3.1 Terminology

Terminology is further challenged by the fact that symptoms of the persistent condition vary widely among patients, with some reporting anxiety and brain fog, others respiratory conditions, and still others persistent cardiovascular conditions. Many patients report multiple symptoms, which may not always match their acute symptoms. In cases of other postviral syndromes, for example viral hepatitis, the transition from the initial acute infection to the more prolonged symptoms are generally described as “acute” and “chronic” [13]. A temporal cutoff has been proposed to separate acute from chronic COVID at three weeks, based on observational data [13]. Other authors have called this syndrome that occurs three weeks after acute infection “post-acute COVID” or “post-COVID syndrome”, which then transitions to “chronic COVID” at 12 weeks [14, 15]. For others, Long COVID is defined to occur in those who have any COVID symptoms >28 days post-diagnosis of the initial infection [11, 15]. The Centers for Disease Control and Prevention (CDC) have proposed staging COVID infection into three phases, with the acute phase defined by the period of active viral replication, a post-acute hyperinflammatory phase (defined as a positive antibody test two weeks after diagnosis), and late sequelae or Long COVID after four weeks [16]. See Table ;1 (Ref. [16, 17]). The consumer press and social media favor the patient-coined term Long COVID without differentiating the three, four, or 12 week markers [14]. Since our understanding of Long COVID is in its infancy and the syndrome continues to surprise epidemiologists, it is perhaps premature to arrive at hard definitions.

3.2 Epidemiology of Long COVID

For better or worse, social media has played and continues to play a major role in the COVID pandemic, including in the recognition of Long COVID as a genuine medical syndrome [18]. Patient support groups such as WeAreBodyPolitic.com and the Long COVID group on Facebook provided the first patient self-reports of Long COVID and allowed these individuals to share their stories outside the scrutiny of the medical establishment. At the time of publication, Long COVID has been discussed more on social media among patients and their families than in the medical literature [7]. This does not mean such social media reports should be discounted or reduced to mere “anecdotal” stories from random patients. Indeed, many descriptions of Long COVID on social media come from healthcare professionals who became infected on the job and have the medical expertise to describe their symptoms accurately [7]. A Symptom Study app was developed in the United Kingdom to crowd-source data about COVID-related experiences directly from patients; this app became a source of information about Long COVID as well. Information obtained from almost 4 million individuals found that about 10% of COVID patients experience symptoms that last three weeks or longer [5]. Other studies have found the rate of persistent symptoms to occur in much larger proportions of those who have had acute COVID infections [19, 20, 21, 22, 23].

While men are at elevated risk for contracting the SARS-CoV-2 infection, women appear to be at greater risk of developing Long COVID in the aftermath of the acute infection [24]. Patients with comorbidities, particularly obesity (body mass index ≥30) and/or psychiatric disorders, are more likely to have prolonged symptoms of COVID disease [17, 20]. There have been no conclusive studies that can associate specific symptoms of acute COVID with persistent symptoms of Long COVID [25], nor can the severity of the acute infection be associated with the likelihood of developing Long COVID [26].

3.3 Symptoms of Long COVID

Long COVID may be described as persistent symptoms in patients who have recovered from acute SARS-CoV-2 infection, with the most frequently reported symptoms fatigue, exercise intolerance, brain fog, cognitive deficits, disordered sleep patterns, and a range of autonomic symptoms, such as night sweats, gastroparesis, gastrointestinal disturbances, and peripheral vasoconstriction [7]. This list is not exhaustive; other frequently reported symptoms include dyspnea, joint pain, chest pain, cough, and anosmia [19]. While chills and fever associated with acute SARS-CoV-2 infection tend to resolve with viral clearance, symptoms of fatigue and cough were more likely to persist [20]. More symptoms of Long COVID have also been described: myocarditis, pericarditis, microvascular angina, cardiac arrhythmias including atrial flutter, atrial fibrillation, and ventricular tachycardia, dysautonomia (postural orthostatic tachycardic syndrome), mast cell activation syndrome, interstitial lung disease, thromboembolic conditions, myelopathy, neuropathy, neurodegenerative disorders, renal impairment, hepatitis, abnormalities in liver enzymes, and dystonia [3]. Loss of the sense of smell and/or taste is commonly reported as a symptom of both acute and Long COVID [22, 27]. In addition, symptoms such as new-onset diabetes, new-onset hypertension, new-onset thyroiditis, new-onset allergies, and new-onset anaphylaxis have been reported in the setting of acute infection, but it is not clear if these symptoms persist after the acute infection resolves to become part of the Long COVID syndrome [3]. Symptoms persisting after acute infection are frequently reported and may be present for an extended period of time, see Table 2 (Ref. [19, 20, 21, 22, 23, 28]).

Certain symptoms are puzzling. For example, disruptions in autonomic function have been reported subsequent to acute COVID infection that result in orthostatic intolerance syndrome. It is not clear if this condition relates to a virus-mediated attack or an attack mediated by the immune system in the wake of COVID infection [14]. Indeed, symptoms such as these that may occur subsequent to acute infection may even be unrelated to the virus. Autonomic symptoms, such as heart palpitations, tachycardia, dyspnea, syncope, and so on have been reported among a case series of six patients in early 2020 who were suspected to have had acute COVID (one case was confirmed, five others has suspected COVID with symptoms compatible with the disease) [14]. These early data were gathered at a time when COVID testing was not widely available. The six patients in this case series were all females between the ages of 26 and 50 and all presented with orthostatic intolerance with resting or postural hypotension and/or tachycardia [14]. In a person with any sort of viral infection, hypovolemia may occur, which can be further exacerbated by prolonged bed rest and subsequent deconditioning. This hypovolemic state can diminish cardiac output, reduce stroke volume, interfere with the baroreflexes, and reduce the body’s neurological sympathetic response [14].

The loss of the sense of smell is reported often in both acute and Long COVID. It is intriguing that the anosmia associated with acute COVID infection is usually not accompanied by rhinitis [27, 29]. ACE2 receptors, the entry point for the SARS-CoV-2 virus, are densely expressed in the nasal mucosa, and anosmia was likewise common in patients suffering from the Severe Acute Respiratory Syndrome (SARS) epidemic more than a decade ago [30]. Initially, it had been suspected that anosmia was indicative of central nervous system involvement, but two factors point against this. First, most acute COVID patients who experience anosmia recover their sense of smell within a week or two after infection [31]. Second, central nervous system symptoms occur in far fewer patients than anosmia [32], suggesting that they are unrelated. The virus may instead target non-neuronal cells that express ACE2 receptors, which would include the olfactory epithelium sustentacular cells, microvillar cells, Bowman’s gland cells, horizontal basal cells, and olfactory bulb pericytes, among others [33]. The persistence of anosmia in some Long COVID patients may be the result of slow recovery of these non-neuronal cells.

Dermatological manifestations of COVID may occur in the acute phase and can persist, but are less well described in the literature. A case report of acute vasculitis in an 11-year-old COVID patient reported erythematous lesions on the feet and ulcerative lesions with dyschromia of the nails [34]. Other cutaneous symptoms may include pernio, morbilliform, urticaria, papulo-squamous eruptions and chilblains [34]. A study of 163 acute COVID patients with dermatological symptoms reported that 6.8% of acute COVID patients with pernio (“COVID toes”) had pernio that lasted more than 60 days [35].

While fever is a hallmark symptom of acute COVID infection, it seems to be rare in Long COVID [7]. However, most other symptoms of acute COVID can also occur in Long COVID. Long COVID often involves multiple symptoms; a survey of 274 COVID patients reporting persisting symptoms, found the median number of lingering symptoms was seven [20].

Biomarkers for Long COVID have not yet been extensively investigated. In a study of 384 hospitalized COVID Patients in the United Kingdom followed for a median of 54 days post-discharge, some patients exhibited elevated biomarkers. Among the COVID patients who had abnormally elevated D-dimer and C-reactive protein levels at hospital discharge, 30.1% and 9.5%, respectively, continued to have these elevated levels at follow-up four to six weeks post-discharge [28]. A single-center study from London reported that 30% of 229 patients hospitalized with acute COVID had elevated D-dimer levels a median of 54 days after hospital discharge [28]. The D-dimer score at hospital admission was recorded for 176 COVID patients and had a median value of 785 and an interquartile range of 510 to 1486. At predischarge, this value was 878.5 (547.4–2522.5) and at follow-up four to six weeks later, it was 384 (242–665). The meaning of these D-dimer levels is not clear [28]. Upon hospital admission, 87% of this same cohort had a chest X-ray, of which 15% were normal, 29% indeterminate, and 56% typical of COVID patients. About two-thirds of patients received a chest X-ray at follow-up, of which 62% were considered normal, 27% showed improvement, 2% were unchanged, and 9% showed significant deterioration. It is interesting, that of the patients with a chest X-ray showing marked deterioration (n = 23), 9% had had normal X-rays at admission, 48% had indeterminate radiographic findings, and 43% had “typical COVID” chest X-rays [28]. It is worth noting that more than half of those with normal or indeterminate chest radiographs during acute COVID showed deterioration at follow-up, suggesting that Long COVID may be more dangerous than just lingering mild symptoms.

Mental symptoms have also been reported. A frequent complaint among Long COVID patients is brain fog, confusion, changes in cognition, and loss of memory [36]. Patients also reported emotional distress with Long COVID, manifesting as fearfulness, worry about their health, concern that they might never recover, all of which could be exacerbated by lack of consistent Long COVID care or dismissal of their symptoms by healthcare professionals and family [36]. Anxiety and depression are frequently reported with Long COVID but it is not always clear if Long COVID sequelae, new-onset conditions, or if the patient had pre-existing mental health disorders or risk factors for psychological distress. After all, COVID infection is a distressing condition with many unknowns and living in pandemic conditions for months on end has been emotionally challenging for everyone, especially for healthcare professionals and others on the frontlines of care [37]. The sometimes-promoted view of COVID as a dichotomous condition, that is, either one has it or one has recovered, can further promote frustration and even anxiety among those trying to navigate this novel syndrome [36].

3.4 Is Long COVID more than one syndrome?

Long COVID sometimes occurs as a prolonged illness where acute infection transitions seamlessly to a long period, in which a subset of the initial symptoms persist. For other patients, Long COVID is a relapsing/remitting condition where patients initially recover from acute illness, then report cyclic recurrence of certain symptoms [7]. This distinction in natural course may be important to understanding Long COVID. For instance, it has been observed that patients who suffer from moderate to severe or very severe acute COVID infections may exhibit Long COVID in the form of prolonged symptoms, while those who have mild cases of the acute infection are more likely to develop the relapsing/remitting form of Long COVID [16, 38]. Thus, Long COVID may exhibit as many as three distinct and unrelated manifestations: persistent residual symptoms of the acute infection, symptoms related to organ dysfunction caused by the acute infection, and new symptoms [26].

Patients with severe cases of COVID treated in intensive care units (ICUs) may experience post-ICU syndrome—not unique to COVID—but which may be confused with Long COVID [17]. Patients with post-ICU syndrome may experience cognitive impairment, memory loss, shorter attention span, deterioration of executive function, muscle weakness or atrophy, joint contractures, diaphragmatic dysfunction, laryngeal injury, dysphagia, dysphonia, anxiety, and depression [39]. COVID patients in the ICU are exposed to conditions that may exacerbate post-ICU syndrome, for example, they may be isolated; have little to no contact with family and friends; have less than usual access to clinicians and rehabilitation services due to hospital staffing constraints during the pandemic; have been sedated or intubated; and lack adequate information about this new and potentially fatal disease [40]. Post-ICU syndrome is persistent. In a study of 196 patients who had been hospitalized in an ICU unit for acute respiratory distress syndrome, at a median of 33 to 39 months after their ICU stay, 52% reported continuous or recurring symptoms, 38% had prolonged anxiety, 32% had depression, and 23% had symptoms akin to posttraumatic stress disorder [41, 42].

Persistent symptoms following viral infection are not unique to COVID. For example, the Epstein-Barr and Guillain-Barré viruses are associated with chronic symptoms [43] and the mosquito-borne Chikungunya virus is likewise associated with periodic recurrences of symptoms over months following the initial illness [44]. Patients with SARS, a coronavirus disease caused by a virus similar to the SARS-CoV-2, have also reported long-term symptoms that include fatigue, weakness, musculoskeletal pain, depression, and poor sleep quality, in a condition named Chronic Post-SARS Syndrome [45].

Organ damage may occur in acute COVID infections that persists after viral clearance, including damage to the pulmonary, cardiovascular, thromboembolic, neurological, and renal systems [26]. While cardiac symptoms of acute COVID infection are not frequently reported, a study of 100 COVID patients using magnetic resonance imaging reported that 78% of those who had recovered from the acute infection still had some degree of cardiac involvement in the form of myocardial inflammation, regional fibrosis, or pericardial enhancement; in this study 67% of patients had no or only mild cardiac symptoms during acute illness [46]. Further study is warranted to determine whether those who have cardiac dysfunction following acute COVID infection have pre-existing cardiac conditions or risk factors for cardiovascular disease.

Acute COVID infection is associated with an elevated risk for venous thromboembolism (VTE) [47] but the risk of VTE in patients who recover from COVID is not known [48]. VTE is not typically listed among the Long COVID symptoms but should be considered in future studies.

Viral reinfection cannot be ruled out as a potential occurrence, particularly in patients with suppressed immune systems [17]. A case study reports that a 57-year-old man with a confirmed but asymptomatic case of COVID developed a mild but symptomatic case of COVID about three months later. It is not clear whether this was reinfection from a community-based source, viral reinfection, or a delayed immune response [49]. Cases of potential reinfection are rare but have been reported; there is no strong evidence with respect to whether a recovered COVID patient can become reinfected. In this context, it is important to note that replication-competent virus is rarely found in recovered COVID patients after 20 days on onset of acute symptoms [50]. On the other hand, it has been proposed that the virus may be able to sequester itself in so-called “immunologically privileged locations”, from which it is difficult for the body to remove the virus [26].

Fatigue is among the most frequently reported Long COVID symptoms, but fatigue is a diffuse symptom with multiple potential etiologies, including post viral fatigue, which may occur after any number of viral infections and is not unique to COVID [17, 51]. Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are well-known syndromes with an obscure etiology; many patients diagnosed with ME/CFS had a viral infection prior to onset of symptoms but this was not necessarily a COVID infection [7]. ME/CFS includes symptoms of physical exhaustion, poor sleep, depressed mood, memory deficits and “accelerated aging” [17]. The fatigue may also be related to the Epstein-Barré virus, a herpes virus which is associated with relapsing/remitting patterns that seems to fit Long COVID symptomology [17]. It is not clear if ME/CFS is a disease or a constellation of symptoms, but it has transitioned from being viewed as a biopsychosocial phenomenon to being more widely recognized as a form of chronic illness [52]. The symptoms of ME/CFS and Long COVID overlap in many cases, and it is not clear if they may be the same condition in some patients or unrelated conditions despite their symptomatic similarities.

3.5 The role of immunobiography

Immunobiography describes a patient’s personal history of pathogenic exposures and the presence of antigens, which can influence that patient’s inflammatory response to other stimuli [53, 54]. The plasticity of the immune system preserves an individual record or biography of the individual’s experiences and continuous adaptation to pathogens. Thus, immunobiography can help explain the genetic contributions to differences in immune systems and may explain sex-based differences as well [53, 55]. Since the immune system undergoes remodeling with advancing age, the aging body becomes more and more vulnerable to infections, malignancies, and autoimmune disorders [56]. For example, over time, the body accumulates material produced by living organisms, including cellular debris, metabolites, molecular aggregates from incomplete degradation of non-enzymatic reactions, and a variety of other products known as “molecular garbage”, all of which reduce the body’s ability to fight off new pathogens [57]. It is not known if and to what extent immunobiography can help differentiate those patients with acute COVID infection who will go on to develop Long COVID versus those who will fully recover in a short period of time.

3.6 Special populations and Long COVID

The term inflammaging (inflammation + aging) refers to chronic subclinical systemic inflammation associated with aging and can be assessed with specific biomarkers, such as C-reactive protein, interleukin (IL)-6, IL-18, and tumor necrosis factor [54, 55]. Inflammaging may be described as the chronic condition that underlies the aging process [53]. The concept of inflammaging may have profound ramifications for Long COVID among geriatric COVID survivors, who may be at elevated risk for morbidity, disability, frailty, and other infections [55].

Chronic inflammation has been linked to many chronic conditions including metabolic syndrome, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular diseases, cancer, autoimmune disorders, neurodegenerative conditions, and others [58]. With aging, a more complex, multisystem, chronic inflammatory state may occur and factors such as unhealthful diet, obesity, comorbidities, sedentary lifestyle, stress, social isolation imposed by the pandemic, disordered sleep, and mental health problems may exacerbate this age-related condition [58].

Cellular senescence may contribute to the pathogenesis of sustained chronic inflammation. Cellular senescence may occur for any number of reasons: genomic instability, metabolic disorders, oxidative stress, energy crises, and others [54, 59]. Cellular senescence stops normal cell proliferation, resists apoptosis, and can cause the massive release of senescence-associated secretory phenotype (SASP) molecules, including various cytokines, chemokines, and other molecular species [55]. Because the SARS-CoV-2 may activate a powerful inflammatory response, it has been speculated that this “cytokine storm” may cause an immune system paralysis of sorts, starting with a hyperinflammatory phase followed by the compensatory anti-inflammatory response, leading to immunosuppression and increasing the patient’s vulnerability to secondary infections and immunosenescence [55]. With immune system paralysis, a patient may be in a hyperinflammatory state yet lose the ability to react to a new inflammatory insult [55]. Cellular senescence of various tissue systems may launch a vicious cycle where senescence results in SASP-related pro-inflammatory factors leading to inflammation and triggering more cellular senescence [55].

The trajectory of acute COVID seems to differ markedly among pediatric, young adult, and geriatric patients with children far less likely to experience severe symptoms than adults and seniors. However, just as with adult patients, Long COVID may occur in healthy children who do not experience severe symptoms with acute COVID [60]. A case report described five pediatric patients (80% female) between the ages of 9 and 15 years (median 12) with diagnosed COVID infections who had COVID symptoms that persisted between six and eight months [60]. Two months after the initial onset of acute COVID, all five children reported symptoms of fatigue, dyspnea, chest pain, and palpitations. Three of the children reported abdominal pain, memory loss, depression, cutaneous symptoms, and myalgia. Two children had remitting fever, problems sleeping, joint pain, diarrhea, and vomiting. One child had problems with taste and smell for two months after onset of acute COVID as well as poor appetite, chronic coughing, and numbness. Four of the five children suffered symptoms every day while one of the five had intermittent symptoms characterized by “good days and bad days” [60]. Thus, Long COVID may affect pediatric patients.

Inequities in healthcare have been a hallmark of COVID infections in many parts of the world and such disparities may become evident with the emergence of Long COVID syndrome. In addition to disadvantaged communities of minority populations and those of low socioeconomic status, it may be that individuals with mental health disorders, learning disabilities, or problems communicating (language barrier, dementia) face unequal care and treatment [15].

4.1 Guidelines

The National Institute for Health and Care Excellence (NICE) has published a “living guideline” to address the emerging condition of Long COVID [15]. NICE guidelines recommend for suspected cases of Long COVID blood tests (full blood count; clotting profile; renal, liver, and thyroid functions; C-reactive protein) as well as tests of cardiac and pulmonary function [15]. However, gastrointestinal, neurological, endocrine, and other problems may also occur in Long COVID [15]. In some cases, an appropriate diagnostic assessment of Long COVID requires a multidisciplinary approach and may require multidisciplinary treatment and rehabilitation [15]. More guidance and awareness are needed as patients with Long COVID report difficulty in obtaining an accurate diagnosis, getting appropriate care, and even finding healthcare professionals who show them professional empathy [36].

Of course, any guidelines right now would be at best “living documents”, subject to revision with lived clinical experience [3]. Establishing consistent Long COVID terminology and setting forth a comprehensive clinical description of the condition is crucial, which may be premature at this point. The guidelines should note the apparent relapsing-remitting nature of the syndrome, at least in some cases. Furthermore, the current emphasis on social support and cognitive behavioral therapy sometimes observed may undermine the fact that Long COVID appears to be a distinct pathological condition (or more than one), rather than the byproduct of mental stress [3].