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Clinical Review State of the Art Review

Long covid—mechanisms, risk factors, and management

BMJ 2021; 374 doi: https://doi.org/x.1136/bmj.n1648 (Published 26 July 2021) Cite this equally: BMJ 2021;374:n1648

Read our latest coverage of the coronavirus pandemic

1. Harry Crook , research bananaane,
2. Sanara Raza , enquiry assistant1,
3. Joseph Nowell , enquiry assistant1,
4. Megan Young , clinical research officer1,
5. Paul Edison , clinical senior lecturer , honorary professor12

1. ^aneFaculty of Medicine, Imperial College London, London, Uk
2. ²Cardiff University, Cardiff, UK

1. Correspondence to P Edison paul.edison{at}imperial.ac.uk

Abstract

Since its emergence in Wuhan, Communist china, covid-nineteen has spread and had a profound outcome on the lives and wellness of people around the earth. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent testify has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this status is at present coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very balmy acute disease to the about astringent forms. Like acute covid-xix, long covid can involve multiple organs and tin affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, slumber disturbances, symptoms of post-traumatic stress disorder, muscle hurting, concentration bug, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and not-hospitalized patients and describes the persistent symptoms they suffer. Risk factors for acute covid-nineteen and long covid and possible therapeutic options are as well discussed.

Introduction

Coronavirus illness 2019 (covid-nineteen) has spread across the world. Equally of 4 July 2021, more than 183 million confirmed cases of covid-19 have been recorded worldwide, and more than iii.97 million deaths take been reported by the Globe Health System .1 The clinical spectrum of covid-19 ranges from asymptomatic infection to fatal disease.23 The virus responsible for causing covid-19, astringent acute respiratory syndrome coronavirus 2 (SARS-CoV-ii), enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor.4 Once internalized, the virus undergoes replication and maturation, provoking an inflammatory response that involves the activation and infiltration of allowed cells by various cytokines in some patients.5 The ACE2 receptor is present in numerous prison cell types throughout the human torso, including in the oral and nasal mucosa, lungs, heart, gastrointestinal tract, liver, kidneys, spleen, brain, and arterial and venous endothelial cells, highlighting how SARS-CoV-2 can cause harm to multiple organs.67

The affect of covid-19 thus far has been unparalleled, and long term symptoms could have a further devastating consequence.eight Recent prove shows that a range of symptoms can remain after the clearance of the acute infection in many people who have had covid-19, and this condition is known every bit long covid. The National Institute for Health and Care Excellence (Nice) defines long covid as the symptoms that go on or develop afterwards acute covid-19 infection and which cannot be explained by an alternative diagnosis. This term includes ongoing symptomatic covid-19, from four to 12 weeks post-infection, and post-covid-19 syndrome, across 12 weeks post-infection.9 Conversely, The National Institutes of Health (NIH) uses the US Centers for Affliction Command and Prevention (CDC) definition of long covid, which describes the condition as sequelae that extend beyond iv weeks after initial infection.10 People with long covid exhibit interest and impairment in the structure and role of multiple organs.11121314 Numerous symptoms of long covid have been reported and attributed to various organs, an overview of which tin be seen in fig 1. Long term symptoms following covid-xix have been observed across the spectrum of disease severity. This review examines the long term impact of symptoms reported following covid-nineteen infection and discusses the current epidemiological understanding of long covid, the risk factors that may predispose a person to develop the status, and the treatment and management guidelines aimed at treating it.

Fig one

Multi-organ complications of covid-nineteen and long covid. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptor. Once these cells accept been invaded, the virus can cause a multitude of damage ultimately leading to numerous persistent symptoms, some of which are outlined here

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Methods

We searched PubMed and Embase databases for articles published between January 2020 and May 2021. Our search terms were "long covid" or "post-covid-xix" or "COVID long-haulers" or "SARS-CoV-ii" and "epidemiology" or "fatigue" or "fatigue syndrome" or "dyspnoea" or "breathlessness" or "shortness of breath" or "cardiac" or "cardiovascular" or "centre" or "cognition" or "cognitive impairment" or "mental health" or "low" or "anxiety" or "psychiatric" or "central nervous system" or "autonomic nervous system" or "isolation" or "loneliness" or "sleeplessness" or "sleep" or "scent" or "taste" or "olfactory" or "gustatory" or "risk factors" or "treatment". To avoid unintentionally removing articles, no filters were practical. Nosotros retrieved 61 881 articles in the first case. To screen manufactures, titles were read by authors first, followed by abstracts to further narrow downward the number of records considered. To avoid unnecessary exclusion of studies, limited exclusion and inclusion criteria were practical. We excluded papers that were not relevant to or did not mention long covid, while studies mentioning long covid in any chapters were initially included owing to the novelty of the field. Furthermore, we considered long covid studies regardless of their cohort sizes or study pattern. We discovered and read fully 227 articles on long covid, and nosotros discussed each to decide which would be included in the finalized commodity. Nosotros performed further manual searching for additional articles and treatment guidelines using relevant databases, including overnice.org.britain and clinicaltrials.gov. In total, 218 references were included. Studies examining long covid are express, therefore limited exclusion criteria were applied.

Studies of long covid

Studies have assessed people who have had covid-19 to examine the symptoms associated with long covid. These studies are summarized in table 1. The manufactures included throughout this review were selected in favor of quality, with big observational studies of greatest involvement. Nigh of the studies included are cross-sectional or accomplice observational studies with large cohorts; however, because of the novelty of the illness and paucity of data, studies involving smaller cohorts and example series were also included. Any patient with covid-19 may develop long covid, regardless of the severity of their infection and the intensity of the treatment they received. Patients treated on wards and intensive care units (ICUs) show little deviation in incidence of long term symptoms associated with covid-19.17 The proportion of people that develop long covid symptoms, whether they are treated with oxygen alone, with continuous positive airway pressure, or with invasive ventilation, is similar.16 Many patients with mild acute symptoms also develop long covid symptoms,xiii in fact, studies show minimal differences between the prevalence of long covid symptoms betwixt hospitalized and not-hospitalized covid-xix patients.19

Tabular array 1

Summary of studies that take explored the persisting symptoms mail-covid-19 infection, or during long covid

Epidemiology

The reported incidence and mortality rates of covid-nineteen vary between countries, making it hard to accurately predict the number of patients who volition progress to long covid. Similarly, the accurate reporting of long covid is complicated. The disparity in this epidemiological data is likely the event of several factors, including differences in the base population, the accurateness of diagnosis, the reporting systems, and the capability of healthcare systems. Although determining the exact epidemiological information of long covid is difficult, this data is needed to inform healthcare systems and governments when developing support and treatment algorithms. The volume of published literature describing cases of patients with covid-19 who later on develop long covid symptoms is continually growing, which will permit for an improved understanding of its epidemiology.

The electric current disparities between long covid epidemiology reporting are attributable to many reasons, including the length of follow-up period, population assessed, accuracy of self-reporting, and symptoms examined. Studies around the world take reported various incidence rates for long covid with dissimilar follow-upwardly exam times after the astute infection, including 76% of people at 6 months,50 32.six% at 60 days,51 87% at 60 days,15 and 96% at 90 days.52 These finding are non fully corroborative, simply they show that a substantial proportion of people who accept had covid-19 may develop long covid. The Britain Office for National Statistics (ONS) has released data on the prevalence of long covid symptoms.53 They estimated that the five week prevalence of whatever symptom amongst survey respondents who tested positive for covid-19 between 22 April and 14 December 2020 was 22.i%, while the 12 week prevalence was 9.9%. These figures are worrying for patients, service providers, and governments, with many patients likely to develop long covid and require long term support and treatment. Further studies are required to consolidate our epidemiological understanding of long covid.

Covid-nineteen variants of concern

Since the start of the pandemic, several covid-19 variants have emerged that accept an increased transmissibility and may result in more severe acute affliction. In the UK, 1 of the kickoff variants of business to appear was the so called "Kent variant," from the B.one.1.7 lineage, now termed the Alpha variant. This variant has approximately 50% increased transmissibility54 and likely increases astute affliction severity.55 Equally of 30 June 2021, the Blastoff variant has been confirmed in more than than 275 000 cases in the UK56 and spread to at least 136 countries around the earth.57 Other variants of concern or under investigation include the Beta, Gamma, Zeta, Theta, and Kappa variants.56 The CDC reports the emergence of variants of concern and interest in the United states.58 New covid-19 variants will continue to sally and spread every bit we progress through the pandemic, for example, the Eta and Delta variants have arisen, with over 161 000 cases of the rapidly spreading Delta variant confirmed in the Britain, as of 30 June 2021.56 Recently, the Lambda variant has emerged, which volition require shut monitoring. The ability of these viral strains to inflict long term complications needs to be examined fully. To speculate, it may be that one variant causes more damaging long term effects than others and, therefore, patients infected with such a variant who go along to develop long covid symptoms may crave boosted support, too as more rapid and intense treatment strategies to combat their long term symptoms.

Long covid definition

Long covid gained widespread attention following an business relationship published on v May 2020 in BMJ Opinion where an infectious disease professor shared his experience of seven weeks on a "rollercoaster of ill health" following covid-nineteen.59 The patient-made term long covid was then fabricated popular following the rise in the use of #LongCovid on Twitter.lx This, plus the growing number of peer reviewed articles published since, has highlighted a mail service-covid-nineteen syndrome that can terminal for many weeks after the acute infection. Long covid is now a recognized term in scientific literature. The NICE guidelines on managing the long term effects of covid-199 and the CDC10 define long covid patients or covid long haulers as individuals with ongoing symptoms of covid-nineteen that persist beyond iv weeks from initial infection.

Symptoms

Fatigue

Fatigue is more profound than being overtired; it is unrelenting exhaustion and a constant state of weariness that reduces a person's energy, motivation, and concentration. Following the SARS outbreak, upwardly to 60% of patients reported ongoing fatigue at 12 months post-obit recovery from the acute illness.61 In long covid, fatigue is i of the most reported manifestations, with the ONS estimating the five calendar week prevalence of fatigue to exist 11.9% among people who accept had covid-19.53 Fatigue is a common persisting symptom regardless of severity of the acute stage of covid-nineteen. One cross-exclusive study found that 92.nine% and 93.5% of hospitalized and non-hospitalized covid-xix patients, respectively, reported ongoing fatigue at 79 days post-obit onset of affliction.19 Many other cross-sectional and accomplice studies written report that chronic fatigue is the most frequently reported symptom following recovery from acute covid-19,1517202743 with i showing no clan between covid-xix severity and long term fatigue.20 These findings prove that fatigue is a major manifestation of long covid.

Possible mechanisms

Chronic fatigue following viral infection may be the outcome of miscommunication in the inflammatory response pathways62; yet, a cross-sectional analytical study plant no association between pro-inflammatory markers and long term fatigue in covid-19 patients with persisting fatigue.twenty It is likely that a range of fundamental, peripheral, and psychological factors play a role in the evolution of post-covid-xix fatigue. A narrative review explains that congestion of the glymphatic system and the subsequent toxic build-upwardly inside the primal nervous system (CNS), caused by an increased resistance to cerebrospinal fluid drainage through the cribriform plate as a consequence of olfactory neuron damage, may contribute to post-covid-19 fatigue.63

Hypometabolism in the frontal lobe and cerebellum has likewise been implicated in covid-xix patients with fatigue and is likely caused by systemic inflammation and prison cell mediated immune mechanisms, rather than straight viral neuro-invasion.6465 It is unknown whether this finding continues into long covid.

Negative psychological and social factors associated with the covid-xix pandemic have also been linked to chronic fatigue.6667 Lastly, peripheral factors such equally direct SARS-CoV-two infection of skeletal muscle, resulting in harm, weakness, and inflammation to muscle fibers and neuromuscular junctions may contribute to fatigue.68697071 Overall, information technology is probable that several factors and mechanisms play a role in the development of postal service-covid-19 fatigue. Figure 2 further outlines these possible mechanisms.

Fig 2

Long term sequalae of covid-nineteen
(1) In the alveoli of the lungs: (A) Chronic inflammation results in the sustained production of pro-inflammatory cytokines and reactive oxygen species (ROS) which are released into the surrounding tissue and bloodstream. (B) Endothelial damage triggers the activation of fibroblasts, which deposit collagen and fibronectin resulting in fibrotic changes. (C) Endothelial injury, complement activation, platelet activation, and platelet-leukocyte interactions, release of pro-inflammatory cytokines, disruption of normal coagulant pathways, and hypoxia may result in the development of a prolonged hyperinflammatory and hypercoagulable state, increasing the run a risk of thrombosis.
(2) In the heart: (A) chronic inflammation of cardiomyocytes can effect in myositis and cause cardiomyocytes expiry. (B) Dysfunction of the afferent autonomic nervous system can crusade complications such as postural orthostatic tachycardia syndrome. (C) Prolonged inflammation and cellular impairment prompts fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis. (D) Fibrotic changes are accompanied past an increase in cardiac fibromyoblasts, while impairment to desmosomal proteins results in reduced cell-to-jail cell adhesion.
(3) In the fundamental nervous system: (A) The long term allowed response activates glial cells which chronically damage neurons. (B) Hyperinflammatory and hypercoagulable states lead to an increased take a chance of thrombotic events. (C) Claret-brain barrier damage and dysregulation results in pathological permeability, assuasive blood derived substances and leukocytes to infiltrate the encephalon parenchyma. (D) Chronic inflammation in the brainstem may crusade autonomic dysfunction. (E) The effects of long covid in the brain can lead to cognitive impairment.
(four) Possible mechanisms causing post-covid-19 fatigue. A range of cardinal, peripheral, and psychological factors may cause chronic fatigue in long covid. Chronic inflammation in the brain, as well every bit at the neuromuscular junctions, may result in long term fatigue. In skeletal muscle, sarcolemma damage and cobweb atrophy and damage may play a role in fatigue, as might a number of psychological and social factors

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Post-COVID-nineteen fatigue has been compared with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with many overlaps between the two.72 Symptoms common to both ME/CFS and long covid include fatigue, neurological/pain, neurocognitive/psychiatric, neuroendocrine, autonomic, and allowed symptoms, with both ME/CFS and long covid patients having long symptom durations, reduced daily activeness, and post-exertional malaise.72 ME/CFS remains enigmatic, therefore, enquiry into long covid may assist in developing understanding of ME/CFS and vice versa.

Dyspnea

Breathlessness is common in people with long covid. The ONS estimates that shortness of breath has a prevalence of 4.6% at five weeks mail service-covid-nineteen infection, regardless of presence of acute respiratory symptoms or illness severity.53 Abnormalities in diffusion capacity for carbon monoxide, full lung capacity, forced expiratory volume in the start 2d, forced vital capacity, and small airway function, have been seen in hospitalized covid-19 patients at time of belch, approximately one month following onset of symptoms, showing that lung part in people who have had covid-19 may have time to recover.73 Several studies have found that dyspnea is a common manifestation post-obit covid-19 infection,1617 and i study reported that 43.4% of 143 patients assessed were still experiencing dyspnea at 60 days later on covid-19 onset.15

Possible mechanisms

As covid-19 is principally a respiratory affliction, acute illness tin can cause substantial damage to the lungs and respiratory tract via SARS-CoV-2 replication inside endothelial cells, resulting in endothelial damage and an intense immune and inflammatory reaction.7475 Those who overcome the astute infection may develop long term lung abnormalities, leading to dyspnea76; however, most individuals who develop long term breathing difficulties mail-covid-xix accept no signs of permanent or longlasting lung impairment.2877 It is probable that only those at high risk of developing animate difficulties, including older people, those who endure acute respiratory distress syndrome, those who have extended hospital stays, and those with pre-existing lung abnormalities, are prone to develop fibrotic-like changes to lung tissue.78 The fibrotic state observed in some patients with ongoing dyspnea may be provoked past cytokines such as interleukin-six, which is raised in covid-1979 and is involved in the formation of pulmonary fibrosis.fourscore Pulmonary vascular thromboembolisms have been observed in patients with covid-1981 and may have detrimental consequences in patients with long covid. An overview of the possible mechanism causing dyspnea is outlined in fig 2.

Cardiovascular abnormalities

Cardiac injury and elevated cardiac troponin levels are associated with a significantly increased take chances of mortality in patients admitted to hospital with astute covid-19 infection.8283 Persisting cardiovascular abnormalities may be burdensome for people with long covid. A cohort study showed cardiac involvement, ongoing myocardial inflammation, and elevated serum troponin levels in many people with covid-19 at 71 days following diagnosis,23 while a large case series showed that chest pain, mayhap owing to myocarditis, was a common manifestation in patients 60.3 days following onset of covid-xix symptoms, with 21.vii% of the 143 patient assessed reporting chest pain.15 Those considered at low chance of astringent covid-nineteen, such as young, competitive athletes, have also been found to have residual myocarditis long afterward recovery from covid-19.84 In improver to cardiac complaints, studies have highlighted an emerging trend in the development of new onset postural orthostatic tachycardia syndrome (POTS) in individuals post-covid-nineteen infection, because of autonomic dysfunction.8586878889

Possible mechanisms

ACE2 receptors are highly expressed in the center,xc providing a direct route of infection for SARS-CoV-2. Studies have shown that sarcomere disruption and fragmentation, enucleation, transcriptional changes, and an intense local immune response occurs in cardiomyocytes infected by SARS-CoV-2.9192 Pathological responses to acute cardiac injury and viral myocarditis, such as endothelial damage and microthrombosis, tin atomic number 82 to the evolution of coagulopathy,93 while chronic hypoxia and an increase in pulmonary arterial pressure and ventricular strain may further precipitate the incidence of cardiac injury in people who take had covid-nineteen.94 Furthermore, sustained immune activation can lead to fibrotic changes95 and displacement of desmosomal proteins,96 which could be arrhythmogenic. Viral infection has previously been shown to precede POTS97 and, with the ACE2 receptor expressed on neurons, viral infection by SARS-CoV-two may have direct negative consequences on the autonomic nervous system.98 A complex combination of infection, an autonomic nervous system induced pro-inflammatory response, and a level of autoimmunity may all contribute to the establishment of autonomic dysfunction and POTS.89Figure 2 depicts these mechanisms.

Noesis and mental health

Studies take explored cognitive role and deficits in patients with covid-nineteen and suggest that the virus can cause septic encephalopathy, non-immunological effects such as hypotension, hypoxia, and vascular thrombosis, and immunological effects such as adaptive autoimmunity, microglial activation, and a maladaptive cytokine profile.99 Additionally, patients admitted to infirmary with covid-19 accept presented with a range of complaints including encephalopathy, cognitive damage, cerebrovascular events/disease, seizures, hypoxic encephalon injuries, corticospinal tract signs, dysexecutive syndrome, an altered mental status, and psychiatric weather condition.24100101 These findings reveal that neurological symptoms associated with covid-19 are mutual, diverse, and could pose substantial issues for rehabilitation and ongoing care following recovery from covid-19. Information technology is unknown who is most affected past cerebral complaints induced by covid-19 and how long they persist; however, patient experiences and published summaries of long covid have described "brain fog" to exist a common and debilitating symptom.102103104

Critical illness, severe acute respiratory syndrome, and long term ventilator support are known to have detrimental effects on long term cognition. Before the covid-xix pandemic, a retrospective study of 1040 ICU treated patients who had respiratory failure, daze, or both during hospital stays, constitute that 71% had delirium which lasted around four months following discharge.105 A similar written report found that, at 3 months post-discharge, xl% of ICU treated patients had cognition scores like those of patients with moderate traumatic brain injury, while 26% had scores like to patients with mild Alzheimer'southward affliction. Delirium was also widely reported, with a longer duration of delirium associated with worse knowledge.106 With many covid-nineteen patients requiring ICU access and mechanical ventilation, long term cognitive harm and delirium are probable to pose considerable bug.

Stroke and headache are prevalent in those recovered from astute covid-nineteen, with the ONS estimating the 5 week prevalence of headache at 10.1% of all covid-nineteen survivors.1318344353 Exaggerated levels of systemic inflammation, observed in some patients as a "cytokine storm," in addition to activation glial cells, poses a substantial risk to the brain and increases the likelihood of neurological manifestations including encephalitis and stroke.74 Hypercoagulability107 and cardio-embolisms, formed considering of virus related cardiac injury,108 are manifestations that could result in increased incidences of stroke following covid-xix infection. Covid-xix has also been associated with an increased hazard of developing neurological conditions including Guillain-Barré syndrome,109 and neurodegenerative conditions such as Alzheimer's disease.110

The pandemic has had a negative effect on mental health, with people who accept had covid-nineteen exhibiting long term psychiatric symptoms including post-traumatic stress disorder (PTSD), depression, anxiety, and obsessive-compulsive symptoms post-obit recovery from the acute infection.3637111112 Quarantine, isolation, and social distancing besides accept damaging furnishings on mental health and noesis. A rapid review article states that the longer a person is confined to quarantine, the poorer the outcomes for their mental health,67 while periods of isolation and the inability to work can crusade feet, loneliness, and financial concerns, and living through a global wellness crisis can pb to avoidance behaviors and behavioral changes.113 The mental health of the older population is profoundly affected by social distancing and similar measures. By assessing the associations between loneliness, physical activity, and mental health both before and during the pandemic, one study found that negative changes of these factors were not solely owing to longitudinal situations before 2020, therefore the pandemic exerted extra unfavorable effects on loneliness, physical activity, and mental health.114 People living in care homes, including people with dementia, are vulnerable to covid-nineteen and to other impacts of the pandemic. Those with dementia in care homes accept been observed to become more than depressed, broken-hearted, agitated, and lonely.115 Protracted social isolation has resulted in exacerbation of neuropsychiatric and behavioral disturbances, including apathy, anxiety, agitation, colorlessness, and confusion in dementia patients living in care homes, to a greater caste than for care home residents without dementia.116117

Sleeplessness is likewise commonly reported following recovery from covid-19, with many studies finding poor sleep quality and sleep disturbances to be frequent post-obit recovery from acute illness.16253144118119 Furthermore, a retrospective study of medical records of covid-19 patients treated in Seoul, Southward Korea, found that afterwards prescriptions to care for fever, coughing, and rhinorrhea, medications for slumber issues were the next most prescribed treatments.120 Knowledge of the covid-19 decease toll too has a negative impact on quality of slumber, stress, feet, and other negative emotions,121 and sleep problems have been shown to be associated with covid-nineteen related loneliness.122 This leads us to question whether post-covid-19 sleep disturbances are a outcome of covid-19 infection, the negative effects of the pandemic, or a combination of both.

Possible mechanisms

Coronaviruses including SARS-CoV-2 tin infect the central nervous system (CNS) via hematogenous or neuronal retrograde neuro-invasive routes.123 The entry mechanism and subsequent CNS infection may explicate the high incidence of neuro-inflammation seen in patients with covid-19, and may result in damaging long term effects, with associations of viral infections and chronic neuro-inflammation with neurodegenerative and psychiatric disorders already elucidated.123124 SARS-CoV-two may as well touch the permeability of the claret-brain barrier, which would enable peripheral cytokines and other blood derived substances to enter the CNS and further drive neuro-inflammation.125 Thrombo-inflammatory pathways may be the cause of the increased prevalence of stroke in covid-19,126 while "brain fog" may evolve from PTSD or deconditioning following disquisitional affliction and invasive handling.127 Evidence suggests that a directly viral encephalitis, systemic inflammation, peripheral organ dysfunction, and cerebrovascular changes may contribute to the development of long term sequalae post-obit covid-19.128Figure 2 outlines the potential mechanisms occurring within the CNS.

Olfactory and gustatory dysfunction

Abnormalities of odour and taste accept been reported to persist following recovery from covid-19. The ONS estimated the 5 week prevalence of loss of smell and loss of sense of taste as 7.9% and 8.two% of all people who have had covid-19, respectively.53 Other studies take establish varying prevalence of olfactory and gustatory dysfunction, ranging from 11% to 45.ane% of cohorts of patients who have recovered from astute covid-19.223947

Possible mechanisms

Non-neuronal expression of the ACE2 receptor may enable entry of the SARS-CoV-2 virus into olfactory support cells, stem cells, and perivascular cells. This local infection could crusade an inflammatory response which subsequently reduces the function of olfactory sensory neurons. Additionally, by damaging the back up cells responsible for local water and ionic residual, SARS-CoV-2 may indirectly reduce signaling from sensory neurons to the brain,129 resulting in a loss of sense of aroma.

ACE2 receptors are also expressed on the mucous membrane of the oral cavity, peculiarly on the tongue,130 therefore SARS-CoV-2 has a direct route of entry into oral tissue, which may result in cellular injury and dysfunction. Moreover, SARS-CoV-2 may demark to sialic acid receptors,131 causing an increase in gustatory threshold and resulting in degradation of gustatory particles before they tin be detected.132 Another possible mechanism of gustatory dysfunction in covid-19 and long covid concerns the functional link betwixt sense of taste and smell, whereby gustatory perception is reduced because of antecedent olfactory sensory dysfunction.133

Other commonly reported manifestations

Covid-nineteen infection tin result in multi-organ harm in individuals with depression or high hazard for severe acute disease.213 Studies bear witness the presence of astute kidney injury in discharged patients who have recovered from covid-xix.134135136 Although the long term effects of covid-19 on the kidneys are not fully elucidated, a report assessing kidney office in patients with covid-19 found that 35% had decreased kidney role at 6 months post-discharge.50

Acutely, pancreatitis triggered past SARS-CoV-2 has been seen in people with covid-nineteen,6137 while serum amylase and lipase levels have been observed to be higher in people with severe affliction compared with mild cases, and computed tomography images have shown pancreatic injury.138 A cross exclusive report found that 40% of patients with covid-xix who were at low take chances of severe disease, assessed 141 days following infection, had mild impairment of the pancreas. This impairment was associated with diarrhea, fever, headache, and dyspnea.13 Postmortem and case studies have highlighted the bear on that covid-nineteen has on the spleen, including atrophy of lymphoid follicles, a subtract in T and B lymphocytes leading to lymphocytopenia, and thrombotic events such as infarcts.139140141 A cantankerous sectional study found mild harm of the spleen in 4% of those assessed at 141 days following clearance of covid-xix.xiii Other organs and tissues, such as the liver, gastrointestinal tract, musculus, and blood vessels express the ACE2 receptor and are susceptible to direct damage from SARS-CoV-2 and indirect impairment through elevated systemic inflammation.142143144 Alterations in gut microbiota145 and subacute thyroiditis142 have been observed following covid-nineteen infection.

Possible mechanisms

Kidney injury may occur through several mechanisms associated with covid-xix, including sepsis143 and lung injury leading to hemodynamic changes and hypoxemia.144 The ACE2 receptor is highly expressed in the pancreas,4 peradventure to a greater level than in the lungs138; however, it is unclear whether pancreatic damage is a straight result of viral infection within the pancreas, or acquired by the systemic inflammatory response seen during covid-19. 146 The spleen as well expresses ACE2 receptors6 and may be directly attacked by the virus, rather than the intense systemic inflammation being the master cause of splenic harm.139 Chronic systemic inflammation is frequently observed long after the clearance of acute covid-19 infection,13 therefore, it is likely that this elevated inflammatory state causes long term complications in multiple organs in people with long covid.

Risk factors

Run a risk factors for severe covid-19 and hospital admission, and risk factors for death as a result of covid-xix include older age, male sexual activity, non-white ethnicity, existence disabled, and pre-existing comorbidities including obesity, cardiovascular disease, respiratory disease, and hypertension.21319147148 Linked to risk of covid-19 severity and possibly the gamble of long covid, the role of allowed suppression is still being debated. Immune suppression may take protective effects against long term effects of covid-19 infection149150151; however, these findings are conflicted.152153

The risk factors for developing long covid are less appreciated. To explore the characteristics associated with symptoms of long covid, 274 non-hospitalized patients who had covid-nineteen were interviewed between 14 and 21 days post-obit their positive test. Hazard factors for not returning to "usual health" included age (P=0.01), with the ≥fifty years age group having the greatest odds ratio, and number of pre-existing medical conditions (P=0.003), with a greater number of weather condition associated with a greater odds ratio of not returning to "usual health." Of the pre-existing conditions, having hypertension (odds ratio (OR)=i.3, P=0.018), obesity (OR=2.31, P=0.002), a psychiatric condition (OR=2.32, P=0.007), or an immunosuppressive condition (OR=two.33, P=0.047) corresponded with the greatest odds of not returning to "usual health."18

A cross exclusive study identified an association betwixt the severity of acute covid-nineteen infection and mail-recovery manifestations in people who accept had covid-19, showing that a more severe acute phase may transform into the development of more astringent symptoms of long covid.43 A cohort study, meanwhile, corroborated this finding, with patients with more v symptoms during the initial covid-19 infection and those that required hospital admission more likely to feel long covid symptoms.34

Although sure factors may increment the chance of both severe covid-xix and long covid, some factors associated with covid-19 practice not also increment risk for long covid. Male sex and older historic period are associated with an increased gamble of severe covid-nineteen, however, the ONS reported that the prevalence of any long covid symptoms is higher in women compared with men (23.6% versus xx.7%), while the age group estimated to be near greatly afflicted by long covid symptoms is 35-49 years (26.8%), followed by 50-69 years (26.i%), and the ≥70 years group (18%).53 Furthermore, a prospective cohort written report assessing recovered patients found no baseline clinical features associated with the subsequent development of long covid symptoms.154 Male sex, age, and pre-existing conditions including obesity, diabetes, and cardiovascular disease have shown no association with the gamble of developing long covid. However, pre-beingness of asthma has been constitute to be significantly associated with long covid.34

Handling and management of long covid

WHO and the Long Covid Forum Group agree that research priorities for long covid include improving clinical characterization and the research and evolution of therapeutics.155156 Clinical characterization of patients with long covid is essential to provide appropriate treatment options. Gaining an understanding of why certain disease phenotypes arise in different individuals is an important piece of the puzzle. A review, which included perspectives from patients with long covid, suggested that the status may actually exist four different syndromes.102 Recognizing which patients belong to which subgroup of long covid, and understanding the pathophysiology, will exist of import in deciding the handling they receive.

Guidelines

Diverse guidelines focus on treating and managing long covid, or have included recommendations for long covid in their guidelines for treating covid-19.ix Guidelines recommend how to identify, refer, and treat patients with long covid. The holistic assessment, investigation, and direction approaches suggested by NICE9 are outlined in fig 3. In Jan 2021, WHO updated its covid-19 guidance to include a new chapter focused on caring for patients post-covid-19.157 These guidelines go into little item almost long covid, notwithstanding. Similarly, the NIH has released treatment guidelines for covid-19,158 but little guidance on managing long covid. The CDC is expected to release guidance on long covid management soon.159 The European Lodge of Cardiology has too released guidelines on the diagnosis and management of cardiovascular disease during the pandemic.160 The guidelines for treating and managing long covid will undoubtedly evolve as new evidence comes to calorie-free; yet, other general guidelines, such as Testify Based Medicine'southward guidance on post-infectious syndromes may be useful for treating long covid.161

Pulmonary symptoms

Pulmonary symptoms are common during long covid. NICE recommends that breathlessness may be investigated using an exercise tolerance exam suited to the person's ability, for example the ane minute sit-to-stand test, and handling and direction should be multidisciplinary, with advice and education given on managing breathlessness. Furthermore, the guidelines recommend offer patients with continuing respiratory symptoms a chest radiograph by 12 weeks after infection.9 Blood oxygen levels can exist monitored using a pulse oximeter.

Recommendations from the Mayo Clinic propose that shortness of breath can exist self-managed by limiting factors that exacerbate dyspnea, including stopping smoking, avoiding pollutants, avoiding extremes in temperature, and exercising,162 nevertheless, chronic shortness of jiff may require further intervention. Recognized non-pharmacological strategies for managing dyspnea include animate exercises,163 pulmonary rehabilitation,164 and maintaining optimal body positioning for postural relief.165 Meanwhile, a systematic review has establish that oral opioids tin be used to care for dyspnea,166 therefore this class of drugs may evidence useful for treating the condition in people with long covid.

Patients with pulmonary fibrosis resulting from covid-nineteen should be managed in accordance with Prissy guidelines on idiopathic pulmonary fibrosis,167 while antifibrotic therapies may be advantageous.168 Exacerbations of bronchiectasis should exist treated with antimicrobial prescribing,169 while non-antimicrobial therapies, including airway clearance, may be considered.170 Modified rehabilitation practices, including stretching, torso rotations, acupressure, and massage have shown beneficial long term effects on respiratory symptoms in mild covid-19 patients in a small trial.171

Cardiovascular symptoms

The NICE guidelines on long covid country that practice tolerance tests may be undertaken to measure heart office, while lying and standing blood pressure and heart rate recordings should exist performed if postural orthostatic tachycardia syndrome (POTS) is suspected.9 Urgent referral should occur for people that have symptoms of a life threating complication, such as cardiac chest pain.

The European Club of Cardiology has released comprehensive guidance for the diagnosis and management of cardiovascular affliction during the covid-19 pandemic.160 The range of cardiovascular atmospheric condition that can manifest in long covid translates to a wide range of potential therapeutic options, therefore, ongoing investigation and ascertainment of cardiac biomarkers is important. Nice guidelines recommend β blockers for several cardiac complaints, including angina,172 cardiac arrhythmias,173 and acute coronary syndromes,174 therefore, β blockers may exist useful in the treatment of cardiovascular manifestations of long covid. Myocarditis may resolve naturally over time; however, supportive and/or immunomodulating therapy may improve recovery, every bit a systematic review describes.175 A review has likewise suggested that anticoagulants may exist used to reduce the risks associated with hypercoagulability.176 Meanwhile, communication and didactics, agents to maintain vascular tone, and agents to manage palpitations have been shown by a randomized controlled trial and discussed in a review to be advantageous in the handling of POTS.89177

Treating fatigue, cognitive, and neuropsychiatric symptoms

Chronic fatigue is a common manifestation of long covid. NICE recommends that cocky-management and support are of import in managing fatigue, owing to the poor availability of covid-xix specific treatment.9 A condition that may overlap with long covid fatigue is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), therefore, the handling algorithm designed for treating ME/CFS may bear witness useful in treating post-covid-19 fatigue. Squeamish has specific guidelines that outline how to refer and treat ME/CFS patients; these include cognitive behavioral therapy (CBT) and graded exercise therapy (Get).178 Following backlash over these guidelines from the ME Association,179 nonetheless, Squeamish aims to publish revised guidelines in August 2021.180

Randomized controlled trials take shown that CBT is beneficial in the treatment of chronic fatigue,181 however, this is conflicted by findings from a re-analysis of a Cochrane review which question its effectiveness and show a loftier incidence of agin events. This re-analysis study states that if a trial of a drug or surgical procedure demonstrated similarly high rates of agin effects, then it would not be accepted as a condom treatment choice, therefore CBT should take to adhere to the same level of scrutiny.182

Another management strategy for fatigue is pacing, whereby patients manage tasks and activities to avoid over-exertion and exacerbating fatigue. Nice guidelines for ME/CFS178 describe pacing as a cocky-direction strategy, however guidance and education from healthcare professionals may be useful for patients. Evidence from randomized controlled trials for the use of pacing in long covid is yet to exist seen.

The implementation of group therapy via videoconferencing in people with early psychosis during the covid-nineteen pandemic shows promising results, with a pilot study showing improvements in psychotic symptoms and self-esteem,183 yet, a review article provides information to suggest that CBT is ineffective in reducing long covid symptoms, including fatigue, with only 10% of participants achieving clinically meaningful improvements.184

GET is a structured intervention plan consisting of physical activities with a therapeutic goal.185 A systematic review of practise therapy for CFS ended that patients with ME/CFS mostly feel less fatigued and have improved sleep and concrete office post-obit completion of exercise therapy, to a greater degree than post-obit a program of either adaptive pacing or supportive listening.186 The NICE guidelines on ME/CFS recommend Go; however, in July 2020 NICE released a argument urging caution when implementing Get for people recovering from covid-19, stating that with guidelines currently beingness updated, these recommendations may modify.187 This statement accompanies concerns over the potential negative effects of Get, including postal service-exertional malaise.188

Evidence specific to covid-nineteen is lacking, therefore cognitive impairment should exist managed with support, including setting tailored, doable goals and implementing validated screening tools.9 Managing cerebral impairment volition require a holistic approach, however, patients should be advised that most people gradually recover from cerebral damage following severe affliction.106189 The holistic arroyo to treatment should extend to the services offered, with professionals including occupational and speech and language therapists addressing cerebral changes.190 Cognitive impairment in long covid, sometimes called "encephalon fog," has been compared to "chemobrain."191 The Mayo clinic recommendations propose strategies to manage chemobrain including repeating exercises, tracking what influences deficits, and using stress relief and coping strategies. Furthermore, medications including methylphenidate, donepezil, modafinil, and memantine may exist considered.192 These strategies may prove useful for long covid. Specific to long covid, luteolin, a natural flavonoid, may convalesce cognitive impairment by inhibiting mast cell and microglia activation,191 but clinical trials are required.

Slumber disturbances may be managed by following relevant guidelines on indisposition,193 and a range of treatment strategies tin can be considered.194195196197 Patients with mental health problems aslope or every bit a result of long covid tin can be managed following the relevant guidelines: depression,198 anxiety,199 PTSD,200 obsessive-compulsive disorder,201 and other mental wellness problems.202 Care home residents, including those with dementia, who acquire long covid have boosted needs.116 Discussing mental health bug with patients requires compassion and understanding.203

Treating other organ impairments

Electric current evidence for the recovery of renal function following covid-19 is lacking. Considering that early on and shut follow-ups with nephrologists accept previously been benign,204 postal service-covid-19 patients with renal dysfunction may do good from early and ongoing monitoring. Covid-19 tin disrupt and alter the microbiome of the gut, which may permit for opportunistic infections.145 Covid-xix associated destructive thyroiditis can effect in incident hyperthyroidism, which tin can be treated with corticosteroids.142 Overall, shut follow-upward of patients with long covid and adequate investigative procedures should be kept up to accurately diagnose and treat specific symptoms.

Repurposing drugs for long covid

Antihistamines have been implicated equally a possible treatment for covid-19, with a study that employed cellular experiments suggesting that histamine-one antagonists may exist able to reduce the covid-19 infection charge per unit by inhibiting SARS-CoV-2 from inbound ACE2 expressing cells.205 Systematic reviews and molecular studies take suggested that histamine-1 and histamine-2 antagonists are feasible candidates for further clinical trials in covid-19.206207208 It remains to be seen whether antihistamines have potential for treating long covid. Antidepressants accept been proposed to reduce the effects of long covid. Antidepressant employ has been associated with reduced chance of intubation or death in covid-19,209 while a meta-assay of antidepressant drug treatment for major depressive disorder has shown that use of antidepressants, including serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, results in a reduction in peripheral inflammatory markers.210

Emerging treatments

Clinical trials exploring the efficacy of hyperbaric oxygen (NCT04842448), montelukast (NCT04695704), and deupirfenidone (NCT04652518) to treat respiratory conditions in long covid are ongoing. A trial of animate exercises and singing is also under way to assess their utility in improving breathing abnormalities in patients with long covid (NCT04810065).

A trial to assess the effectiveness of an 8 week do plan in patients with long covid and fatigue is ongoing (NCT04841759). Vitamin C supplementation may prove useful in treating fatigue in patients with long covid, with a systematic review concluding that loftier dose intravenous vitamin C could be a benign handling choice.211 LOVIT-COVID (NCT04401150) is an ongoing clinical trial aimed at assessing the effects of loftier dose intravenous vitamin C on hospitalized patients with covid-19.

Two trials examining the furnishings of nicotinamide riboside, a dietary supplement, are ongoing (NCT04809974, NCT04604704) with the expectation that the molecule reduces cognitive symptoms and fatigue by modulating the pro-inflammatory response.212

A clinical trial is currently ongoing assessing the effectiveness of a probiotic supplement to normalize the composition of the gut microbiome and reduce inflammation in long covid (NCT04813718). The understanding of long term sequalae of covid-19 infection in the gastrointestinal tract will evolve, with studies currently ongoing (NCT04691895), which volition subsequently affect treatment.

Other potential treatments are molecules that suppress the intense inflammatory response seen in covid-19. Leronlimab is a monoclonal antibody that blocks the role of CCL-5. It has been shown to be effective and safety in HIV213 and reduces plasma interleukin-six levels in covid-19.214 Clinical trials are ongoing to evaluate the efficacy of leronlimab post-covid-19 (NCT04343651, NCT04347239, NCT04678830). Another antibody treatment, tocilizumab, blocks interleukin-6 receptors and has shown efficacy in a small trial of patients with covid-nineteen patients.215 Trials to explore the effects of tocilizumab are ongoing (NCT04330638). The anti-oxidative and anti-inflammatory function of melatonin may likewise be useful in treating long covid.216 Lastly, adjuvant treatments, such as adaptogens, are being explored for their effectiveness in treating long covid (NCT04795557).

Decision

With many people having been infected and continuing to be infected with covid-19, the long term implications are of increasing concern. Hither, we have reviewed the studies that have explored the persisting symptoms of long covid, and take addressed the possible run a risk factors associated with developing long covid and the treatment options that may be useful in alleviating its symptoms. Currently, long covid remains enigmatic and, with the question of the impact that new variants of covid-19 volition take on the incidence and severity of long covid still looming big, information technology is important that research continues to explore postal service-covid-nineteen syndrome. Greater understanding of the pathogenesis, take chances factors, symptoms, and methods of treating long covid is required to reduce the strain and demand on people with the status and the healthcare systems that will endeavor to support them.

How patients were involved in the creation of this article

Members of a long covid focus grouping were contacted and requested to review the initial drafts of this article. The feedback received assisted in developing and focusing our review towards the experiences of different symptoms experienced by patients with long covid. Cognition and mental health were of particular interest to patients, which we take addressed in this commodity.

Research Questions

• What is the precise epidemiology of long covid and how volition novel variants of covid-nineteen affect the epidemiology and severity of long covid?

• What are the major risk factors for long covid and how practice we best reduce an individual'due south risk of developing long term mail-covid-19 symptoms?

• Which symptoms, or set of symptoms, tin we use to allocate long covid, clinically and phenotypically, with the aim of improving diagnosis and management?

• What is the optimal handling and management strategy for long covid and is this strategy non-specific or will it require targeting and tailoring to specific patients?

Footnotes

• Land of the Art Reviews are commissioned on the ground of their relevance to academics and specialists in the United states and internationally. For this reason they are written predominantly by US authors

• Contributors: HC, SR, JN, and MY performed the primary literature search and drafted parts of the manuscript; HC was the beginning author of the manuscript who drafted the manuscript and revised it; PE was responsible for the concept and design of the piece of work. PE reviewed and revised the manuscript. PE is the guarantor.

• Competing interests: We have read and understood the BMJ policy on proclamation of interests and declare the following interests: PE was funded by the Medical Research Quango and now by Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer's Research, UK, Alzheimer's Drug Discovery Foundation, Alzheimer'due south Society, UK, Medical Research Quango, Alzheimer's Clan US, Van-Geest foundation, and European Union grants. PE is a consultant to Roche, Pfizer, and Novo Nordisk. He has received educational and enquiry grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He is a fellow member of the Scientific Advisory Lath at Novo Nordisk.

• Provenance and peer review: deputed; externally peer reviewed.

This article is made freely bachelor for use in accord with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and impress the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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