In March 2020, the World Health Organization (WHO) declared a pandemic due to the illness caused by coronavirus 2019 (COVID-19), caused by the type 2 coronavirus infection responsible for severe acute respiratory syndrome (SARS-CoV-2). The clinical and epidemiological characteristics, pathogenesis, and complications of patients with COVID-19 in the acute phase have been widely reported, however the long-term consequences of the disease are yet not well defined1,2.

As of early July 2021, over 191 million people had already been infected by SARS-CoV-2 around the world and the pandemic was still spreading widely in multiple countries. In its acute phase, severe COVID-19 is characterised by acute pulmonary disease that can manifest as pneumonia and with acute respiratory distress syndrome3. Numerous extrapulmonary manifestations have been described in multiple systems, including haematological, cardiovascular, renal, digestive, neurological, endocrine, ophthalmological and dermatological symptoms3,4.

Mean symptom duration in the acute phase of the disease is 11.5 ± 5.7 days5. However, it has been observed that up to 10–15% of patients with COVID-19 can present persistent symptomatology weeks or even months after infection, though this percent may be even higher. The symptomatology reported after the acute phase is highly heterogeneous and includes fatigue, dyspnoea, chest pain, palpitations, gastrointestinal symptoms, mental confusion, anxiety, and depression, among many other associated symptoms6.

Recent studies suggest that the so-called long COVID syndrome is emerging as a prevalent syndrome and refers to a highly diverse set of symptoms that persist long after a confirmed SARS-CoV-2 infection yet does not seem to have a clear association with the severity of the acute phase of COVID-197.

As of yet there is no consensus regarding the definition and timeline associated with the long-term symptoms of COVID-19. The terminology used to describe this clinical presentation varies widely in the literature and includes terms, among others, such as ‘long haulers’, ‘late sequelae of COVID-19’, ‘chronic COVID-19 syndrome’, ‘post-acute COVID-19 syndrome’ (PACS), and ‘persistent COVID-19 syndrome’8.

One of the most widely used terms is long COVID, collectively coined by patients themselves through social media, as the contraction of the long-term, cyclical, progressive, and multiphase disease9. The WHO currently recommends using the term ‘post-COVID-19 condition’ to refer to this clinical presentation, as it does not imply causality nor duration, and there are already specific ICD-10 (U09) and ICD-11 (RA02) codes to identify it10.

With the aim of unifying criteria, the National Institute for Health and Care Excellence proposed the following definitions to describe the various symptomatic phases of SARS-CoV-2 infection11. Acute COVID-19 generally lasts up to 4 weeks from the onset of symptoms. When symptoms last longer than 4 weeks or late or long-term symptoms appear, then the term ‘post-acute COVID-19’ is used. The latter term encompasses both patients with long COVID (LC) and post-COVID-19 sequelae.

LC applies to symptoms that remain 4 or even 12 weeks beyond the acute infection, or that appear later on in the case of subjects with asymptomatic infection, but without the presence of irreversible organ damage. In terms of post-COVID-19 sequelae, patients tend to present a history of severe acute COVID-19 and symptoms resulting from structural damage secondary to complications suffered during the acute phase12. Making this distinction is important since these 2 sub-types of post-acute COVID-19 affect different patient profiles. While sequelae are predominant in older males, typically around 70 years-old and with associated comorbidities, LC tends to present in middle-aged women, around 40 years-old, without significant health issues.

Three clinical phenotypes within LC have been described: permanent (no changes during follow-up), relapsing/recurring (episodic and fluctuating course, with intervals of symptom exacerbation and remission), and slowly progressive improvement13.

The fact that some patients with COVID-19 experience symptoms after recovering from acute infection is to be expected. Other infections, such as those caused by the Epstein-Barr virus, Giardia lamblia, Coxiella burnetii, Borrelia burgdorferi (Lyme disease) and the Ross River virus, as well as other coronaviruses such as SARS-CoV and MERS-CoV (causes of severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS], respectively), are also associated with a higher risk of post-infectious sequelae.

These sequelae include long-term symptoms (months, even years) in the absence of active infection and include debilitating fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disorders14. These acute, post-infection syndromes show a clear clinical and pathophysiological parallel with long COVID syndrome, particularly with SARS and MERS due to the phylogenetic similarities between the pathogenic coronaviruses responsible. The overlap of the genome sequence identity of SARS-CoV-2 is 79% with SARS-CoV-1 and 50% with MERS-CoV15,16.

The potential mechanisms that contribute to the pathophysiology of LC are not yet clear, as numerous factors have been suggested (Fig. 1). A key element may be the presence of a state of chronic hyperinflammation17. The virus, in relation to the lungs, activates innate immunity, resulting in an inflammatory cytokine release cascade, including interleukin 6 (IL-6), IL-1, tumour necrosis factor alpha, and reactive oxygen species. This systemic cytokine elevation becomes involved in the development of pulmonary fibrosis18 and cardiac and neurological lesions secondary to endothelial damage caused by the activation of fibroblasts with collagen and fibronectin deposition.

Figure 1.

Etiopathogenetic mechanisms of long COVID-19.

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In addition, damage to the blood–brain barrier (BBB) has been observed with increased permeability for neurotoxic substances. Likewise, elevated levels of IL-6 can disrupt muscle metabolic homoeostasis19 and exacerbate muscle loss, which is why some authors postulate that skeletal muscle may be impacted both by direct infection by SARS-CoV-2 of the myocytes, cells with elevated expression of the angiotensin-converting enzyme 2 receptor (ACE2), and indirectly through systemic cytokine release and subsequent muscle homoeostasis disruption, resulting in fatigue and muscle weakness.

Some studies20 have aimed to detect the presence of T cells and NK lymphocytes in these patients and so it seems long COVID is characterised by alterations in the TCD4+ and TCD8+ cells, with two clinically important profiles distinguished: one that is more inflammatory (decrease in TCD4+ and increase in TCD8+) and another that is more immune (increase in TCD4+ and TCD8+).

Other suggested mechanisms include the autoimmune, via the existence of autoantibodies that act against modulator proteins which would disrupt immune function21. Another mechanism that may be involved is the hypercoagulability state associated with SARS-CoV-2 infection (thromboinflammatory state), responsible for the disproportionately high (20-30%) rates of thrombotic complications observed in patients with COVID-1922.

In addition, a hypothesis has been proposed in which SARS-CoV-2 infection may affect the autonomic nervous system,23 resulting in autonomic dysfunction mediated by the virus itself. This dysautonomia manifests as various syndromes of orthostatic intolerance including orthostatic hypotension, vasovagal syncope, and postural orthostatic tachycardia syndrome (POTS).

Another etiopathogenetic hypothesis may be the persistence of the virus in the body due to a weak or absent antibody response24, relapses or reinfections, and other factors related to COVID-19 such as: immobilisation, nutrition disorders, mental disorders such as post-traumatic stress, or alterations in the intestinal microbiota25.

Persistent symptoms following SARS-CoV-2 infection occur in both patients who required hospitalisation due to severe COVID-19 presentation and those who presented with mild paucisymptomatic disease, and even in subjects with asymptomatic infection26.

Published studies have produced varying results on the prevalence of LC (Table 1). In the United Kingdom, around 10% of patients with documented SARS-CoV-2 infection remained symptomatic after 3 weeks, and a smaller proportion during months following acute infection27.

An observational cohort study conducted in Michigan (United States)28 which used a telephone survey to evaluate 488 patients discharged from hospital due to COVID-19 found that 32.6% of the patients reported persistent symptoms at 3 months, with 18.9% of the subjects with new or worsening symptoms; dyspnoea (23%) was the most prevalent symptom. A total of 38.5% of the patients were not able to return to their activities of daily living and 48.8% reported being emotionally affected by their health.

Other studies have reported even higher rates of prevalence. In Italy29, 87.4% of 143 patients discharged from hospital due to COVID-19 presented persistent symptoms at mean follow-up of 2 months after the onset of symptoms, with the most common symptoms being fatigue (53.1%), dyspnoea (43.4%), joint pain (27.3%), and chest pain (21.7%). In a study conducted in France30, 66% of patients still had symptoms at 60 days of follow-up. In a prospective cohort study conducted in Wuhan (China)31 which evaluated 1,733 subjects 6 months after onset of COVID-19 symptoms, the majority of the patients (76%) reported at least one symptom, the most common being fatigue/muscle weakness (63%), sleep difficulties (26%), and anxiety/depression (23%).

There are 2 studies in Spain that stand out32,33. One retrospective multicentre cohort study conducted at 4 centres in Andalusia32 analysed symptom prevalence in 962 patients who required hospitalisation during the acute phase: up to 63.9% presented symptoms after 6 months of follow-up, predominantly respiratory symptoms (42%), followed by systemic (36.1%), neurological (20.8%), and psychological (12.2%). Another national study conducted in the Primary Care service33 via an online survey with 2,120 individual participants with a history of COVID-19 concluded that 5% of patients presented at least one symptom after an average of 185 days post-acute infection.

One of the main lines of investigation is the development of tools to be able to predict the likelihood of developing LC. The risk factors related to LC have not been described in the majority of previous studies. It has been suggested that experiencing more than 5 symptoms in the first 7 days increases the risk of developing persistent symptoms11. Though the presence of anosmia, particularly in adults over the age of 70, has been related to a better prognosis in patients hospitalised due to COVID-1934, it is considered to be the most predictive symptom for LC12.

A German study35, which included 958 non-hospitalised patients, found a significant association between the presence of long-term symptoms and a lower baseline level of IgG subclass antibodies, and the presence of anosmia and diarrhoea during acute COVID-19. Persistent symptoms have also been related to female sex, a larger number of symptoms at the start of the clinical picture, and admission to Intensive Care36.

In summary, and in the absence of more rigorous studies, it is estimated that around 10–20% of subjects infected with SARS-CoV-2 will develop LC, although this prevalence varies due to the differences in methodology used and the populations analysed, particularly between studies including hospitalised patients and outpatient patients. What’s more, in many cases no differentiation is made between true persistence of symptoms and sequelae of severe acute disease12.

The clinical presentation of patients with long COVID is highly heterogeneous. Over 200 associated symptoms affecting different organs and systems have been described37 (Fig. 2). The most common long-term symptoms are fatigue (52%), cardiorespiratory symptoms (30–42%), and neurological symptoms (40%)38, including symptoms of dysautonomia39.

Figure 2.

Symptomatology of long COVID-19.

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As we have seen, the symptoms of LC are just as heterogeneous as those observed in the acute phase of the disease and can manifest in an ongoing, fluctuating, or changing manner.

In the absence of a solid and standardised foundation for patients with long COVID, various clinical guidelines have been published with recommendations on long-term follow-up for said patients, both internationally11 and nationally12,60,61, and post-COVID-19 specialized consultation units have been set up in many hospitals.

These recommendations coincide in that, due to the complexity of this viral infection and the potential involvement of multiple systems and organs, a multidisciplinary assessment involving different medical specialists is needed to allow doctors to optimally monitor patient progress and offer the best possible care and management. Said recommendations suggest the need for an initial evaluation that includes a comprehensive physical examination, lab testing, and imaging tests. In addition, studying patient comorbidities and social and functional staus is also essential. All of this will enable doctors to perform a comprehensive assessment of the patient’s baseline condition23.

The proposed follow-up strategies recommend performing a basic analysis that includes a complete blood count, erythrocyte sedimentation rate, blood sugar, lipid profile, renal, ions, hepatic panel, albumin, lactate dehydrogenase, C-reactive protein, thyroid function tests, iron metabolism, vitamin B12, folic acid, vitamin D, calcium, phosphorus, and coagulation tests as well as, in certain circumstances, and depending on the medical history and examination, other specific analytical assessments according to patient symptoms. In certain circumstances (persistent lymphopenia or altered lymphocyte count), it may be convenient to perform a basic cellular immunity study, including lymphocyte subpopulations (B cells, T cells, TCD4+, TCD8+), immunoglobulins, and a supplementary study to enable us to rule out other alternative illnesses12.

The need to perform imaging studies in the follow-up of patients with COVID-19 remains a topic of controversy. The British Thoracic Society guidelines recommend performing a chest X-ray at 12 weeks in those patients who have experienced significant respiratory illness during the acute phase and, if alterations are observed, performing a chest CT with high-resolution reconstructions and contrast, according to the pulmonary thromboembolism protocol62,63.

Other authors recommend performing a baseline pre-contrast high-resolution chest CT at 6 and 12 months and, if fibrotic alterations persist, to repeat this at 24 and 36 months64. One reasonable instruction would be to perform a chest CT in patients with persistent respiratory symptoms and alterations in their pulmonary function tests (PFT), or if anomalies persist in chest X-rays 3 months post-discharge or resolution of clinical pneumonia, this being a time when acute lesions should have resolved and would now be considered chronic64.

Other supplementary tests that could be conducted depending on symptomatology include electrocardiogram, transthoracic echocardiogram, PFT, stress test, Holter monitor, ambulatory blood pressure monitoring or self-measured blood pressure monitoring, tilt table test for patients with dysautonomia symptomatology, and any other test considered necessary after conducting a thorough medical history and physical examination12.

The guidelines recommend an initial consultation with patients who present persistent symptoms 4 weeks after acute COVID-19. This assessment may be in-person or over the phone depending on the warning signs, need to perform a physical examination, the patient’s medical history, the severity and impact of the symptoms on their quality of life, or difficulties communicating. Follow-up strategies adhere to stricter protocols in hospitalised patients, with the recommendation being an initial telephone assessment at 4 weeks post-hospital discharge, followed by an in-person appointment at 12 weeks. If at that time the patient is asymptomatic, they will be given the all-clear; otherwise, they will be scheduled for follow-up65.

The use of questionnaires or health measurement scales has been proposed as potentially useful in these patients since they allow doctors to make a comparison with their prior health status. It also enables follow-up of symptom evolution and helps determine the prognosis of the disease and standardise criteria among health professionals66. Diverse scales are currently used to evaluate the most frequent symptoms (Table 2), however there is a need to develop a specific measurement scale that globally reflects how these patients are affected12.

In general, there is a trend towards spontaneous improvement of persistent post-COVID-19 symptoms, however it is difficult to determine the percent of patients who improve, and the time needed to achieve improvement, based on the heterogeneity of the studies published to date. Some prospective studies indicate that COVID-19 vaccination in patients with LC may significantly improve persistent symptoms, however more data are needed to confirm this theory67.

Though various national and international clinical trials are currently under way, no specific treatment for LC is currently available. While we wait for results that can guide us towards more effective and specific therapies, in the majority of cases symptomatic treatment is used, both pharmacological (analgesics, anti-inflammatory agents, bronchodilators, cough suppressants, antiemetic agents, antidepressants, anxiolytics, etc.) and non-pharmacological (food supplements, vitamin B12, vitamin D, omega 3). Psychological and emotional support is also essential for these patients, and the need for multidisciplinary rehabilitation services must be considered (occupational therapy, physical therapy).

Persistent symptomatology and adverse events are frequent following SARS-CoV-2 infection, particularly, though not exclusively, after hospitalisation for severe COVID-19. Given the increase in cases and their potential impact on health care systems, there is a need to develop specific health plans and clinical follow-up programs with a multidisciplinary nature. This will help guarantee adequate care for this group, as achieving the quality care that these patients deserve may seem a challenge due to the excess demand on the national healthcare system at the current moment. Likewise, to improve clinical practice in this field, it is crucial to promote research strategies that make it possible to improve our knowledge of the pathophysiological aspects of the syndrome, harmonise diagnostic criteria, and develop effective therapies.

Data will be made available on request.

This paper received support from the Center for Biomedical Research Network (CIBERObn, CB06/03/0018) from ISCIII-Madrid (Spain), co-financed by the European Regional Development Fund (ERDF).

María Rosa Bernal-López receives support from the “Nicolás Monardes” program (C1-0005-2020), from the Government of Andalusia, and from the “Miguel Servet Tipo II” program (CPII/00014), from ISCIII-Madrid (Spain), and Almudena López-Sampalo, from “Río Hortega” (CM21/00110). The two latter programs are co-financed by the European Regional Development Fund (ERDF).