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

Abstract

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.

Keywords:

• COVID-19
• long-term effects
• risk factors
• SARS-CoV-2
• long COVID

Introduction

The COVID-19 pandemic has caused devastating loss of life and profoundly impacted the global economy; as of February 6, 2023, >754 million confirmed cases of COVID-19 and >6.8 million deaths worldwide have occurred (WHO Coronavirus \(COVID-19\) Dashboard 2021). The causative virus, SARS-CoV-2, belongs to the betacoronavirus clade that includes SARS-CoV and MERS-CoV, which can cause severe and sometimes fatal respiratory syndrome (Chen et al. 2020; Lu et al. 2020; Verdecchia et al. 2020).

A large proportion of patients recovering from acute COVID-19 continue to have cardiac, pulmonary, neurologic, and other non-specific symptoms as a post-acute condition, even after mild/uncomplicated COVID-19 (Lopez-Leon et al. 2021; Havervall et al. 2021; Jacobson et al. 2021). More than 50 long-term COVID-19 symptoms are described; up to 80% of patients may develop ≥1 long-term symptom, and ∼30% have persistent symptoms up to 6 months post-symptom onset, although heterogeneity in symptom prevalence is noted (Lopez-Leon et al. 2021; Logue et al. 2021; Hayes et al. 2021; Chen et al. 2022). While the lung is the primary organ likely to be impaired or damaged in acute COVID-19, evidence suggests broad tropism of SARS-CoV-2 to the cardiac, renal, digestive, and nervous systems (Bradley et al. 2020; De Felice et al. 2020).

The purpose of this narrative review is to summarise current perspectives and mechanistic insights of long-term COVID-19 sequelae based on organ system, treatment, and patient population. We also explore how the pandemic indirectly affects healthcare provision and long-term patient management.

Methods

This is a focussed narrative review with no formal literature search protocol. Publications were identified from a PubMed search of long-term pulmonary, cardiovascular, neurologic, and gastrointestinal effects post-SARS-CoV-2 infection and treatment. Publications describing risk factors and underlying mechanisms for the above-mentioned sequelae were also identified. Additional relevant references were added from authors’ personal collections. The initial search was performed in October 2020, with subsequent searches in March/October 2021 and November 2022; however, given the rapidly evolving body of knowledge around COVID-19, additional articles of interest were included as they were identified.

COVID-19 onset, clinical course, and prolonged symptoms

Although most people with COVID-19 arising from the ancestral SARS-CoV-2 strain had mild-to-moderate illness, the disease became severe in 10%−15% of cases, with 5% becoming critically ill (Coronavirus Update 36: What We Know About the Long-Term Effects of COVID-19 2020). Notably, the Omicron variant, which was first identified in late 2021 and quickly becoming the predominant strain, is more transmissible yet less virulent than earlier strains, but has strained healthcare systems because of rapid rises in case numbers; reasons for the decrease in disease severity are multifactorial, but include increased vaccination uptake (Iuliano et al., 2022).

Acute COVID-19 lasts up to 4 weeks, symptomatic COVID-19 can last up to 12 weeks, and post-COVID-19 condition is defined as signs/symptoms developing typically about 3 months from COVID-19 onset, continuing for >3 months, and which cannot be explained by alternative diagnoses (Condition WHOCCDWGoP-C 2022; National Institute for Health and Care Excellence \(NICE, 2022) “Long COVID” is a commonly used term to describe symptoms beyond the acute stage (National Institute for Health and Care Excellence: clinical Guidelines 2020); however, many different ‘long COVID’ definitions exist (Yong 2021; Condition WHOCCDWGoP-C 2022). This review considers long COVID to be signs/symptoms continuing or developing >4 weeks post-acute COVID-19 (NICE 2022).

Estimates of the percentage of recovered individuals developing long-term COVID-19 symptoms vary widely from ∼10%−80%, depending on the patient population analysed, inclusion of controls, and follow-up duration (Lopez-Leon et al., 2021; Parums 2021; Chen et al. 2022). Estimates at the upper end of the scale (i.e. 80%) tend to be derived from selected patient samples lacking a control group and/or systematic reviews that include such studies, compounding potential selection biases (Lopez-Leon et al. 2021; Buonsenso et al. 2021; Amin-Chowdhury and Ladhani 2021). More conservative estimates of long COVID ranging from 13%−42% are reported in studies utilizing case–control matching to individuals with no SARS-CoV-2 infection (Sudre et al. 2021; Taquet et al. 2021). An estimated 6.2% of individuals may experience long COVID symptom clusters, including 3.7%, 3.2%, and 2.2% with ongoing respiratory problems, persistent fatigue with body pain or mood swings, and cognitive issues, respectively (Global Burden of Disease Long CC 2022). Additionally, symptom prevalence can vary depending on the time period (e.g. 4 − 12 vs >12 weeks post-acute COVID-19) (Jennings et al. 2021).

Pulmonary effects

SARS-CoV-2 enters lungs via ACE2-expressing type 2 pneumocytes, initiating acute systemic inflammatory responses and cytokine storm, leading to lung-resident dendritic cell activation and antiviral cytokine release by activated T lymphocytes, ultimately resulting in lung injury (Zhao et al. 2020). While long-term pulmonary COVID-19 complications are not fully understood, studies of other respiratory viral infections indicate that lasting effects can occur (e.g. permanent pulmonary damage post-acute pneumonia with SARS and avian flu H7N9 infections) (Ngai et al. 2010; Salehi et al. 2020; Shaw et al. 2021).

Post-mortem studies of COVID-19 patients from Switzerland, Italy, and Germany report diffuse alveolar damage in the majority of autopsies (Carsana et al. 2020; Menter et al. 2020; Schaller et al. 2020). A Chinese study of 165 patients with chest CT results reported diffuse alveolar damage in 14% of patients, although long-term consequences are unknown (Jin et al. 2020). A Chinese study of 55 COVID-19 survivors reported radiologic abnormalities in 71% of patients and interstitial thickening in 27% of patients 3 months post-discharge (Zhao et al. 2020). A prospective longitudinal cohort study of 83 patients hospitalized for severe COVID-19 but not requiring mechanical ventilation found that 33% had pulmonary diffusion abnormality and 24% had persistent radiologic abnormalities 12 months post-discharge (Wu et al., 2021).

CT images in patients post-SARS-CoV-2 infection identified long-term pulmonary sequelae, including interstitial pulmonary fibrosis, reduced pulmonary function, and diffuse alveolar damage (Zhao et al. 2020; Salehi et al. 2020; Jin et al. 2020). A meta-analysis of 15 studies of 102 − 44,799 patients, and median study follow-up times ranging from 14 − 110 days, found that lung disease symptoms were common in recovered patients with prevalence (95% CI) of 19% (7%−34%) for cough, 16% (10%−22%) for chest pain/discomfort, 10% (6%−16%) for reduced pulmonary diffusing capacity, and 5% (3%−8%) for pulmonary fibrosis (Lopez-Leon et al. 2021). Another meta-analysis of 6770 patients from 18 studies with a 6-month and 12 studies with a 12-month follow-up found that impaired diffusion capacity (35% prevalence) was the most common abnormality, which was most likely observed in those with severe COVID-19 (Lee et al. 2022). Prospective studies are further evaluating these complications and will help identify those most at risk (Fraser 2020; Shaw et al. 2021).

Cardiovascular effects

Multiple direct and indirect cardiovascular complications may continue to have long-term consequences post-resolution of SARS-CoV-2 infection, including acute myocardial injury, acute coronary syndrome, cardiogenic shock, myocarditis, heart failure, dysrhythmias, and venous thromboembolism (Driggin et al. 2020; Yancy and Fonarow 2020; Cormican et al. 2021). SARS-CoV-2 entry into cardiovascular cells is facilitated by ACE2 on surfaces of myocytes, coronary endothelial cells, pericytes, and arterial smooth muscle, increasing risk of organ damage and myocardial infarction (Chen et al. 2020; Cormican et al. 2021). SARS-CoV-2 may also infect myocardial cells directly, causing cytopathic effects and tissue destruction, or by immune dysregulation and hyperactivity (Shah et al. 2021). Long-term effects of this damage are unclear, and further study warranted.

A German autopsy study of 39 individuals with COVID-19 found frequent infection (62% of individuals) of the myocardium with SARS-CoV-2 using RT-PCR; however, none were diagnosed antemortem with myocarditis (Lindner et al. 2020). Comorbidities in these patients included hypertension (44%), coronary artery disease (82%), and diabetes mellitus (18%). Further investigation is warranted on long-term consequences of cardiac infection.

Myocarditis is an important cause of sudden death during exercise in athletes, and is a concern following SARS-CoV-2 infection. Multicentre registry data documenting CV outcomes in athletes following SARS-CoV-2 infection are being collected to assess cardiac pathology, including those with asymptomatic or mild infection (Kim et al. 2021). In a German study, 100 patients who recently recovered from SARS-CoV-2 infection, confirmed by real-time RT-PCR, were evaluated for myocardial injury (Puntmann et al. 2020). Cardiovascular involvement was detected by cardiac magnetic resonance in 78/100 patients and myocardial inflammation (abnormal native T1 and T2 measures) in 60/100 patients (Puntmann et al. 2020).

In a large case–control cohort utilising the US Department of Veterans Affairs (DVA) electronic healthcare database, long-term cardiovascular sequelae identified in individuals with COVID-19 included hypertension, cardiac dysrhythmias (particularly tachycardia), circulatory defects, chest pain, coronary atherosclerosis, and heart failure (Al-Aly et al. 2021; Ståhlberg et al. 2021). Notably, these cardiovascular conditions were more likely to occur in individuals hospitalized for COVID-19 versus those who had not (Al-Aly et al. 2021). In another case–control cohort study using the same database, those surviving the first 30 days post-COVID-19 had increased risk at 12 months for cardiovascular disease including cardiac disorders (stroke, transient ischaemic attacks), dysrhythmias (atrial fibrillation, sinus tachycardia and bradycardia, ventricular arrhythmia, atrial flutter), pericarditis/myocarditis, ischaemic heart disease (acute coronary disease, ischaemic cardiomyopathy, angina), other cardiac disorders (heart failure, non-ischaemic cardiomyopathy, cardiac arrest, cardiogenic shock), and thromboembolic disorders (pulmonary embolism, deep vein and superficial vein thrombosis) (Xie et al. 2022). In a cross-sectional study of individuals who recovered from COVID-19, patients reporting palpitations and/or fatigue with exercise in the post-acute COVID-19 phase had significantly higher NT-proBNP levels, significantly lower nitric oxide levels, and regional increases in ¹⁸F-FDG uptake on cardiac PET, compatible with myocardial fatigue (Sarıçam et al. 2021). Decreased oxygen consumption in COVID-19 cases, compared with controls, particularly during exercise, has been tied to chronotropic incompetence in combination with stroke volume limitations largely attributed to diminished increases in left ventricular end-diastolic volume and insufficient increases in ejection fraction (Szekely et al. 2021).

Neurologic effects

Many studies have investigated sensory deficits, mainly loss of smell and taste; however, pathogenesis is still unclear (Mastrangelo et al. 2021). A systematic review found anosmia and hyposmia prevalence to be 12% and 30%, respectively, >12 weeks post-COVID-19; corresponding percentages for ageusia and hypogeusia were 12% and 31% (Trott et al. 2022). Sensory deficit symptoms can persist for several weeks, but little is known about long-term sequelae (Patel et al. 2020; Kosugi et al. 2020; Paderno et al. 2020; Lee et al. 2020; Otte et al. 2020; Meini et al. 2020; Sayin and Yazici^, 2020). There are high rates of COVID-19 − related olfactory and gustatory dysfunction resolution in the first month post-symptom onset, with 90% of individuals recovering smell and taste senses at 90 days (Tan et al. 2022). However, complete resolution may not be achieved in a notable percentage of individuals (10%−15% after 45 days follow-up) (Paderno et al. 2020). Patients often had ongoing symptoms at study end, suggesting further follow-up and longer-term prospective studies are needed (Patel et al. 2020; Kosugi et al. 2020; Paderno et al. 2020).

Currently available evidence suggests SARS-CoV-2 can cause nervous system damage and alterations (Liotta et al. 2020; Troyer et al. 2020). Long-term consequences are unknown, but may potentially include cognitive deficits, and delayed neurologic complications, such as Parkinson’s disease, Alzheimer’s disease, and neuropsychiatric disorders (Troyer et al. 2020; Abboud et al. 2020; Heneka et al. 2020; Lennon 2020; Serrano-Castro et al. 2020; Ali Awan et al. 2021). Some evidence exists of cognitive decline 2 − 3 weeks post-infection in recovered patients, which could be a result of inflammatory responses to severe infection, leading to cytokine storm syndrome, and vascular injury causing stroke, hypoxia, or delirium (Zhou et al. 2020; Cothran et al. 2020;Ali Awan et al. 2021; Ceban et al. 2022). Other suggested mechanisms leading to cerebral sequelae associated with SARS-CoV-2 infection include viral neurotropism (e.g. leading to infiltration of virus-laden immune cells, blood − brain barrier breaks, or olfactory system infiltration), and pandemic-associated psychological burden caused by stressors affecting cognitive ability (Ali Awan et al. 2021; Douaud et al. 2022).

Longitudinal studies are therefore needed to determine long-term effects of COVID-19 on neurological and cognitive function (Abboud et al. 2020; Serrano-Castro et al. 2020; Zhou et al. 2020). A Swedish study of 323 patients with mild COVID-19 reported the most common long-term symptoms were loss of smell (15%), fatigue, and loss of taste (both 8%) (Havervall et al. 2021). Loss of smell persisted for ≥8 months in 9% of patients (Havervall et al. 2021). In an Italian study of 312 COVID-19 survivors, 86% of whom were hospitalised but not requiring ICU admission, 75% of evaluable patients showed impairment in ≥1 of 6 cognitive functions at 6 months (COVID-19 BioB Outpatient Clinic Study group, 2022). Moreover, COVID-19 survivors scored lower than healthy controls in psychomotor coordination, attention and speed-of-information processing, verbal fluency, and executive functioning (COVID-19 BioB Outpatient Clinic Study group 2022). Several studies and systematic reviews have investigated prevalence of neurologic and cognitive function sequelae in long COVID. A Dutch online survey study of individuals experiencing long COVID-19 symptoms found 37%, 36%, and 47% were at risk of PTSD, anxiety, and depression, respectively, 3 months post-infection (Houben-Wilke et al. 2022). A systematic review and meta-analysis of 21 studies assessing health-related quality of life and psychiatric problems in COVID-19 survivors identified a pooled prevalence of PTSD, depression, and anxiety of 18%, 12%, and 17%, respectively (Dorri et al. 2021). Another systematic review and meta-analysis, which included 18 studies of >10,000 COVID-19 survivors, reported fatigue (37%), brain fog (32%), sleep disturbances (31%), and memory issues (28%) to be the most frequent long-term neurologic sequelae post-infection (Premraj et al. 2022). Notably, these post-acute neurologic and psychiatric sequelae are similar to post-acute ICU syndrome, which includes new or worsening mental (predominantly PTSD, anxiety, depression) and cognitive (predominantly memory and executive function dysfunction) health impairments (Schwab et al. 2022).

Gastrointestinal effects

While gastrointestinal symptoms of acute COVID-19, such as diarrhoea, constipation, vomiting, abdominal pain, and acid reflux, are recognised, comparatively less data are available on these symptoms in long COVID (Choudhury et al. 2022; Gang et al. 2022). In a systematic review and meta-analysis of 50 studies, the frequency of overall gastrointestinal symptoms was 12% and 22% in acute COVID-19 and long COVID, respectively, and gastrointestinal manifestations in long COVID did not appear related to acute COVID-19 severity (Choudhury et al. 2022). Proposed mechanisms associated with gastrointestinal symptoms from SARS-CoV-2 infection include activation of signal transduction pathways in epithelial cells, triggering vascular endothelial growth factor production and then leading to vascular permeability and inflammation (Gang et al. 2022). For patients with long COVID, gastrointestinal symptoms have been associated with diminished richness of the gut microbiota (Gang et al. 2022).

Long-term consequences in children

Prevalence, associated mechanisms, and outcomes of long COVID in children are not well elucidated, although a milder phenotype compared with older populations has been described (Stephenson et al. 2022). Long COVID prevalence in children varies greatly (1.6%−70%), with fatigue, headache, arthro-myalgia, dyspnoea, and smell and taste alterations most commonly experienced (Pellegrino et al. 2022). Female sex, having underlying comorbidities, and increasing age appear associated with persistent COVID-19 symptoms among children (Behnood et al. 2022). Frequencies of many reported persistent COVID-19 symptoms in children are similar in SARS-CoV-2 − positive cases and controls, (Behnood et al. 2022) which may be related to difficulties in distinguishing long COVID effects from those of extended lockdown measures in this population.

Notably, multisystem inflammatory syndrome in children (MIS-C) is a newly reported illness that appears associated with SARS-CoV-2 (Belot et al. 2020). MIS-C, which has similar characteristics to toxic shock syndrome and Kawasaki disease, (Rowley et al. 2020) can appear several weeks post-SARS-CoV-2 infection. A French study of 21 children and adolescents with MIS-C reported a median (range) of 36 (18 − 45) days between reported COVID-19 contact and onset of MIS-C symptoms (Toubiana et al. 2020). MIS-C has been associated with cardiovascular complications. In this French study, 76% of patients had myocarditis and 10% showed significant electrocardiographic changes (Toubiana et al. 2020). A US study conducted in 186 children (median age 8.3 years) with MIS-C associated with SARS-CoV-2, in whom 70% were SARS-CoV-2 RT-PCR or antibody positive, reported common cardiovascular involvement (in 80% of children), and 8% of children had coronary artery aneurysms (Feldstein et al. 2020). A New York State study of 99 patients ≤20-years-old with MIS-C reported coronary artery aneurysms in 9% of patients (Dufort et al. 2020). In children with COVID-19-associated MIS-C, 14% had coronary lesions and 12%−25% giant aneurysms (Singh-Grewal et al. 2020). A meta-analysis of 11 observational studies assessing cardiovascular outcomes in 547 patients with MIS-C, found generally favourable mid-term outcomes in the majority of patients, including low mortality rate and normalization of left ventricular systolic dysfunction, but some patients showed persistent abnormalities and mitral regurgitation at 6 months (Yasuhara et al. 2023). The long-term effects of MIS-C are unclear. A preliminary report suggests that cardiac abnormalities tend to resolve in most children by 2 months post-infection (Capone et al. 2021). However, large ongoing observational cohort studies will provide better insight into long-term consequences of MIS-C (e.g. the MUSIC study) (Truong et al. 2022).

Other body systems

While the nature and extent of long-term COVID-19 consequences are unclear, many other affected body systems and clinical manifestations may emerge, including diabetes mellitus and mucormycosis (Figure 1) (Coronavirus Update 36: What We Know About the Long-Term Effects of COVID-19, 2020; Cothran et al. 2020; Adapa et al. 2020; Long-term sequelae and COVID-19 – what we know so far 2020; Samidoust et al. 2020; Segars et al. 2020; Al-Aly et al. 2021; Mansoor et al. 2021; Yasmin et al. 2021; Lai et al. 2022; Wrona and Skrypnik 2022. However, the increasingly diverse number of reports across multiple organ systems and subspecialties goes beyond the scope of this review.

Figure 1. Possible long-term effects of COVID-19 on different body systems.

* For example, Parkinson’s disease, multiple sclerosis, Alzheimer’s disease

^† For example, depression, anxiety, fatigue, PTSD, substance abuse

^‡ For example, loss of smell/taste

Possible mechanisms underlying long COVID

Several published reviews have in-depth discussions of potential pathophysiological mechanisms of long-term sequelae; here we provide a succinct overview (Figure 2). Candidate mechanisms potentially contributing to pathogenesis include SARS-CoV-2 persistence; reactivation of other viruses (in particular Epstein-Barr virus); virus-triggered autoimmunity; persistent tissue damage and immunity-triggered inflammation; and formation of microthrombi in the vascular bed of different tissues (e.g. endothelial cell activation) (Covid-19 Commission of the Accademia Nazionale dei Lincei 2022; Monje and Iwasaki 2022; Newell and Waickman 2022). Host microbiome alterations may also play a role (Batiha et al. 2022; Liu et al. 2022). Endothelial damage and subsequent endothelial dysfunction may be a mechanism as long-term viral infection/chronic hypoxia/inflammatory response can lead to persistent vascular endothelial injury followed by coagulation and microthrombosis, and finally systemic functional impairments and clinical sequelae (Wang et al. 2022). Impaired endothelial function has been observed in convalescent COVID-19 patients, (Ambrosino et al. 2022) while elevation of ANG-1 and P-SEL may represent a long-term angiogenesis response for wound-repair of endothelial injuries (Patel et al. 2022).

Figure 2. Possible mechanisms underlying the long-term sequelae of COVID-19.

Risk factors

Risk factors for development of severe COVID-19 include age >60 years, and chronic health conditions, including hypertension, diabetes, underlying cardiovascular, respiratory, and kidney diseases, and malignancy (Driggin et al. 2020; Chen et al. 2020; Grasselli et al. 2020; Suleyman et al. 2020; World Health Organization 2020; Cormican et al. 2021). Risk factors for prolonged illness are emerging; these include age ≥65 years, female sex, Black or Asian race, Hispanic ethnicity, and active smoking (Figure 3) (Coronavirus Update 36: What We Know About the Long-Term Effects of COVID-19, 2020; Lavery et al. 2020; Sigfrid et al. 2021; Bai et al. 2022). An app-based 2020 study of >4000 users reported the likelihood of long COVID increased with older age and female sex (Sudre et al. 2020). In a US DVA electronic healthcare database study of >180,000 patients, burden of long COVID manifestations was higher in veterans with poor health status and increased by acute COVID-19 severity (Xie et al. 2021). In a longitudinal, prospective cohort study of 1038 patients with laboratory-confirmed SARS-CoV-2 infection, COVID-19-associated hospitalization, having diabetes, and higher BMI were associated with development of long COVID (Yoo et al. 2022).

Figure 3. Risk factors for long-term sequelae of COVID-19.

Figure 4. Suggested components of a follow-up program.

Long-term effects are not restricted to these vulnerable groups; younger individuals (<50 years) with no or few comorbidities can have prolonged illness, even after mild or uncomplicated COVID-19 (Tenforde et al. 2020; Jacobson et al. 2021). For instance, a meta-analysis that included 20 studies and 7840 patients found that risk of persistent cough, chest pain, anosmia, and palpitation was not associated with the severity of acute COVID-19 (Dirican and Bal 2022).

Implications

Globally, almost 650 million people have recovered from COVID-19; among them, many will have long-term health consequences, perhaps for life. These long-term health consequences will not only affect these people and their families but also, collectively, add a sizable burden to healthcare systems. The pandemic has resulted in widespread job losses and school closures (Nicola et al. 2020). Children have suffered from being away from a learning environment, especially those from lower income households (Townsend 2020; Bayham and Fenichel 2020; Masonbrink and Hurley 2020; Van Lancker and Parolin 2020). Stay-at-home orders may have other negative impacts, such as decline in mental health, increased alcohol consumption, and increased weight in some populations, (Flanagan et al. 2021) while delay or avoidance of routine medical care because of COVID-19 may lead to poor management of underlying conditions, missed routine vaccinations, missed early detection, and delayed diagnoses of new conditions (Czeisler et al. 2020). Because of the nature of their jobs, healthcare workers (HCWs) have particularly experienced detrimental pandemic-related effects, including stress, anxiety, depression, and insomnia, constrained resources, working to exhaustion, and being at personal risk of infection (Awan et al. 2021). In a meta-analysis of 47 studies, which compared anxiety and depression prevalence among frontline versus non-frontline HCWs, prevalence was higher among the former and nurses had higher rates than doctors (Sun et al. 2021).

Barriers to recovery from long-term COVID-19 effects include pre-existing health status, health disparities, and access to care. The latter may vary by geographic area, age, and socioeconomic group (Nunez et al. 2020). Quality of care may vary, and some regions may have difficulties accessing healthcare, during a hospital surge, or obtaining vaccines. COVID-19-associated health disparities can be due to population size, Black race, poverty, disability, and education level; these may be at the individual level or on a systemic level (Parcha et al. 2020; Johnson et al. 2020; Abedi et al. 2021). Economic consequences of long COVID are also far reaching. For instance, the annual cost of treatment has been estimated at ∼$9000/person; additionally, affected individuals often need to leave employment or work reduced hours, representing direct earning losses (Cutler 2022).

To improve our understanding of long-term COVID-19 health effects, large-scale standardised data collection is vital, and study of COVID-19 risk and long-term effects is underway at 37 US academic centres (Study of COVID-19 Risk and Long-Term Effects Underway at 37 U.S. Academic Medical Centers 2021). Follow-up studies of people previously infected with SARS-CoV-2 are also underway, including an international, prospective, observational study of patients across 42 countries hospitalised for COVID-19 who agree to regularly complete standardised survey instruments for ≤3 years to measure long-term physical and psychosocial sequelae (Cardiovascular Consequences After COVID-19 2021; Evaluate Long Term Cardiovascular and Pulmonary Complications After COVID-19 With Point of Care Ultrasound 2021; Sigfrid et al. 2021). Ideally a well-defined, long-term, follow-up and surveillance program should include clinical assessment, investigations, and ongoing medical management and monitoring (Figure 4). Such a program could provide more information on persistent medical conditions post-COVID-19 and whether COVID-19 exacerbated underlying conditions. Measurement metrics could include duration of long-term adverse effects, need for follow-up medical care (e.g. medical appointments, long-term medications), re-hospitalizations, and time to return to normal daily living activities and to work or school. Surveillance and follow-up programs can inform actionable steps, including enhancing prevention and treatment efforts for the most vulnerable. Surveillance and follow-up will also allow researchers to determine whether any new SARS-CoV-2 variants of concern have different long-term effects than the ancestral virus. For instance, a UK case-controlled, observational study found that the long COVID risk was lower after Omicron versus Delta infection (reduced by ∼24%−50% depending on age and time since vaccination) (Antonelli et al. 2022).

Prevention of COVID-19 altogether with vaccination is the best way to reduce long COVID risk. This goal is now attainable with availability of approved vaccines, the administration of >13 billion vaccination doses worldwide, and the COVAX initiative, which aims to guarantee fair and equitable access of vaccines globally (WHO Coronavirus \(COVID-19\) Dashboard 2021; COVAX 2021). Although rare side effects have been reported, (Bozkurt et al. 2021; Palaiodimou et al. 2021) the benefit-risk balance is favourable for vaccination across ages and sexes (Bozkurt et al. 2021). It is unknown whether individuals who contract COVID-19 post-vaccination are less likely to suffer from long-term consequences, although data from systematic literature reviews and database studies are emerging (Notarte et al. 2022; Gao et al. 2022; Taquet et al. 2022). Interestingly, early reports of vaccination in individuals with long COVID suggest that vaccination is safe in this group, but also that persistent symptoms improve in a subset of individuals (Arnold et al. 2021).^,Additionally, vaccination among adults was reported to result in decreased likelihood of experiencing long COVID (Ayoubkhani et al. 2022). Further research is ongoing in this area.

Conclusions

With almost 650 million recovered COVID-19 patients, a need exists for further research into the different patterns and underlying mechanisms of long COVID. Prospective studies will examine these effects; meanwhile, clinicians should ensure that patients are followed-up and managed appropriately, especially those at risk. Healthcare systems worldwide should follow-up and support patients recovering from COVID-19. Surveillance programs could enhance vaccination and treatment efforts for the most vulnerable, measure and understand treatment protocols, and determine ways to improve treatment and management. Such steps may help improve patients’ health and quality of life and avoid further healthcare resource strains.

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