Long-Term effects of COVID-19: a review of current perspectives and mechanistic insights

Although SARS-CoV-2, responsible for COVID-19, is primarily a respiratory infection, a broad spectrum of cardiac, pulmonary, neurologic, and metabolic complications can occur. More than 50 long-term symptoms of COVID-19 have been described, and as many as 80% of patients may develop ≥1 long-term symptom. To summarize current perspectives of long-term sequelae of COVID-19, we conducted a PubMed search describing the long-term cardiovascular, pulmonary, gastrointestinal, and neurologic effects post-SARS-CoV-2 infection and mechanistic insights and risk factors for the above-mentioned sequelae. Emerging risk factors of long-term sequelae include older age (≥65 years), female sex, Black or Asian race, Hispanic ethnicity, and presence of comorbidities. There is an urgent need to better understand ongoing effects of COVID-19. Prospective studies evaluating long-term effects of COVID-19 in all body systems and patient groups will facilitate appropriate management and assess burden of care. Clinicians should ensure patients are followed up and managed appropriately, especially those in at-risk groups. Healthcare systems worldwide need to develop approaches to follow-up and support patients recovering from COVID-19. Surveillance programs can enhance prevention and treatment efforts for those most vulnerable.

[1]  T. Kuno,et al.  Longitudinal Cardiac Outcomes of Multisystem Inflammatory Syndrome in Children: A Systematic Review and Meta-Analysis , 2022, Pediatric Cardiology.

[2]  M. Maniscalco,et al.  Clinical assessment of endothelial function in convalescent COVID-19 patients: a meta-analysis with meta-regressions , 2022, Annals of medicine.

[3]  Shannon Seney,et al.  Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism , 2022, Molecular Medicine.

[4]  Christopher J. L. Murray,et al.  Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. , 2022, JAMA.

[5]  Ali I. Al-Gareeb,et al.  Pathophysiology of Post-COVID syndromes: a new perspective , 2022, Virology Journal.

[6]  Kehu Yang,et al.  Risk of incident diabetes after COVID-19 infection: A systematic review and meta-analysis , 2022, Metabolism.

[7]  A. Iwasaki,et al.  The neurobiology of long COVID , 2022, Neuron.

[8]  D. Skrypnik,et al.  New-Onset Diabetes Mellitus, Hypertension, Dyslipidaemia as Sequelae of COVID-19 Infection—Systematic Review , 2022, International journal of environmental research and public health.

[9]  A. Licari,et al.  Prevalence and clinical presentation of long COVID in children: a systematic review , 2022, European Journal of Pediatrics.

[10]  Jong Hyuk Lee,et al.  Pulmonary function and chest computed tomography abnormalities 6–12 months after recovery from COVID-19: a systematic review and meta-analysis , 2022, Respiratory Research.

[11]  G. Lippi,et al.  Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: A systematic review , 2022, eClinicalMedicine.

[12]  S. Pardhan,et al.  The prevalence of sensory changes in post-COVID syndrome: A systematic review and meta-analysis , 2022, Frontiers in Medicine.

[13]  Haiyu Wang,et al.  Microbiota and COVID-19: Long-term and complex influencing factors , 2022, Frontiers in Microbiology.

[14]  A. Waickman,et al.  Inflammation, immunity, and antigen persistence in post-acute sequelae of SARS-CoV-2 infection , 2022, Current Opinion in Immunology.

[15]  K. Khunti,et al.  Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study , 2022, BMJ.

[16]  David M. Cutler The Costs of Long COVID. , 2022, JAMA health forum.

[17]  N. Wenger,et al.  Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort , 2022, Journal of General Internal Medicine.

[18]  V. Novakovic,et al.  Long COVID: The Nature of Thrombotic Sequelae Determines the Necessity of Early Anticoagulation , 2022, Frontiers in Cellular and Infection Microbiology.

[19]  Thomas E. Nichols,et al.  SARS-CoV-2 is associated with changes in brain structure in UK Biobank , 2022, Nature.

[20]  Benjamin Bowe,et al.  Long-term cardiovascular outcomes of COVID-19 , 2022, Nature Medicine.

[21]  G. Martinotti,et al.  Suicide in Healthcare Workers: Determinants, Challenges, and the Impact of COVID-19 , 2022, Frontiers in Psychiatry.

[22]  Sarah Houben-Wilke,et al.  The Impact of Long COVID-19 on Mental Health: Observational 6-Month Follow-Up Study , 2022, JMIR mental health.

[23]  Karl A. Soetebier,et al.  Trends in Disease Severity and Health Care Utilization During the Early Omicron Variant Period Compared with Previous SARS-CoV-2 High Transmission Periods — United States, December 2020–January 2022 , 2022, MMWR. Morbidity and mortality weekly report.

[24]  C. Robba,et al.  Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis , 2022, Journal of the Neurological Sciences.

[25]  Siddharth Singh,et al.  Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis , 2022, Therapeutic advances in gastroenterology.

[26]  K. Schwab,et al.  Postacute Sequelae of COVID-19 Critical Illness , 2022, Critical Care Clinics.

[27]  S. Ng,et al.  Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome , 2022, Gut.

[28]  Nelson B Rodrigues,et al.  Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis , 2021, Brain, Behavior, and Immunity.

[29]  Z. Al-Aly,et al.  Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status , 2021, Nature Communications.

[30]  R. Shafran,et al.  Persistent symptoms following SARS-CoV-2 infection amongst children and young people: A meta-analysis of controlled and uncontrolled studies , 2021, Journal of Infection.

[31]  N. Sculthorpe,et al.  More Than 100 Persistent Symptoms of SARS-CoV-2 (Long COVID): A Scoping Review , 2021, Frontiers in Medicine.

[32]  M. Taquet,et al.  Six-month sequelae of post-vaccination SARS-CoV-2 infection: A retrospective cohort study of 10,024 breakthrough infections , 2021, Brain, Behavior, and Immunity.

[33]  F. Benedetti,et al.  Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life , 2021, European Archives of Psychiatry and Clinical Neuroscience.

[34]  F. Rahimi,et al.  Psychological problems and reduced health-related quality of life in the COVID-19 survivors , 2021, Journal of Affective Disorders Reports.

[35]  D. de Berardis,et al.  COVID-19 Associated Mucormycosis: A Systematic Review from Diagnostic Challenges to Management , 2021, Diseases.

[36]  Yishay Szekely,et al.  Cardiorespiratory Abnormalities in Patients Recovering from Coronavirus Disease 2019 , 2021, Journal of the American Society of Echocardiography.

[37]  J. Geddes,et al.  Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19 , 2021, PLoS medicine.

[38]  M. Di Giannantonio,et al.  SARS-CoV-2 and the Brain: What Do We Know about the Causality of ‘Cognitive COVID? , 2021, Journal of clinical medicine.

[39]  B. McCrindle,et al.  The NHLBI Study on Long-terM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC): Design and Objectives: Design and Rationale of the MUSIC Study. , 2021, American heart journal.

[40]  Jeroen J. Bax,et al.  Post-COVID-19 Tachycardia Syndrome: A Distinct Phenotype of Post-Acute COVID-19 Syndrome , 2021, The American Journal of Medicine.

[41]  R. Friedman,et al.  Six Month Follow-up of Patients With Multi-System Inflammatory Syndrome in Children , 2021, Pediatrics.

[42]  P. Sun,et al.  The Psychological Impact of COVID-19 Pandemic on Health Care Workers: A Systematic Review and Meta-Analysis , 2021, Frontiers in Psychology.

[43]  S. Ladhani,et al.  Causation or confounding: why controls are critical for characterizing long COVID , 2021, Nature Medicine.

[44]  S. Yong Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments , 2021, Infectious diseases.

[45]  P. Nilsson,et al.  Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers. , 2021, JAMA.

[46]  W. Lim,et al.  Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol , 2021, The Lancet Regional Health - Europe.

[47]  David A. Drew,et al.  Attributes and predictors of long COVID , 2021, Nature Medicine.

[48]  P. Cinque,et al.  Smell and taste disorders in COVID-19: From pathogenesis to clinical features and outcomes , 2021, Neuroscience Letters.

[49]  P. Grant,et al.  Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic , 2021, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[50]  C. Wolf,et al.  Sequelae in Adults at 6 Months After COVID-19 Infection , 2021, JAMA network open.

[51]  Benjamin Bowe,et al.  High-dimensional characterization of post-acute sequelae of COVID-19 , 2021, Nature.

[52]  Jeffrey L. Anderson,et al.  SARS-CoV-2 as an inflammatory cardiovascular disease: current knowledge and future challenges , 2020, Future cardiology.

[53]  Jean Y. Ko,et al.  Characteristics of Hospitalized COVID-19 Patients Discharged and Experiencing Same-Hospital Readmission — United States, March–August 2020 , 2020, MMWR. Morbidity and mortality weekly report.

[54]  B. Levine,et al.  Coronavirus Disease 2019 and the Athletic Heart: Emerging Perspectives on Pathology, Risks, and Return to Play. , 2020, JAMA cardiology.

[55]  E. Townsend Debate: The impact of school closures and lockdown on mental health in young people , 2020, Child and adolescent mental health.

[56]  Corby K. Martin,et al.  The Impact of COVID‐19 Stay‐At‐Home Orders on Health Behaviors in Adults , 2020, Obesity.

[57]  M. Fouad,et al.  Geographic Variation in Racial Disparities in Health and Coronavirus Disease-2019 (COVID-19) Mortality , 2020, Mayo Clinic Proceedings: Innovations, Quality & Outcomes.

[58]  I. Koralnik,et al.  Frequent neurologic manifestations and encephalopathy‐associated morbidity in Covid‐19 patients , 2020, Annals of clinical and translational neurology.

[59]  A. Gholamrezanezhad,et al.  The lingering manifestations of COVID-19 during and after convalescence: update on long-term pulmonary consequences of coronavirus disease 2019 (COVID-19) , 2020, La radiologia medica.

[60]  G. Cooper,et al.  Clinical Characteristics, Hospitalization, and Mortality Rates of Coronavirus Disease 2019 Among Liver Transplant Patients in the United States: A Multicenter Research Network Study , 2020, Gastroenterology.

[61]  W. Lim,et al.  What is the recovery rate and risk of long-term consequences following a diagnosis of COVID-19? - A harmonised, global longitudinal observational study , 2020, medRxiv.

[62]  Kristy L Marynak,et al.  Delay or Avoidance of Medical Care Because of COVID-19–Related Concerns — United States, June 2020 , 2020, MMWR. Morbidity and mortality weekly report.

[63]  V. Abedi,et al.  Racial, Economic, and Health Inequality and COVID-19 Infection in the United States , 2020, Journal of Racial and Ethnic Health Disparities.

[64]  Emily Fraser Long term respiratory complications of covid-19 , 2020, BMJ.

[65]  Allen Cheng,et al.  Update on the COVID‐19‐associated inflammatory syndrome in children and adolescents; paediatric inflammatory multisystem syndrome‐temporally associated with SARS‐CoV‐2 , 2020, Journal of paediatrics and child health.

[66]  Jay S. Steingrub,et al.  Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network — United States, March–June 2020 , 2020, MMWR. Morbidity and mortality weekly report.

[67]  G. Fonarow,et al.  Coronavirus Disease 2019 (COVID-19) and the Heart-Is Heart Failure the Next Chapter? , 2020, JAMA cardiology.

[68]  Eike Nagel,et al.  Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19) , 2020, JAMA cardiology.

[69]  P. Kirchhof,et al.  Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases. , 2020, JAMA cardiology.

[70]  Yanfeng Gao,et al.  Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery , 2020, EClinicalMedicine.

[71]  D. Lombardi,et al.  Olfactory and Gustatory Outcomes in COVID-19: A Prospective Evaluation in Nonhospitalized Subjects , 2020, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[72]  Shaojia Lu,et al.  The landscape of cognitive function in recovered COVID-19 patients , 2020, Journal of Psychiatric Research.

[73]  J. Luers,et al.  Persisting olfactory dysfunction in patients after recovering from COVID-19 , 2020, Journal of Infection.

[74]  T. Cothran,et al.  A brewing storm: The neuropsychological sequelae of hyperinflammation due to COVID-19 , 2020, Brain, Behavior, and Immunity.

[75]  E. Hurley,et al.  Advocating for Children During the COVID-19 School Closures , 2020, Pediatrics.

[76]  Z. Yazıcı,et al.  Taste and Smell Impairment in SARS-CoV-2 Recovers Early and Spontaneously: Experimental Data Strongly Linked to Clinical Data , 2020, ACS chemical neuroscience.

[77]  M. Heneka,et al.  Immediate and long-term consequences of COVID-19 infections for the development of neurological disease , 2020, Alzheimer's Research & Therapy.

[78]  Daniel S. Cormican,et al.  Severe Acute Respiratory Syndrome Coronavirus-2 Cardiovascular Complications: Implications for Cardiothoracic Anesthesiology , 2020, Journal of Cardiothoracic and Vascular Anesthesia.

[79]  Jérémie F. Cohen,et al.  Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study , 2020, BMJ.

[80]  E. Charani,et al.  New-onset anosmia and ageusia in adult patients diagnosed with SARS-CoV-2 infection , 2020, Clinical Microbiology and Infection.

[81]  M. Zervos,et al.  Clinical Characteristics and Morbidity Associated With Coronavirus Disease 2019 in a Series of Patients in Metropolitan Detroit , 2020, JAMA network open.

[82]  Sreedhar Adapa,et al.  COVID-19 Pandemic Causing Acute Kidney Injury and Impact on Patients With Chronic Kidney Disease and Renal Transplantation , 2020, Journal of clinical medicine research.

[83]  Y. Arkha,et al.  COVID-19 and SARS-Cov-2 Infection: Pathophysiology and Clinical Effects on the Nervous System , 2020, World Neurosurgery.

[84]  M. A. Fornazieri,et al.  Incomplete and late recovery of sudden olfactory dysfunction in COVID-19 , 2020, Brazilian Journal of Otorhinolaryngology.

[85]  Hao Li,et al.  A Pattern Categorization of CT Findings to Predict Outcome of COVID-19 Pneumonia , 2020, Frontiers in Public Health.

[86]  A. T. Roberts,et al.  Olfactory and gustatory dysfunctions in 100 patients hospitalized for COVID-19: sex differences and recovery time in real-life , 2020, European Archives of Oto-Rhino-Laryngology.

[87]  R. Claus,et al.  Postmortem Examination of Patients With COVID-19. , 2020, JAMA.

[88]  K. Mertz,et al.  Postmortem examination of COVID‐19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction , 2020, Histopathology.

[89]  D. Munoz,et al.  Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the Central Nervous System , 2020, Trends in Neurosciences.

[90]  F. R. de Fonseca,et al.  Influencia de la infección SARS-CoV-2 sobre enfermedades neurodegenerativas y neuropsiquiátricas: ¿una pandemia demorada? , 2020, Neurología.

[91]  M. Agha,et al.  The socio-economic implications of the coronavirus pandemic (COVID-19): A review , 2020, International Journal of Surgery.

[92]  H. Taylor,et al.  Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: what is known? , 2020, Fertility and Sterility.

[93]  H. Prigerson,et al.  Responding to Healthcare Disparities and Challenges With Access to Care During COVID-19 , 2020, Health equity.

[94]  J. Kohn,et al.  Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms , 2020, Brain, Behavior, and Immunity.

[95]  S. Merler,et al.  Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. , 2020, JAMA.

[96]  Yi Feng,et al.  The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2 , 2020, Cardiovascular research.

[97]  Giuseppe Biondi-Zoccai,et al.  Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic , 2020, Journal of the American College of Cardiology.

[98]  S. Kim,et al.  Prevalence and Duration of Acute Loss of Smell or Taste in COVID-19 Patients , 2020, Journal of Korean medical science.

[99]  Qianyun Liu,et al.  Emerging coronaviruses: Genome structure, replication, and pathogenesis , 2020, Journal of medical virology.

[100]  D. Hui,et al.  The long‐term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status , 2010, Respirology.

[101]  OUP accepted manuscript , 2022, The Journal of Infectious Diseases.