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Clinical Review Country of the Art Review Long covid—mechanisms, risk factors, and direction
BMJ 2021; 374 doi: https://doi.org/ten.1136/bmj.n1648 (Published 26 July 2021) Cite this as: BMJ 2021;374:n1648 Read our latest coverage of the coronavirus pandemic
- Harry Crook , enquiry assistant1,
- Sanara Raza , inquiry assistantane,
- Joseph Nowell , research banana1,
- Megan Young , clinical research officeholderi,
- Paul Edison , clinical senior lecturer , honorary professor12
- 1Kinesthesia of Medicine, Imperial College London, London, Britain
- iiCardiff University, Cardiff, Britain
- Correspondence to P Edison paul.edison{at}imperial.ac.uk
Abstract
Since its emergence in Wuhan, Communist china, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Contempo evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-two infection, and this status is at present coined long covid by recognized research institutes. Studies accept shown that long covid tin can affect the whole spectrum of people with covid-19, from those with very balmy acute disease to the well-nigh astringent forms. Similar acute covid-19, long covid can involve multiple organs and can affect many systems including, simply not express to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cerebral impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle hurting, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-nineteen and long covid and possible therapeutic options are as well discussed.
Introduction
Coronavirus disease 2019 (covid-19) has spread across the world. As of four July 2021, more than 183 million confirmed cases of covid-nineteen have been recorded worldwide, and more than than 3.97 million deaths have been reported by the World Health Organization .ane 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-2), enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor.four Once internalized, the virus undergoes replication and maturation, provoking an inflammatory response that involves the activation and infiltration of immune cells past various cytokines in some patients.5 The ACE2 receptor is nowadays in numerous cell types throughout the human body, including in the oral and nasal mucosa, lungs, heart, alimentary canal, liver, kidneys, spleen, encephalon, and arterial and venous endothelial cells, highlighting how SARS-CoV-2 tin cause damage to multiple organs.67
The impact of covid-19 thus far has been unparalleled, and long term symptoms could have a farther devastating upshot.8 Recent evidence shows that a range of symptoms tin remain later on the clearance of the acute infection in many people who accept had covid-nineteen, and this status is known as long covid. The National Institute for Health and Care Excellence (NICE) defines long covid as the symptoms that keep or develop after acute covid-19 infection and which cannot be explained past an alternative diagnosis. This term includes ongoing symptomatic covid-nineteen, from four to 12 weeks post-infection, and mail service-covid-19 syndrome, beyond 12 weeks post-infection.ix 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 every bit sequelae that extend beyond iv weeks after initial infection.10 People with long covid exhibit involvement and impairment in the construction and function of multiple organs.11121314 Numerous symptoms of long covid have been reported and attributed to diverse organs, an overview of which can be seen in fig ane. Long term symptoms following covid-19 have been observed across the spectrum of disease severity. This review examines the long term bear upon of symptoms reported following covid-19 infection and discusses the electric current epidemiological agreement of long covid, the take chances factors that may predispose a person to develop the condition, and the treatment and management guidelines aimed at treating information technology.
Fig ane
Multi-organ complications of covid-19 and long covid. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptor. Once these cells have 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
Nosotros searched PubMed and Embase databases for articles published betwixt January 2020 and May 2021. Our search terms were "long covid" or "post-covid-19" or "COVID long-haulers" or "SARS-CoV-2" and "epidemiology" or "fatigue" or "fatigue syndrome" or "dyspnoea" or "breathlessness" or "shortness of breath" or "cardiac" or "cardiovascular" or "heart" or "noesis" or "cognitive impairment" or "mental health" or "depression" or "feet" or "psychiatric" or "central nervous system" or "autonomic nervous arrangement" or "isolation" or "loneliness" or "sleeplessness" or "sleep" or "smell" or "gustatory modality" or "olfactory" or "gustatory" or "risk factors" or "treatment". To avoid unintentionally removing manufactures, no filters were applied. We retrieved 61 881 manufactures in the start example. To screen articles, titles were read by authors first, followed by abstracts to farther narrow down the number of records considered. To avert unnecessary exclusion of studies, limited exclusion and inclusion criteria were practical. Nosotros 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. Nosotros discovered and read fully 227 articles on long covid, and nosotros discussed each to determine which would exist included in the finalized article. Nosotros performed farther manual searching for additional articles and treatment guidelines using relevant databases, including prissy.org.uk and clinicaltrials.gov. In total, 218 references were included. Studies examining long covid are limited, therefore express exclusion criteria were practical.
Studies of long covid
Studies have assessed people who have had covid-xix to examine the symptoms associated with long covid. These studies are summarized in tabular array 1. The articles included throughout this review were selected in favor of quality, with large observational studies of greatest interest. Most of the studies included are cross-sectional or cohort observational studies with large cohorts; however, because of the novelty of the disease and paucity of information, 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) prove little difference in incidence of long term symptoms associated with covid-nineteen.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 like.16 Many patients with balmy acute symptoms besides develop long covid symptoms,13 in fact, studies bear witness minimal differences between the prevalence of long covid symptoms between hospitalized and not-hospitalized covid-19 patients.nineteen
Table 1
Summary of studies that take explored the persisting symptoms postal service-covid-19 infection, or during long covid
Epidemiology
The reported incidence and mortality rates of covid-19 vary between countries, making it difficult to accurately predict the number of patients who will progress to long covid. Similarly, the authentic reporting of long covid is complicated. The disparity in this epidemiological information is probable the result of several factors, including differences in the base population, the accuracy of diagnosis, the reporting systems, and the capability of healthcare systems. Although determining the exact epidemiological data of long covid is difficult, this information is needed to inform healthcare systems and governments when developing support and treatment algorithms. The book of published literature describing cases of patients with covid-19 who subsequently develop long covid symptoms is continually growing, which volition permit for an improved agreement of its epidemiology.
The current disparities betwixt long covid epidemiology reporting are owing to many reasons, including the length of follow-up menstruum, population assessed, accurateness of cocky-reporting, and symptoms examined. Studies around the world have reported various incidence rates for long covid with different follow-upwardly test times later on the acute infection, including 76% of people at six months,50 32.vi% at sixty days,51 87% at sixty days,15 and 96% at 90 days.52 These finding are not fully corroborative, just they prove that a substantial proportion of people who have had covid-19 may develop long covid. The Britain Function for National Statistics (ONS) has released information on the prevalence of long covid symptoms.53 They estimated that the v week prevalence of any symptom among survey respondents who tested positive for covid-xix between 22 April and 14 Dec 2020 was 22.1%, while the 12 calendar 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-19 variants of business organisation
Since the start of the pandemic, several covid-19 variants have emerged that have an increased transmissibility and may result in more severe acute disease. In the UK, i of the beginning variants of business organization to announced was the so chosen "Kent variant," from the B.i.1.7 lineage, at present termed the Blastoff variant. This variant has approximately l% increased transmissibility54 and likely increases acute disease severity.55 As of thirty June 2021, the Alpha variant has been confirmed in more than 275 000 cases in the UK56 and spread to at least 136 countries around the world.57 Other variants of business organization or nether investigation include the Beta, Gamma, Zeta, Theta, and Kappa variants.56 The CDC reports the emergence of variants of business and interest in the U.s.a..58 New covid-nineteen variants will continue to sally and spread equally we progress through the pandemic, for case, the Eta and Delta variants have arisen, with over 161 000 cases of the speedily spreading Delta variant confirmed in the UK, equally of 30 June 2021.56 Recently, the Lambda variant has emerged, which will require close monitoring. The ability of these viral strains to inflict long term complications needs to exist examined fully. To speculate, information technology may be that one variant causes more damaging long term effects than others and, therefore, patients infected with such a variant who continue to develop long covid symptoms may require boosted support, every bit well every bit more than rapid and intense treatment strategies to combat their long term symptoms.
Long covid definition
Long covid gained widespread attending following an account published on 5 May 2020 in BMJ Opinion where an infectious disease professor shared his experience of seven weeks on a "rollercoaster of sick health" following covid-19.59 The patient-fabricated term long covid was then made pop post-obit the rise in the use of #LongCovid on Twitter.60 This, plus the growing number of peer reviewed articles published since, has highlighted a mail service-covid-19 syndrome that can final for many weeks later the acute infection. Long covid is at present 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 every bit individuals with ongoing symptoms of covid-xix that persist beyond four weeks from initial infection.
Symptoms
Fatigue
Fatigue is more profound than being overtired; information technology is unrelenting burnout and a constant state of weariness that reduces a person's energy, motivation, and concentration. Following the SARS outbreak, up to sixty% of patients reported ongoing fatigue at 12 months following recovery from the acute illness.61 In long covid, fatigue is one of the well-nigh reported manifestations, with the ONS estimating the five week prevalence of fatigue to exist 11.9% among people who have had covid-19.53 Fatigue is a common persisting symptom regardless of severity of the astute stage of covid-19. One cross-exclusive study found that 92.9% and 93.v% of hospitalized and non-hospitalized covid-nineteen patients, respectively, reported ongoing fatigue at 79 days following onset of illness.19 Many other cross-sectional and accomplice studies study that chronic fatigue is the nigh frequently reported symptom post-obit recovery from astute covid-19,1517202743 with ane showing no association between covid-19 severity and long term fatigue.20 These findings show that fatigue is a major manifestation of long covid.
Possible mechanisms
Chronic fatigue following viral infection may be the result of miscommunication in the inflammatory response pathways62; however, a cross-sectional analytical written report institute no association between pro-inflammatory markers and long term fatigue in covid-nineteen patients with persisting fatigue.20 It is likely that a range of central, peripheral, and psychological factors play a role in the evolution of post-covid-19 fatigue. A narrative review explains that congestion of the glymphatic system and the subsequent toxic build-up within the central nervous system (CNS), acquired past an increased resistance to cerebrospinal fluid drainage through the cribriform plate as a outcome of olfactory neuron damage, may contribute to post-covid-19 fatigue.63
Hypometabolism in the frontal lobe and cerebellum has too been implicated in covid-xix patients with fatigue and is likely caused past systemic inflammation and cell mediated immune mechanisms, rather than directly viral neuro-invasion.6465 Information technology is unknown whether this finding continues into long covid.
Negative psychological and social factors associated with the covid-19 pandemic accept also been linked to chronic fatigue.6667 Lastly, peripheral factors such as direct SARS-CoV-two infection of skeletal musculus, resulting in damage, 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 evolution of post-covid-nineteen fatigue. Effigy 2 farther outlines these possible mechanisms.
Fig 2
Long term sequalae of covid-xix
(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 impairment 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 effect in the development of a prolonged hyperinflammatory and hypercoagulable state, increasing the risk of thrombosis.
(2) In the heart: (A) chronic inflammation of cardiomyocytes can result in myositis and cause cardiomyocytes decease. (B) Dysfunction of the afferent autonomic nervous system tin can cause complications such as postural orthostatic tachycardia syndrome. (C) Prolonged inflammation and cellular damage prompts fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis. (D) Fibrotic changes are accompanied past an increase in cardiac fibromyoblasts, while harm to desmosomal proteins results in reduced prison cell-to-cell adhesion.
(3) In the central nervous organization: (A) The long term immune response activates glial cells which chronically damage neurons. (B) Hyperinflammatory and hypercoagulable states atomic number 82 to an increased risk of thrombotic events. (C) Blood-brain barrier damage and dysregulation results in pathological permeability, assuasive blood derived substances and leukocytes to infiltrate the brain parenchyma. (D) Chronic inflammation in the brainstem may cause autonomic dysfunction. (Due east) The effects of long covid in the encephalon tin can atomic number 82 to cognitive harm.
(4) Possible mechanisms causing post-covid-19 fatigue. A range of cardinal, peripheral, and psychological factors may crusade chronic fatigue in long covid. Chronic inflammation in the encephalon, as well as at the neuromuscular junctions, may result in long term fatigue. In skeletal muscle, sarcolemma harm and fiber atrophy and damage may play a role in fatigue, as might a number of psychological and social factors
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Postal service-COVID-19 fatigue has been compared with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with many overlaps between the two.72 Symptoms mutual to both ME/CFS and long covid include fatigue, neurological/hurting, neurocognitive/psychiatric, neuroendocrine, autonomic, and immune symptoms, with both ME/CFS and long covid patients having long symptom durations, reduced daily activity, and postal service-exertional malaise.72 ME/CFS remains enigmatic, therefore, research into long covid may assist in developing agreement of ME/CFS and vice versa.
Dyspnea
Breathlessness is mutual in people with long covid. The ONS estimates that shortness of breath has a prevalence of four.six% at v weeks post-covid-19 infection, regardless of presence of astute respiratory symptoms or disease severity.53 Abnormalities in diffusion capacity for carbon monoxide, total lung capacity, forced expiratory volume in the commencement 2nd, forced vital chapters, and small airway function, take been seen in hospitalized covid-nineteen patients at time of discharge, approximately i calendar month following onset of symptoms, showing that lung function in people who take had covid-nineteen may have time to recover.73 Several studies accept found that dyspnea is a common manifestation following covid-19 infection,1617 and one study reported that 43.four% of 143 patients assessed were yet experiencing dyspnea at 60 days after covid-nineteen onset.15
Possible mechanisms
As covid-xix is principally a respiratory illness, acute affliction 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 allowed and inflammatory reaction.7475 Those who overcome the acute infection may develop long term lung abnormalities, leading to dyspnea76; however, most individuals who develop long term animate difficulties post-covid-19 have no signs of permanent or longlasting lung harm.2877 It is probable that only those at high risk of developing animate difficulties, including older people, those who endure astute respiratory distress syndrome, those who have extended infirmary stays, and those with pre-existing lung abnormalities, are prone to develop fibrotic-similar changes to lung tissue.78 The fibrotic land observed in some patients with ongoing dyspnea may be provoked by cytokines such as interleukin-six, which is raised in covid-1979 and is involved in the formation of pulmonary fibrosis.eighty 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 run a risk 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 accomplice 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 big instance series showed that chest pain, peradventure owing to myocarditis, was a common manifestation in patients 60.3 days following onset of covid-19 symptoms, with 21.7% of the 143 patient assessed reporting chest pain.xv Those considered at low risk of severe covid-19, such as young, competitive athletes, accept besides been found to have rest myocarditis long afterwards recovery from covid-19.84 In add-on to cardiac complaints, studies have highlighted an emerging trend in the evolution of new onset postural orthostatic tachycardia syndrome (POTS) in individuals post-covid-19 infection, because of autonomic dysfunction.8586878889
Possible mechanisms
ACE2 receptors are highly expressed in the heart,90 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 past SARS-CoV-2.9192 Pathological responses to acute cardiac injury and viral myocarditis, such equally endothelial damage and microthrombosis, can lead to the development 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 accept had covid-19.94 Furthermore, sustained immune activation tin lead to fibrotic changes95 and displacement of desmosomal proteins,96 which could exist arrhythmogenic. Viral infection has previously been shown to precede POTS97 and, with the ACE2 receptor expressed on neurons, viral infection by SARS-CoV-2 may have direct negative consequences on the autonomic nervous system.98 A complex combination of infection, an autonomic nervous organisation 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.
Cognition and mental health
Studies have explored cognitive function and deficits in patients with covid-19 and suggest that the virus tin can crusade 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 hospital with covid-nineteen have presented with a range of complaints including encephalopathy, cognitive harm, cerebrovascular events/illness, seizures, hypoxic brain injuries, corticospinal tract signs, dysexecutive syndrome, an altered mental condition, and psychiatric conditions.24100101 These findings reveal that neurological symptoms associated with covid-19 are common, diverse, and could pose substantial problems for rehabilitation and ongoing intendance following recovery from covid-19. Information technology is unknown who is near affected by cognitive complaints induced by covid-19 and how long they persist; however, patient experiences and published summaries of long covid take described "encephalon fog" to be a common and debilitating symptom.102103104
Critical disease, severe acute respiratory syndrome, and long term ventilator support are known to accept detrimental effects on long term noesis. Earlier the covid-19 pandemic, a retrospective report of 1040 ICU treated patients who had respiratory failure, shock, or both during hospital stays, establish that 71% had delirium which lasted around four months following discharge.105 A similar study institute that, at 3 months post-discharge, twoscore% of ICU treated patients had noesis scores like those of patients with moderate traumatic brain injury, while 26% had scores like to patients with mild Alzheimer's disease. Delirium was too widely reported, with a longer elapsing of delirium associated with worse cognition.106 With many covid-19 patients requiring ICU admission and mechanical ventilation, long term cognitive harm and delirium are likely to pose considerable bug.
Stroke and headache are prevalent in those recovered from acute covid-19, with the ONS estimating the 5 week prevalence of headache at ten.1% of all covid-xix survivors.1318344353 Exaggerated levels of systemic inflammation, observed in some patients as a "cytokine tempest," in addition to activation glial cells, poses a substantial gamble to the encephalon and increases the likelihood of neurological manifestations including encephalitis and stroke.74 Hypercoagulability107 and cardio-embolisms, formed because of virus related cardiac injury,108 are manifestations that could result in increased incidences of stroke post-obit covid-nineteen infection. Covid-xix has also been associated with an increased run a risk of developing neurological conditions including Guillain-Barré syndrome,109 and neurodegenerative weather condition such equally Alzheimer's disease.110
The pandemic has had a negative consequence on mental wellness, with people who have had covid-xix exhibiting long term psychiatric symptoms including postal service-traumatic stress disorder (PTSD), low, feet, and obsessive-compulsive symptoms following recovery from the acute infection.3637111112 Quarantine, isolation, and social distancing also accept damaging effects on mental health and cognition. A rapid review article states that the longer a person is confined to quarantine, the poorer the outcomes for their mental wellness,67 while periods of isolation and the inability to work can cause anxiety, loneliness, and financial concerns, and living through a global health crisis tin can pb to abstention behaviors and behavioral changes.113 The mental health of the older population is profoundly affected past social distancing and similar measures. By assessing the associations between loneliness, physical activity, and mental health both earlier 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 intendance homes accept been observed to go more than depressed, anxious, agitated, and lone.115 Protracted social isolation has resulted in exacerbation of neuropsychiatric and behavioral disturbances, including apathy, feet, agitation, boredom, and confusion in dementia patients living in intendance homes, to a greater caste than for care home residents without dementia.116117
Sleeplessness is also commonly reported following recovery from covid-19, with many studies finding poor sleep quality and slumber disturbances to be frequent following recovery from acute illness.16253144118119 Furthermore, a retrospective written report of medical records of covid-19 patients treated in Seoul, South Korea, found that afterward prescriptions to treat fever, cough, and rhinorrhea, medications for sleep problems were the side by side most prescribed treatments.120 Noesis of the covid-nineteen death toll also has a negative impact on quality of slumber, stress, anxiety, and other negative emotions,121 and sleep problems have been shown to exist associated with covid-19 related loneliness.122 This leads united states to question whether mail service-covid-19 sleep disturbances are a event of covid-19 infection, the negative furnishings of the pandemic, or a combination of both.
Possible mechanisms
Coronaviruses including SARS-CoV-two tin can infect the fundamental nervous arrangement (CNS) via hematogenous or neuronal retrograde neuro-invasive routes.123 The entry mechanism and subsequent CNS infection may explain the high incidence of neuro-inflammation seen in patients with covid-19, and may result in dissentious long term furnishings, with associations of viral infections and chronic neuro-inflammation with neurodegenerative and psychiatric disorders already elucidated.123124 SARS-CoV-2 may also touch on the permeability of the blood-brain barrier, which would enable peripheral cytokines and other blood derived substances to enter the CNS and further bulldoze neuro-inflammation.125 Thrombo-inflammatory pathways may be the cause of the increased prevalence of stroke in covid-nineteen,126 while "brain fog" may evolve from PTSD or deconditioning following critical illness and invasive handling.127 Evidence suggests that a direct viral encephalitis, systemic inflammation, peripheral organ dysfunction, and cerebrovascular changes may contribute to the evolution of long term sequalae following covid-19.128Figure two outlines the potential mechanisms occurring within the CNS.
Olfactory and gustatory dysfunction
Abnormalities of smell and sense of 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 taste as vii.9% and 8.two% of all people who have had covid-19, respectively.53 Other studies have constitute varying prevalence of olfactory and gustatory dysfunction, ranging from 11% to 45.1% of cohorts of patients who accept recovered from acute covid-nineteen.223947
Possible mechanisms
Non-neuronal expression of the ACE2 receptor may enable entry of the SARS-CoV-ii virus into olfactory support cells, stem cells, and perivascular cells. This local infection could cause an inflammatory response which subsequently reduces the office of olfactory sensory neurons. Additionally, by damaging the back up cells responsible for local water and ionic balance, SARS-CoV-2 may indirectly reduce signaling from sensory neurons to the brain,129 resulting in a loss of sense of smell.
ACE2 receptors are as well expressed on the mucous membrane of the oral cavity, particularly on the natural language,130 therefore SARS-CoV-2 has a directly road of entry into oral tissue, which may result in cellular injury and dysfunction. Moreover, SARS-CoV-2 may bind to sialic acrid receptors,131 causing an increase in gustatory threshold and resulting in degradation of gustatory particles before they can be detected.132 Another possible mechanism of gustatory dysfunction in covid-nineteen and long covid concerns the functional link between taste and smell, whereby gustatory perception is reduced because of antecedent olfactory sensory dysfunction.133
Other commonly reported manifestations
Covid-nineteen infection can result in multi-organ impairment in individuals with low or high chance for severe acute disease.213 Studies bear witness the presence of astute kidney injury in discharged patients who have recovered from covid-19.134135136 Although the long term effects of covid-19 on the kidneys are non fully elucidated, a study assessing kidney function in patients with covid-xix constitute that 35% had decreased kidney function at 6 months postal service-belch.fifty
Acutely, pancreatitis triggered by SARS-CoV-ii has been seen in people with covid-19,6137 while serum amylase and lipase levels have been observed to be college in people with severe illness compared with balmy cases, and computed tomography images have shown pancreatic injury.138 A cantankerous sectional study plant that twoscore% of patients with covid-19 who were at low risk of severe affliction, assessed 141 days post-obit infection, had mild damage of the pancreas. This damage was associated with diarrhea, fever, headache, and dyspnea.thirteen Postmortem and case studies have highlighted the impact that covid-nineteen has on the spleen, including cloudburst of lymphoid follicles, a decrease in T and B lymphocytes leading to lymphocytopenia, and thrombotic events such as infarcts.139140141 A cantankerous exclusive study found mild impairment of the spleen in iv% of those assessed at 141 days following clearance of covid-19.13 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 damage 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-19, including sepsis143 and lung injury leading to hemodynamic changes and hypoxemia.144 The ACE2 receptor is highly expressed in the pancreas,four perhaps to a greater level than in the lungs138; nonetheless, information technology is unclear whether pancreatic damage is a direct result of viral infection inside the pancreas, or caused by the systemic inflammatory response seen during covid-19. 146 The spleen also expresses ACE2 receptors6 and may exist directly attacked by the virus, rather than the intense systemic inflammation being the master cause of splenic damage.139 Chronic systemic inflammation is often observed long after the clearance of acute covid-nineteen infection,thirteen therefore, it is likely that this elevated inflammatory state causes long term complications in multiple organs in people with long covid.
Take chances factors
Risk factors for severe covid-19 and hospital admission, and hazard factors for death as a outcome of covid-19 include older historic period, male sex, non-white ethnicity, being disabled, and pre-existing comorbidities including obesity, cardiovascular disease, respiratory affliction, and hypertension.21319147148 Linked to adventure of covid-19 severity and possibly the gamble of long covid, the part of immune suppression is nevertheless being debated. Immune suppression may have protective furnishings against long term furnishings of covid-19 infection149150151; still, 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-19 were interviewed between fourteen and 21 days post-obit their positive test. Gamble 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)=ane.3, P=0.018), obesity (OR=ii.31, P=0.002), a psychiatric status (OR=2.32, P=0.007), or an immunosuppressive condition (OR=2.33, P=0.047) corresponded with the greatest odds of not returning to "usual health."xviii
A cross exclusive report identified an association between the severity of astute covid-xix infection and post-recovery manifestations in people who have had covid-19, showing that a more severe astute 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 than than five symptoms during the initial covid-xix infection and those that required hospital admission more probable to experience long covid symptoms.34
Although sure factors may increase the risk of both severe covid-19 and long covid, some factors associated with covid-19 do non also increment risk for long covid. Male sexual practice and older historic period are associated with an increased risk of severe covid-19, still, the ONS reported that the prevalence of any long covid symptoms is higher in women compared with men (23.6% versus 20.vii%), while the age grouping estimated to be most profoundly affected by long covid symptoms is 35-49 years (26.eight%), followed by 50-69 years (26.1%), and the ≥70 years group (xviii%).53 Furthermore, a prospective accomplice study assessing recovered patients constitute no baseline clinical features associated with the subsequent development of long covid symptoms.154 Male sex, age, and pre-existing atmospheric condition including obesity, diabetes, and cardiovascular disease accept shown no association with the risk of developing long covid. However, pre-existence of asthma has been establish to be significantly associated with long covid.34
Treatment and management of long covid
WHO and the Long Covid Forum Group concord that research priorities for long covid include improving clinical characterization and the inquiry and development of therapeutics.155156 Clinical characterization of patients with long covid is essential to provide appropriate treatment options. Gaining an agreement 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 condition may actually be 4 unlike syndromes.102 Recognizing which patients belong to which subgroup of long covid, and understanding the pathophysiology, will be of import in deciding the treatment they receive.
Guidelines
Various guidelines focus on treating and managing long covid, or have included recommendations for long covid in their guidelines for treating covid-nineteen.9 Guidelines recommend how to place, refer, and care for patients with long covid. The holistic assessment, investigation, and management approaches suggested by NICE9 are outlined in fig 3. In January 2021, WHO updated its covid-xix guidance to include a new chapter focused on caring for patients post-covid-19.157 These guidelines go into little item about long covid, however. 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 shortly.159 The European Society of Cardiology has besides released guidelines on the diagnosis and management of cardiovascular disease during the pandemic.160 The guidelines for treating and managing long covid volition undoubtedly evolve equally new evidence comes to light; however, other full general guidelines, such equally Evidence Based Medicine's guidance on mail service-infectious syndromes may exist 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 test suited to the person's ability, for example the 1 minute sit down-to-stand test, and treatment and management should be multidisciplinary, with advice and education given on managing breathlessness. Furthermore, the guidelines recommend offering patients with continuing respiratory symptoms a chest radiograph by 12 weeks after infection.nine Blood oxygen levels can be monitored using a pulse oximeter.
Recommendations from the Mayo Clinic suggest that shortness of breath can be self-managed by limiting factors that exacerbate dyspnea, including stopping smoking, avoiding pollutants, avoiding extremes in temperature, and exercising,162 however, chronic shortness of breath may require further intervention. Recognized non-pharmacological strategies for managing dyspnea include breathing exercises,163 pulmonary rehabilitation,164 and maintaining optimal torso positioning for postural relief.165 Meanwhile, a systematic review has found that oral opioids can be used to treat dyspnea,166 therefore this class of drugs may testify useful for treating the condition in people with long covid.
Patients with pulmonary fibrosis resulting from covid-xix should exist managed in accordance with Nice 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 exist considered.170 Modified rehabilitation practices, including stretching, body rotations, acupressure, and massage accept shown benign long term effects on respiratory symptoms in mild covid-19 patients in a small trial.171
Cardiovascular symptoms
The NICE guidelines on long covid state that exercise tolerance tests may exist undertaken to mensurate heart role, while lying and continuing blood pressure level and eye charge per unit recordings should be performed if postural orthostatic tachycardia syndrome (POTS) is suspected.9 Urgent referral should occur for people that take symptoms of a life threating complexity, such as cardiac chest pain.
The European Lodge of Cardiology has released comprehensive guidance for the diagnosis and management of cardiovascular affliction during the covid-19 pandemic.160 The range of cardiovascular conditions that tin can manifest in long covid translates to a wide range of potential therapeutic options, therefore, ongoing investigation and observation of cardiac biomarkers is important. Overnice guidelines recommend β blockers for several cardiac complaints, including angina,172 cardiac arrhythmias,173 and astute coronary syndromes,174 therefore, β blockers may be useful in the treatment of cardiovascular manifestations of long covid. Myocarditis may resolve naturally over fourth dimension; however, supportive and/or immunomodulating therapy may improve recovery, as a systematic review describes.175 A review has as well suggested that anticoagulants may be used to reduce the risks associated with hypercoagulability.176 Meanwhile, advice and pedagogy, 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 treatment of POTS.89177
Treating fatigue, cognitive, and neuropsychiatric symptoms
Chronic fatigue is a common manifestation of long covid. NICE recommends that self-management and support are important in managing fatigue, attributable to the poor availability of covid-19 specific treatment.9 A condition that may overlap with long covid fatigue is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), therefore, the treatment algorithm designed for treating ME/CFS may bear witness useful in treating post-covid-xix fatigue. NICE has specific guidelines that outline how to refer and care for ME/CFS patients; these include cerebral behavioral therapy (CBT) and graded practise therapy (Go).178 Following backfire over these guidelines from the ME Clan,179 nevertheless, NICE aims to publish revised guidelines in August 2021.180
Randomized controlled trials have shown that CBT is benign in the treatment of chronic fatigue,181 however, this is conflicted by findings from a re-assay of a Cochrane review which question its effectiveness and evidence a high incidence of adverse events. This re-analysis study states that if a trial of a drug or surgical procedure demonstrated similarly high rates of adverse effects, so it would not be accustomed as a safe handling pick, therefore CBT should have to adhere to the same level of scrutiny.182
Another direction strategy for fatigue is pacing, whereby patients manage tasks and activities to avert over-exertion and exacerbating fatigue. NICE guidelines for ME/CFS178 depict pacing as a cocky-management strategy, still guidance and education from healthcare professionals may be useful for patients. Testify from randomized controlled trials for the employ of pacing in long covid is yet to be seen.
The implementation of group therapy via videoconferencing in people with early psychosis during the covid-19 pandemic shows promising results, with a pilot written report showing improvements in psychotic symptoms and self-esteem,183 nonetheless, a review article provides information to advise that CBT is ineffective in reducing long covid symptoms, including fatigue, with only 10% of participants achieving clinically meaningful improvements.184
Become is a structured intervention plan consisting of concrete activities with a therapeutic goal.185 A systematic review of exercise therapy for CFS concluded that patients with ME/CFS generally feel less fatigued and take improved sleep and physical function post-obit completion of do therapy, to a greater degree than following a program of either adaptive pacing or supportive listening.186 The NICE guidelines on ME/CFS recommend GET; all the same, in July 2020 Dainty released a statement urging caution when implementing Go for people recovering from covid-19, stating that with guidelines currently existence updated, these recommendations may change.187 This statement accompanies concerns over the potential negative effects of Get, including post-exertional malaise.188
Evidence specific to covid-19 is defective, therefore cognitive impairment should be managed with back up, including setting tailored, achievable goals and implementing validated screening tools.ix Managing cerebral harm volition require a holistic arroyo, notwithstanding, patients should exist brash that most people gradually recover from cognitive impairment post-obit severe illness.106189 The holistic arroyo to treatment should extend to the services offered, with professionals including occupational and spoken language and language therapists addressing cognitive changes.190 Cognitive impairment in long covid, sometimes called "brain fog," has been compared to "chemobrain."191 The Mayo clinic recommendations suggest 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 be 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 just clinical trials are required.
Slumber disturbances may exist managed past following relevant guidelines on insomnia,193 and a range of handling strategies tin can be considered.194195196197 Patients with mental health problems alongside or equally a issue of long covid can exist managed following the relevant guidelines: low,198 anxiety,199 PTSD,200 obsessive-compulsive disorder,201 and other mental health problems.202 Intendance domicile residents, including those with dementia, who acquire long covid have additional needs.116 Discussing mental health problems with patients requires compassion and understanding.203
Treating other organ impairments
Current evidence for the recovery of renal function following covid-nineteen is lacking. Because that early on and close follow-ups with nephrologists take previously been benign,204 post-covid-19 patients with renal dysfunction may benefit from early and ongoing monitoring. Covid-nineteen tin can disrupt and alter the microbiome of the gut, which may allow for opportunistic infections.145 Covid-19 associated subversive thyroiditis tin result in incident hyperthyroidism, which can be treated with corticosteroids.142 Overall, close follow-up of patients with long covid and acceptable investigative procedures should be kept upwardly to accurately diagnose and treat specific symptoms.
Repurposing drugs for long covid
Antihistamines take been implicated as a possible handling for covid-nineteen, with a report that employed cellular experiments suggesting that histamine-1 antagonists may be able to reduce the covid-19 infection charge per unit by inhibiting SARS-CoV-2 from entering ACE2 expressing cells.205 Systematic reviews and molecular studies have suggested that histamine-1 and histamine-two antagonists are feasible candidates for further clinical trials in covid-19.206207208 It remains to be seen whether antihistamines take potential for treating long covid. Antidepressants accept been proposed to reduce the effects of long covid. Antidepressant utilise has been associated with reduced risk of intubation or death in covid-19,209 while a meta-analysis of antidepressant drug handling for major depressive disorder has shown that apply 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 care for respiratory conditions in long covid are ongoing. A trial of breathing exercises and singing is also under style to assess their utility in improving breathing abnormalities in patients with long covid (NCT04810065).
A trial to assess the effectiveness of an 8 week practise program 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 high dose intravenous vitamin C could be a beneficial handling option.211 LOVIT-COVID (NCT04401150) is an ongoing clinical trial aimed at assessing the effects of high dose intravenous vitamin C on hospitalized patients with covid-19.
Two trials examining the effects of nicotinamide riboside, a dietary supplement, are ongoing (NCT04809974, NCT04604704) with the expectation that the molecule reduces cognitive symptoms and fatigue past modulating the pro-inflammatory response.212
A clinical trial is currently ongoing assessing the effectiveness of a probiotic supplement to normalize the limerick of the gut microbiome and reduce inflammation in long covid (NCT04813718). The agreement of long term sequalae of covid-19 infection in the gastrointestinal tract volition evolve, with studies currently ongoing (NCT04691895), which will later bear upon treatment.
Other potential treatments are molecules that suppress the intense inflammatory response seen in covid-19. Leronlimab is a monoclonal antibody that blocks the function of CCL-five. Information technology has been shown to be effective and rubber in HIV213 and reduces plasma interleukin-half-dozen levels in covid-19.214 Clinical trials are ongoing to evaluate the efficacy of leronlimab post-covid-19 (NCT04343651, NCT04347239, NCT04678830). Another antibiotic treatment, tocilizumab, blocks interleukin-6 receptors and has shown efficacy in a pocket-size trial of patients with covid-19 patients.215 Trials to explore the effects of tocilizumab are ongoing (NCT04330638). The anti-oxidative and anti-inflammatory function of melatonin may also 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 business concern. Here, we have reviewed the studies that have explored the persisting symptoms of long covid, and have addressed the possible 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 will have on the incidence and severity of long covid nonetheless looming large, information technology is important that research continues to explore mail-covid-xix syndrome. Greater agreement of the pathogenesis, run a risk factors, symptoms, and methods of treating long covid is required to reduce the strain and demand on people with the condition and the healthcare systems that will endeavor to support them.
How patients were involved in the creation of this commodity
Members of a long covid focus group 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 unlike symptoms experienced past patients with long covid. Cognition and mental wellness were of particular interest to patients, which nosotros have addressed in this article.
Research Questions
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What is the precise epidemiology of long covid and how will novel variants of covid-19 affect the epidemiology and severity of long covid?
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What are the major take a chance factors for long covid and how do we all-time reduce an individual's risk of developing long term post-covid-xix symptoms?
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Which symptoms, or set of symptoms, tin can nosotros use to classify long covid, clinically and phenotypically, with the aim of improving diagnosis and management?
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What is the optimal treatment and direction strategy for long covid and is this strategy not-specific or volition information technology require targeting and tailoring to specific patients?
Footnotes
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Land of the Art Reviews are commissioned on the ground of their relevance to academics and specialists in the U.s.a. and internationally. For this reason they are written predominantly past US authors
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Contributors: HC, SR, JN, and MY performed the primary literature search and drafted parts of the manuscript; HC was the first author of the manuscript who drafted the manuscript and revised it; PE was responsible for the concept and design of the work. PE reviewed and revised the manuscript. PE is the guarantor.
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Competing interests: We take read and understood the BMJ policy on declaration of interests and declare the following interests: PE was funded by the Medical Inquiry Quango and now by Higher Educational activity Funding Council for England (HEFCE). He has also received grants from Alzheimer's Enquiry, UK, Alzheimer'due south Drug Discovery Foundation, Alzheimer's Society, UK, Medical Enquiry Quango, Alzheimer's Clan United states of america, Van-Geest foundation, and European union grants. PE is a consultant to Roche, Pfizer, and Novo Nordisk. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Gorging Radiopharmaceuticals and Eli Lilly. He is a fellow member of the Scientific Advisory Board at Novo Nordisk.
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Provenance and peer review: deputed; externally peer reviewed.
This commodity is fabricated freely available for use in accord with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise adamant past BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and information mining) provided that all copyright notices and merchandise marks are retained.
https://bmj.com/coronavirus/usage
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