most commonly affected organ in acute se- vere COVID-19 infection and its involvement is not unusual in long-term COVID-19. Some patients reported shortness of breath, cough, and chest tightness during the post-COVID- 19 phase for an extended period of time. Dyspnea usually worsens with increased physical exertion such as during ex- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index SA. SeyedAlinaghi et al. 4 ercise. Treatment has not been very effective in eliminating these symptoms, but the intensity of the symptoms usually reduces over time. Some studies like the one by So et al., (52) showed that the radiographic feature was ground glass opacity (44%) and parenchymal band or fibrous stripe (33.9%). Restrictive (16%) and obstructive (8%) patterns were also reported in their systematic review. These abnormalities lasted for a long period of time (15, 53). Musculoskeletal and Rheumatologic As mentioned in the studies by Pinzon RT et al. (14) and Salamanna F et al. (29), manifestations like musculoskele- tal, joint, and body pain have also been reported among long COVID-19 sufferers. Gracia-Ramos et al., (54) studied 90 systematic reviews and reported that vasculitis, including small, medium and large vasculitis, have been seen among long COVID-19 patients. Inflammatory myopathies, systemic lupus erythematosus (SLE), sarcoidosis, and arthritis were also reported. Cuta- neous vasculitis following COVID-19 is usually resistant to treatment and subsides over time. Cardiovascular The heart can also be involved in long COVID-19. Alosaimi et al. (55) concluded that the late cardiac involvements are pericardial effusion, myocarditis, pericarditis, elevated tro- ponin levels, and myocardial edema. Ramadan et al. (56) re- viewed 35 studies in relation to cardiac involvement in long COVID-19. Chest pain, dyspnea, and palpitations were usu- ally reported by these patients. T-wave changes, ST-segment elevation/depression, and right bundle branch block were seen in the electrocardiogram (ECG) of these patients. Us- ing echocardiography, there are reports of reduced left ven- tricular ejection fraction, pericardial effusion, global hypoki- nesis, left ventricular hypertrophy, diastolic dysfunction, and pulmonary hypertension. The researchers concluded that increased T1 intensity, late gadolinium enhancement, in- creased T2 intensity, pericardial effusion, decreased global longitudinal strain, decreased left ventricular ejection frac- tion, myocardial enhancement, pericardial enhancement, myocarditis, myopericarditis, pericarditis, and myocardial infarction may be seen in the cardiac magnetic resonance imaging (MRI) of these patients. Other reported cardiac in- volvements in long COVID-19 were elevated NT-pro-BNP lev- els, and arterial occlusion (in angiogram). Patients with long COVID-19 were more susceptible to heart failure, myocardial infarction, stroke, and arrhythmia. Hepatic and Gastrointestinal Choudhury et al. (57) studied 50 systematic reviews. This re- search reported that long COVID-19 patients were more sus- ceptible to complaints of gastrointestinal manifestations like loss of appetite, dyspepsia, constipation, loss of taste, irri- table bowel syndrome (IBS), abdominal pain, diarrhea, and nausea/vomiting. Renal Urinary problems including urinary tract infections are rare but may be seen among long COVID-19 patients (40, 58). Ocular Ophthalmologic problems among long COVID-19 patients, including conjunctivitis, dry eye, trouble seeing/blurred vi- sion, photophobia, sore eyes, and pain were rarely reported (54, 59). Thrombosis or Embolism and Stroke SeyedAlinaghi et al. (40) reviewed 65 studies. They con- cluded that venous/arterial thrombosis and cardiac/brain stroke may also be seen among long COVID-19 patients. Others Other late and less common complications of COVID-19 in- clude sputum/nasal congestion, hyperhidrosis, rhinorrhea, cough, myalgia/arthralgia, body weight changes, otalgia, sore throat, variations in heart rate, dysphonia, fever palpi- tations, hair loss, dysphagia, speech disturbances, hypopro- teinemia and menstrual problems. 5. Conclusion COVID-19 patients may have late and chronic manifesta- tions. These symptoms are known as long COVID-19 and can last for more than 6 months. Additionally, long COVID- 19 is usually resistant to treatment but may resolve over time. Fatigue and other neuropsychiatric symptoms are the most common late complications among patients with long COVID-19. Respiratory symptoms including dyspnea (dur- ing exercise), cough, and chest tightness were the next most prevalent long-term complications of COVID-19. Since these complications are persistent and late, being aware of the signs and symptoms is essential for the health care providers and patients. 6. Declarations 6.1. Acknowledgments The present study was conducted in collaboration with Khalkhal University of Medical Sciences, Iranian Research Center for HIV/AIDS, Tehran University of Medical Sciences, and the University of Sydney. 6.2. Conflict of interest The authors declare that there is no conflict of interest re- garding the publication of this manuscript. 6.3. Fundings and supports This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 5 Archives of Academic Emergency Medicine. 2023; 11(1): e28 6.4. Authors’ contribution (1) The conception and design of the study: Esmaeil Mehraeen, SeyedAhmad SeyedAlinaghi (2) Acquisition of data: AmirBehzad Bagheri, Armin Razi, Hengameh Mojdeganlou, Paniz Mojdeganlou (3) Analysis and interpretation of data: Amir Masoud Afsahi, Arian Afzalian (4) Drafting the article: Esmaeil Mehraeen, Parinaz Paran- jkhoo, Ramin Shahidi, Pegah Mirzapour, Zahra Pashaei, Mo- hammad Amin Habibi, Parmida Shahbazi, Sahar Noorali- oghli Parikhani, Narjes Sadat Farizani Gohari, Yusuf Popoola (5) Revising it critically for important intellectual content: SeyedAhmad SeyedAlinaghi, Daniel Hackett (6) Final approval of the version to be submitted: SeyedAh- mad SeyedAlinaghi, Esmaeil Mehraeen, Daniel Hackett Final version was read and approved by all author. 6.5. Ethics approval and consent to participate Not applicable 6.6. Consent to publication Not applicable 6.7. 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Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 9 Archives of Academic Emergency Medicine. 2023; 11(1): e28 Figure 1: Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 flow diagram of study retrieval process. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index SA. SeyedAlinaghi et al. 10 Table 1: Quality ratings of included studies in accordance with NIH quality assessment tool First Autor *Question Rating by Reviewers 1 2 3 4 5 6 7 8 9 #1 #2 Fernández-de-las-Peñas C (51) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair De Luca P (60) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair Ahmed JO (50) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair Ali SS (61) Yes Yes NA CD NA Yes CD NA Yes Fair Fair Premraj L (13) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Pinzon RT (14) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair So M (52) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair Long Q, Li J (15) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Patria YN (53) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Vanderlind WM (16) Yes Yes NR NA NA Yes CD Yes Yes Fair Fair Renaud-Charest O (47) Yes Yes NA NA NA Yes CD NA Yes Fair Fair Schou TM (17) Yes Yes NA CD NA Yes CD NA Yes Fair Fair Arora T (18) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Zürcher SJ (48) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair Bourmistrova NW (20) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Badenoch JB (19) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Khraisat B (21) Yes Yes NR CD NA Yes CD Yes Yes Fair Fair Alosaimi B (55) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Ramadan MS (56) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair Choudhury A (57) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair Gracia-Ramos AE (54) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair Behnood SA (59) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Lopez-Leon S (58) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Ahmed H (22) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Alkodaymi MS (23) Yes Yes NR CD NA Yes CD NA Yes Fair Fair Ceban F (24) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Chen C, Haupert SR (25) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Fernández-de-Las-Peñas C (26) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Lopez-Leon S (7) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Michelen M (27) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Nguyen NN (28) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair Salamanna F (29) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair Sandra Willi (62) Yes Yes NR NA NA Yes CD Yes Yes Fair Fair Yang T (30) Yes Yes NR CD NA Yes CD Yes Yes Fair Fair Zeng N (31) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Almas T (32) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Ahmad MS (33) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Healey Q (34) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair d’Ettorre G (35) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Groff D (36) Yes Yes NA NA NA Yes CD Yes Yes Fair Fair Han Q (37) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair Iwu CJ (38) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Iqbal FM (39) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair SeyedAlinaghi S (40) Yes Yes CD CD NA Yes CD Yes Yes Fair Fair Jennings G (41) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair Ma Y (42) Yes Yes NR CD NA Yes CD Yes Yes Fair Fair Malik P (43) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair Cabrera Martimbianco AL (44) Yes Yes NA CD NA Yes CD Yes Yes Fair Fair Sanchez-Ramirez DC (45) Yes Yes CD CD NA Yes CD NA Yes Fair Fair Sandler CX (46) Yes Yes CD NA NA Yes CD Yes Yes Fair Fair NIH = National Institutes of Health; CD = cannot determine; NR = not reported; NA = not applicable. *The NIH Quality Assessment Tool for Case Series Studies (https://www.nhlbi.nih.gov/health-topics/study- quality-assessment-tools) contains nine questions: 1 = Was the study question or objective clearly stated?, 2 = Was the study population clearly and fully described, including a case definition?, 3 = Were the cases consecutive?, 4 = Were the subjects comparable?, 5 = Was the intervention clearly described?, 6 = Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants?, 7 = Was the length of follow-up adequate?, 8 = Were the statistical methods well-described?, 9 = Were the results well-described? This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 11 Archives of Academic Emergency Medicine. 2023; 11(1): e28 Table 2: Characteristics of 50 included studied in the umbrella review F irst A u th o r a n d C o u n try In clu d ed stu d ies S tu d y p o p u la tio n Late complication C o m p lica tio n A ssessm en t m eth o d s T im e o f la te co m p lica tio n o n set T im e o f reco very fro m m en tio n ed S eq u ela e L a te co m p lica tio n s C a rd io va scu la r R en a l H ep a tic a n d G a stro in testin a l R esp ira to ry N eu ro lo g ic a n d P sych ia tric M u scu lo sk eleta la n d R h eu m a to lo g ic S tro k e O cu la r T h ro m b o sis o r E m b o lism Fernández- de-las- Peñas C (51) Spain 35 28, 438 * - 47.1% at onset or hospital admission, 10.2% at 30 days, 16.5% at 60 days, 10.6% at 90 days, and 8.4% at ≥180 days after on- set/hospital discharge - Post-COVID headaches seems to be stable during the first 180 days. De Luca P (60) Italy 16 5582 * - - - Association between SARS-CoV-2 infection and persistent hearing or chemosensory problems in patients with COVID-19 Ahmed JO (50) Iraq 40 55 * * - Average interval between COVID-19 infection to the onset of neurological sequelae was 33.2 days. - Guillain-Barre syndrome was the most commonly reported neurological condition. Transverse myelitis, critical illness neuromyopa- thy/neuropathy, encephalopathy, parkinsonism, optic neuritis, status epilepticus, encephalitis, bell’s palsy, vestibulocochlear neuritis, opsoclonus myoclonus syndrome, and myopathy were also reported. Ali SS (61) Pakistan 10 13 * Magnetic resonance imaging (MRI): 6(46.2%) cases, elec- troencephalography (EEG): 3(23.1%) cases, fluorodeoxyglucose (FDG): 3(23.1%) cases, positron emission tomography (PET): 3(23.1%) cases. - - Cogwheel rigidity was the most common symptom of Parkinsonism in patients. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index SA. SeyedAlinaghi et al. 12 Table 2: Characteristics of 50 included studied in the umbrella review Premraj L (13) Australia 18 10, 530 * - - 3 or more months post- infection Fatigue, cognitive dysfunction (brain fog, memory issues, attention disorder), and Psychiatric manifestations (sleep disturbances, anxiety, and depression) Pinzon RT (14) Indonesia 36 9944 * Chest CT: 13 studies, pulmonary function test (PFT): 10 studies During the first six months after the onset of illness - Fatigue- cognitive disorder; paresthesia; sleep disorder; musculoskeletal pain; and dizziness So M (52) USA 15 3066 * Lung Function Pulmonary function tests (including spirometry, lung volume, and diffusion capacities): 20% (95% CI 13–17%) - - Chest CT abnormalities: glass opacity in 44.1%, parenchymal band or fibrous stripe in 33.9%. Abnormal pulmonary function test: 44.3%, impaired diffusion capacity 34.8%. Restrictive and obstructive patterns:16.4% and 7.7%, respectively. Long Q, Li J (15) China 16 4478 * - - - Fatigue, weakness, psychosocial symptoms, and abnormalities in lung function Patria YN (53) Indonesia 7 378 * Lung function test: (77.56, 95% CI: 47.83–107.29) - - Abnormal lung function for at least several weeks in the recovery period. Vanderlind WM (16) USA 33 9676 * - - - Sleep difficulties, fatigue, anxiety, acute and posttraumatic stress, depression, self-reported cognitive functioning, psychiatric sequalae Renaud- Charest O (47) Canada 8 1058 * The DSM-V criteria (n = 1),13-items Beck’s Depression Inventory (BDI-13) (n = 2), Zung Self-Rating Depression Scale (ZSDS) (n = 1), Depression, Anxiety and Stress Scale (DASS-21) (n = 1), Hospital Anxiety and Depression Scale (HADS) (n = 3), Patient Health Questionnaire (PHQ-9) (n = 1), and Quality of Life in Neurological Disorders (Neuro-QoL) (n = 1). - - Depressive symptoms This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 13 Archives of Academic Emergency Medicine. 2023; 11(1): e28 Table 2: Characteristics of 50 included studied in the umbrella review Schou TM (17) Den- mark 6 751955 * - - - Anxiety and/or depression, post-traumatic stress disorder (PTSD), cognitive deficits, fatigue, and sleep disturbances Arora T (18) UAE 28 97173 * - - - Anxiety, PTSD, stress/distress, depression, anger, fear, worry, sleep quality/insomnia Zürcher SJ (48) Switzer- land 59 11248 * High ZSDS scores: (symbol coding test: Wald = 8.37, p = 0.003), DASS-21 depression scores (Mini-Mental State Examination: β = – 0.039, p = 0.007), performance on tests assessing immediate recall in verbal memory (California Verbal Learning Test: β = – 0.432, p = 0.016), visual reaction times (Test of Everyday Attention: β = 6.298, p = 0.007), executive abilities (Tower of London test: β = – 0.149, p = 0.008) and visuospatial abilities (Rey figure copy and recall: β = – 0.096, p = 0.044). - - Mental health problems Bourmist- rova NW (20) UK 33 4935 * - - - Sleep disturbances (primarily insomnia), PTSD, anxiety, and depression Badenoch JB (19) UK 51 18917 * - - - Sleep problems and fatigue appear to affect roughly one-quarter of survivors. Cognitive impairment, anxiety, post-traumatic symptoms, and depression are also common in the first 6 months. Khraisat B (21) USA 27 9605 * - - - PTSD, anxiety, psychological distress, depression, and sleeping disorders Alosaimi B (55) Saudi Arabia 15 6229 * Cardiac MRI, ECG, Echocardiography, cardiac enzyme (Troponin I or T), and Holter monitoring - - Pericardial effusion, myocarditis, pericarditis, elevated troponin levels, and myocardial edema Ramadan MS (56) Italy 35 52, 609 * Cardiac MRI, echocardiography, troponin, Questionnaires, N-terminal proB-type natriuretic peptide (NT-proBNP), endomyocardial biopsy, 24-hour ECG, clinical assessment, coronary angiography, and registry analysis. 41 to 71 days - Cardiovascular findings in MRI were: increased T1 intensity, late gadolinium enhancement, increased T2 intensity, pericardial effusion, decreased global longitudinal strain, decreased left ventricular ejection fraction, myocardial enhancement, pericardial enhancement, myocarditis, myopericarditis, pericarditis, and myocardial infarction as cardiac sequelae. Studies using echocardiography reported reduced left ventricular ejection fraction, pericardial effusion, global hypokinesis, left ventricular hypertrophy, diastolic dysfunction, and pulmonary hypertension. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index SA. SeyedAlinaghi et al. 14 Table 2: Characteristics of 50 included studied in the umbrella review ECG changes: T-wave changes, ST segment elevation/depression, right bundle branch block, and sinus tachycardia. Elevated troponin and NT-pro-BNP levels were also observed. Angiography reports: two-vessel coronary artery disease including left anterior descending artery occlusion and left anterior descending artery occlusion. Cardiac symptoms: chest pain, dyspnea, and palpitations, heart failure, myocardial infarction, stroke, and arrhythmia Choudhury A (57) In- dia 50 401, 289 * - COVID-19 patient follow-up time: from 4 weeks up to 8.4 months - Gastrointestinal (GI) symptoms among COVID-19 patients was 12%, while, the overall frequency of GI symptoms among long-COVID-19 patients was 22%. GI symptoms among severe cases of COVID-19, was 13%, while this was 20% for long-COVID-19 patients after severe COVID-19 infection. GI symptoms: Loss of appetite, dyspepsia, constipation, loss of taste, irritable bowel syndrome (ibs), abdominal pain, diarrhea, and nausea/vomiting Gracia- Ramos AE (54) Mexico 90 99 cases of new- onset rheumatic autoim- mune diseases (RAD) * Organ biopsy, clinical criteria, immunologic blood tests, imaging modalities, synovial fluid analysis, electromyography, and muscle biopsy. 19 to 44 days. - 46 new-onset vasculitis sorted by prevalence: small-vessel vasculitis, medium-vessel vasculitis, and large-vessel vasculitis 32 new-onset sorted by prevalence: spondylarthritis, reactive arthritis 9 new-onset inflammatory myopathies 6 new-onset systemic lupus erythematosus (SLE) Behnood SA (59) UK 22 23,141 children and young people * * * * - From 28 to 324 days with median duration of 125 days - Fatigue, dyspnea, headache, cognitive difficulties, myalgia, abdominal pain, fever, loss of smell, cough, and diarrhea Developing persistent symptoms: cognitive difficulties, headache, loss of smell, sore throat, and sore eyes. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 15 Archives of Academic Emergency Medicine. 2023; 11(1): e28 Table 2: Characteristics of 50 included studied in the umbrella review Lopez- Leon S (58) USA 21 80, 071 chil- dren and ado- les- cents * * * * * * - * - - from 1 to 13 months. - General prevalence of long-COVID-19 in children and adolescents was 25.24%. For hospitalized patients, the prevalence of long-COVID-19 was 29.19%. Mood changes, fatigue, sleep disorders, headache, respiratory symptoms, sputum/nasal congestion, cognition difficulties, loss of appetite, exercise intolerance, altered smell, hyperhidrosis, chest pain, dizziness, rhinorrhea, cough, myalgia/arthralgia, body weight changes, altered taste, otalgia, ophthalmologic problems, abdominal pain, dermatologic problems, sore throat, chest tightness, variations in heart rate, constipation, dysphonia, fever, diarrhea, vomiting, palpitations, hair loss, neurological abnormalities, urinary symptoms, dysphagia, and speech disturbances Compared to controls, children with long-COVID-19 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever. Ahmed H (22) UK 28 2,854 * * * * SF-36 for health-related quality of life, George’s Respiratory Questionnaire (SGRQ), chest CT Up to 6 months after discharge - Post-traumatic stress disorder, depression, and anxiety were considerable beyond 6 months after discharge. Alkodaymi MS (23) USA 63 257, 348 * Physical assessment, ICD-10 codes, electronic medical records 3-12 months after recovery from COVID-19 - Fatigue. Ceban F (24) Canada 81 29, 128 * mesoscale-discovery (MSD) multiplexed immunoassay (Immunological parameters), Self-report, TICS-M (cognitive function), EQ-5D-5L (quality of life), MoCA (cognitive function), SF-20 (quality of life) 3-6 months after testing positive for COVID-19 Median 85 days Fatigue Chen C, Haupert SR (25) USA 50 1, 680, 003 * * - 3-9 months after diagnosis - Fatigue and joint pain This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index SA. SeyedAlinaghi et al. 16 Table 2: Characteristics of 50 included studied in the umbrella review Fernández- de-Las- Peñas C (26) Spain 29 24, 255 * * * * - Median 82 days - Palpitation, fatigue, depression, apnea, throat ache, joint pain Lopez- Leon S (7) USA 15 47, 910 * * Chest X-ray, chest CT, D-dimer, CRP - - Fatigue, depression, shortness of breath Michelen M (27) UK 32 10, 951 * * Self-report, physical assessment Median 221 days - Fatigue, depression, shortness of breath, lung abnormalities Nguyen NN (28) Germany 37 N/A * * * Self-report, physical assessment 35-90 days - Fatigue, depression, apnea, joint pain Salamanna F (29) Italy 145 22, 254 * * * - Abnormal lung functions up to 6 months, car- diovascular up to 8 months - Palpitation, cardiovascular injury, anxiety, depression, fatigue, body aches, olfactory dysfunction, Sandra Willi (62) Switzer- land 31 48, 246 * * * Chest CT, radiological findings 11-90 days Respiratory up to 12 weeks after hospital admission Cardiovascu- lar 11 weeks after onset of COVID-19 symptoms - Impaired pulmonary function, breathlessness, decrease in quality of life, pulmonary fibrosis, myocarditis, fatigue Yang T (30) Ger- many 72 88, 769 * * * * - Average 95 days Average after more than 9 months Fatigue, depression, joint pain, arthralgia, dyspnea, alopecia, anxiety Zeng N (31) China 151 1, 285, 407 * * Chest CT, radiological findings Mental sequela up to 12 months - Abnormal pulmonary function tests, fatigue, memory impairment, depression, PTSD Almas T (32) Ire- land 21 54730 * * * - Chest pain after 60 days of illness, ongoing palpitations after 6-months 60 days – 6 months Fatigue, dyspnea, arthralgia, alopecia, anxiety, hyperhidrosis, insomnia Ahmad MS (33) Saudi Arabia 20 14146 * * * * Standard questionnaires, PFTs, QoL assessment parameters, chest CT, MRI, Spirometry From 4 weeks – 6 months - Fatigue, dyspnea, cough, sore throat, joint pain, chest pain, loss of smell/taste, depression, headache, diarrhea, anxiety, loss of memory Healey Q (34) UK 19 10643 * * * * Chest CT, Biomarkers Up to 4 weeks after acute infection - Fatigue, dyspnea, gustatory dysfunction, cough, olfactory dysfunction, myalgia This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 17 Archives of Academic Emergency Medicine. 2023; 11(1): e28 Table 2: Characteristics of 50 included studied in the umbrella review d’Ettorre G (35) Italy 13 4395 * * * Chest CT, MRI, 6MWT, D-dimer, PFTs From 9 – 291 days - Sleep difficulties, dyspnea, chest pain, loss of smell, PTSD, anxiety, depression, headache, pulmonary fibrosis, muscle weakness, brain fog, dizziness Groff D (36) USA 57 250351 * * PFTs , CT, MRI, PHQ, mMRC, 6MWT, Body plethysmography, Echo, GAD-7, SGRQ, EQ-5D-5L, HADS, MMSE, SF-12, SCIP, WAIS-III, PTSD (DTS), CFQ-11 30 days after illness and beyond Up to 6 months Difficulty concentrating, generalized anxiety disorder, memory deficits, fatigue, cognitive impairment, anosmia, dysgeusia Han Q (37) UK 18 8591 * * * Validated questionnaires, mMRC, HADS, Insomnia Severity Index Up to 12 months From 3-12 months Fatigue, dyspnea, depression, arthromyalgia, anxiety, insomnia, memory loss, concentration difficulties Iwu CJ (38) South Africa 11 86 * * * CT, Biomarkers, laboratory tests, PFTs, validated survey instruments, Vascular changes Up to 6 weeks after infection 12th week after dis- charge Fatigue, cough, sleep disorders, shortness of breath, depression, anxiety Iqbal FM (39) UK 43 12974 * * * MRI, SF-36, WEMWBS, PET scan, CT scan, lmMRC scale, CFS, SF-36, PTSD, HADS questionnaires Up to 12 weeks and beyond - Fatigue, sleep disturbance, dyspnea, anxiety SeyedAli- naghi S (40) Iran 65 N/A * * * * * * * MRI Up to 8-10 weeks and beyond - Lung, liver, kidney, and heart injuries, neurological injuries, cardiac/brain stroke, hypoproteinemia, encephalopathy, thromboembolism, septic shock, multiple organ dysfunction syndromes, psychological distress Jennings G (41) Ireland 39 8293 * * * Spirometry, CT, HRCT, CXR, MRI, PFTs, EQ-5D-5L Up to 31 weeks - Fatigue, Sleep disorder, depression, cognitive impairments, confusion, cough, dyspnea, anxiety, arthralgia, myalgia, headache, chest pain, throat pain, fever, expectoration, weight loss, skin problems, anosmia, ageusia, hair loss Ma Y (42) China 40 10, 945 * * * CT, PFTs, mMRC, GAD-7 scores, 6MWT, EQ-5D-5L Up to 6 months and above at 12 months and beyond Fatigue, mild dyspnea, anxiety, depression, sleep difficulty, difficulty concentrating, myalgia, joint pain, rhinorrhea Malik P (43) USA 12 4828 * * * EQ-5D-5L, VAS scale - - Fatigue, cough, chest pain, dyspnea, anosmia, arthralgia, headache, sleep disturbances, mental health problems, poor QoL This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index SA. SeyedAlinaghi et al. 18 Table 2: Characteristics of 50 included studied in the umbrella review Cabrera Martim- bianco AL (44) Brazil 25 5440 * * * - From 3 to 24 weeks - Chest pain, arthralgia, dyspnea, cough, fatigue, sputum production, sleep disorders, cognitive and memory impairment, myalgia, functional impairment Sanchez- Ramirez DC (45) Canada 24 5323 * * CT, PFTs, mMRC, WPAI, performance-based tests, SPPB, 1-MSTST, 2MWT, 6MWT, EQ-5D-5L, SF-36 up to 6 months after infection - Fatigue, chest pain, cough, dyspnea, poor QoL Sandler CX (46) Australia 21 7639 * Blood count, CXR, CT, PFTs, ECG, Echo, validated multi-item fatigue questionnaire Up to 16–20 weeks From 8 weeks and beyond Fatigue Abbreviations: chest X-ray (CXR), chronic fatigue syndrome (CFS), computed tomography (CT), George’s Respiratory Questionnaire (SGRQ), High-resolution computed tomography (HRCT), Hospital Anxiety and Depression (HADS), Magnetic resonance imaging (MRI), Mini-Mental State Examination (MMSE), Modified Medical Research Council (mMRC), positron emission tomography (PET), posttraumatic stress disorder (PTSD), Pulmonary function tests (PFTs), Quality of Life (QoL), The 36-Item Short Form Survey (SF-36), The Short Physical Performance Battery (SPPB), The Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), Work Productivity and Activity Impairment (WPAI) Supplementary 1: The study search strategy in different databases PubMed Search Query; Time of search: 29 August 2022; Results: 453 ("COVID-19"[mesh] OR "SARS-CoV-2"[mesh] OR COVID-19[tiab] OR SARS-CoV-2[tiab] OR coronavirus disease 2019[tiab] OR severe acute respiratory syndrome coronavirus 2[tiab]) AND (Long-Term Outcome*[tiab] OR Long-Term complication*[tiab] OR Late compli- cation*[tiab] OR Chronic complication*[tiab] OR Long-term effect*[tiab] OR Long-Term Impact*[tiab] OR Consequence*[tiab] OR Seque- lae[tiab] OR Long Covid[tiab] OR Sequel[tiab] OR post-acute COVID syndrome[tiab] OR long-COVID[tiab] OR post-acute COVID19 syn- drome[tiab]) AND (Systematic review[tiab] OR meta-analysis[tiab]) Embase Search Query; Time of search: 29 August 2022; Results: 496 (’coronavirus disease 2019’/exp OR ’severe acute respiratory syndrome coronavirus 2’/exp OR ’COVID-19’:ab,ti OR ’SARS-CoV-2’:ab,ti OR ’coronavirus disease 2019’:ab,ti OR ’severe acute respiratory syndrome coronavirus 2’:ab,ti) AND (‘long COVID’/exp OR ‘Long-Term Outcome*’:ab,ti OR ‘Long-Term complication*’:ab,ti OR ‘Late complication*’:ab,ti OR ‘Chronic complication*’:ab,ti OR ‘Long-term ef- fect*’:ab,ti OR ‘Long-Term Impact*’:ab,ti OR ‘Consequence*’:ab,ti OR ‘Sequelae’:ab,ti OR ‘Long Covid’:ab,ti OR ‘Sequel’:ab,ti OR ‘post- acute COVID syndrome’:ab,ti OR ‘long-COVID’:ab,ti OR ‘post-acute COVID19 syndrome’:ab,ti) AND (‘Systematic review’:ab,ti OR ‘meta- analysis’:ab,ti) Scopus Search Query; Time of search: 29 August 2022; Results: 495 (TITLE-ABS (“COVID-19” OR “SARS-CoV-2” OR “coronavirus disease 2019” OR “severe acute respiratory syndrome coronavirus 2”)) AND (TITLE-ABS (“Long-Term Outcome*” OR “Long-Term complication*” OR “Late complication*” OR “Chronic complication*” OR “Long- term effect*” OR “Long-Term Impact*” OR “Consequence*” OR “Sequelae” OR “Long Covid” OR “Sequel” OR “post-acute COVID syn- drome” OR “long-COVID” OR “post-acute COVID19 syndrome”)) AND (TITLE-ABS (“Systematic review” OR “meta-analysis”)) Web of Science Search Query; Time of search: 29 August 2022; Results: 452 (TS= (“COVID-19” OR “SARS-CoV-2” OR “coronavirus disease 2019” OR “severe acute respiratory syndrome coronavirus 2”)) AND (TS= (“Long-Term Outcome*” OR “Long-Term complication*” OR “Late complication*” OR “Chronic complication*” OR “Long-term effect*” OR “Long-Term Impact*” OR “Consequence*” OR “Sequelae” OR “Long Covid” OR “Sequel” OR “post-acute COVID syndrome” OR “long- COVID” OR “post-acute COVID19 syndrome”)) AND (TS= (“Systematic review” OR “meta-analysis”)) This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index Introduction Methods Results Discussion Conclusion Declarations References