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Clinical Review State of the Art Review Long covid—mechanisms, hazard factors, and direction
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1648 (Published 26 July 2021) Cite this as: BMJ 2021;374:n1648 Read our latest coverage of the coronavirus pandemic
- Harry Cheat , enquiry assistant1,
- Sanara Raza , research assistant1,
- Joseph Nowell , research bananai,
- Megan Young , clinical inquiry officer1,
- Paul Edison , clinical senior lecturer , honorary professor12
- 1Faculty of Medicine, Imperial Higher London, London, UK
- 2Cardiff University, Cardiff, Uk
- Correspondence to P Edison paul.edison{at}imperial.ac.great britain
Abstract
Since its emergence in Wuhan, Mainland china, covid-19 has spread and had a profound upshot on the lives and wellness 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. Recent evidence has shown that a range of persistent symptoms tin can remain long after the acute SARS-CoV-two infection, and this condition is now coined long covid past recognized research institutes. Studies have shown that long covid tin can affect the whole spectrum of people with covid-19, from those with very balmy acute disease to the most severe forms. Like acute covid-xix, long covid tin involve multiple organs and tin can bear on many systems including, simply not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, 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-19 and long covid and possible therapeutic options are also discussed.
Introduction
Coronavirus disease 2019 (covid-nineteen) has spread across the globe. Every bit of 4 July 2021, more than 183 meg confirmed cases of covid-19 have been recorded worldwide, and more than three.97 million deaths accept been reported by the Earth Health Arrangement .i The clinical spectrum of covid-19 ranges from asymptomatic infection to fatal disease.23 The virus responsible for causing covid-19, severe 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 by diverse cytokines in some patients.five The ACE2 receptor is present in numerous cell types throughout the human being body, 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-two can cause impairment to multiple organs.67
The impact of covid-nineteen thus far has been unparalleled, and long term symptoms could have a further devastating effect.8 Recent evidence shows that a range of symptoms can remain after the clearance of the acute infection in many people who have had covid-xix, and this condition is known as long covid. The National Plant for Health and Care Excellence (Dainty) defines long covid as the symptoms that go along or develop after acute covid-19 infection and which cannot be explained past an culling diagnosis. This term includes ongoing symptomatic covid-xix, from iv to 12 weeks postal service-infection, and postal service-covid-19 syndrome, beyond 12 weeks post-infection.9 Conversely, The National Institutes of Health (NIH) uses the U.s. Centers for Disease Control and Prevention (CDC) definition of long covid, which describes the condition every bit sequelae that extend beyond 4 weeks after initial infection.x People with long covid exhibit involvement 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 can exist seen in fig 1. Long term symptoms following covid-xix take been observed beyond the spectrum of disease severity. This review examines the long term touch on of symptoms reported post-obit covid-19 infection and discusses the current epidemiological understanding of long covid, the hazard factors that may predispose a person to develop the status, and the treatment and direction 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. One time these cells have been invaded, the virus tin cause a multitude of harm ultimately leading to numerous persistent symptoms, some of which are outlined here
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Methods
Nosotros searched PubMed and Embase databases for manufactures published between Jan 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 "knowledge" or "cognitive impairment" or "mental health" or "depression" or "feet" or "psychiatric" or "cardinal nervous system" or "autonomic nervous system" or "isolation" or "loneliness" or "sleeplessness" or "slumber" or "scent" or "taste" or "olfactory" or "gustatory" or "hazard factors" or "treatment". To avoid unintentionally removing articles, no filters were applied. We retrieved 61 881 articles in the first instance. To screen articles, titles were read past authors first, followed by abstracts to further narrow down the number of records considered. To avoid unnecessary exclusion of studies, express exclusion and inclusion criteria were applied. We excluded papers that were not relevant to or did not mention long covid, while studies mentioning long covid in any capacity were initially included owing to the novelty of the field. Furthermore, we considered long covid studies regardless of their cohort sizes or report design. We discovered and read fully 227 articles on long covid, and we discussed each to determine which would be included in the finalized article. We performed farther manual searching for additional articles and treatment guidelines using relevant databases, including squeamish.org.united kingdom of great britain and northern ireland and clinicaltrials.gov. In total, 218 references were included. Studies examining long covid are limited, therefore limited exclusion criteria were practical.
Studies of long covid
Studies take assessed people who have had covid-19 to examine the symptoms associated with long covid. These studies are summarized in table ane. The articles included throughout this review were selected in favor of quality, with large observational studies of greatest involvement. Most of the studies included are cross-sectional or accomplice observational studies with large cohorts; however, considering of the novelty of the disease and paucity of data, studies involving smaller cohorts and case series were also included. Any patient with covid-xix 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-nineteen.17 The proportion of people that develop long covid symptoms, whether they are treated with oxygen lonely, with continuous positive airway pressure, or with invasive ventilation, is like.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 between hospitalized and non-hospitalized covid-19 patients.19
Table i
Summary of studies that have explored the persisting symptoms post-covid-19 infection, or during long covid
Epidemiology
The reported incidence and mortality rates of covid-19 vary betwixt countries, making it hard to accurately predict the number of patients who will progress to long covid. Similarly, the accurate reporting of long covid is complicated. The disparity in this epidemiological data is probable the event of several factors, including differences in the base of operations 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 volume of published literature describing cases of patients with covid-19 who afterward develop long covid symptoms is continually growing, which will allow 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 period, population assessed, accuracy of self-reporting, and symptoms examined. Studies effectually the earth take reported diverse incidence rates for long covid with different follow-up examination times subsequently the acute infection, including 76% of people at 6 months,50 32.6% at threescore days,51 87% at 60 days,15 and 96% at 90 days.52 These finding are not fully corroborative, but they show that a substantial proportion of people who have had covid-nineteen may develop long covid. The UK Part for National Statistics (ONS) has released data 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 fourteen December 2020 was 22.1%, while the 12 calendar week prevalence was ix.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-xix variants of business organisation
Since the get-go of the pandemic, several covid-xix variants have emerged that take an increased transmissibility and may result in more severe acute disease. In the UK, one of the first variants of business organisation to appear was the so called "Kent variant," from the B.i.1.7 lineage, now termed the Alpha variant. This variant has approximately 50% increased transmissibility54 and likely increases acute affliction severity.55 Equally of 30 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 concern or under investigation include the Beta, Gamma, Zeta, Theta, and Kappa variants.56 The CDC reports the emergence of variants of business organization and interest in the US.58 New covid-nineteen variants will continue to emerge and spread as we progress through the pandemic, for case, the Eta and Delta variants have arisen, with over 161 000 cases of the rapidly spreading Delta variant confirmed in the UK, as of 30 June 2021.56 Recently, the Lambda variant has emerged, which volition crave close monitoring. The ability of these viral strains to inflict long term complications needs to exist examined fully. To speculate, it may exist that one variant causes more than dissentious long term effects than others and, therefore, patients infected with such a variant who go on to develop long covid symptoms may require boosted back up, besides 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 5 May 2020 in BMJ Stance where an communicable diseases professor shared his experience of seven weeks on a "rollercoaster of sick health" following covid-19.59 The patient-made term long covid was so made popular following the rise in the use of #LongCovid on Twitter.60 This, plus the growing number of peer reviewed articles published since, has highlighted a post-covid-19 syndrome that can last for many weeks after the acute infection. Long covid is now a recognized term in scientific literature. The Prissy 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-xix that persist beyond four weeks from initial infection.
Symptoms
Fatigue
Fatigue is more profound than being overtired; it is unrelenting exhaustion and a abiding state of weariness that reduces a person'due south energy, motivation, and concentration. Following the SARS outbreak, up to 60% of patients reported ongoing fatigue at 12 months post-obit recovery from the acute illness.61 In long covid, fatigue is one of the most reported manifestations, with the ONS estimating the v week prevalence of fatigue to exist 11.9% amid people who take had covid-nineteen.53 Fatigue is a common persisting symptom regardless of severity of the astute phase of covid-19. One cross-sectional report plant that 92.9% and 93.5% of hospitalized and non-hospitalized covid-nineteen patients, respectively, reported ongoing fatigue at 79 days following onset of illness.xix Many other cross-sectional and cohort studies report that chronic fatigue is the nearly frequently reported symptom post-obit recovery from acute covid-19,1517202743 with one showing no clan betwixt covid-19 severity and long term fatigue.20 These findings show that fatigue is a major manifestation of long covid.
Possible mechanisms
Chronic fatigue post-obit viral infection may exist the effect of miscommunication in the inflammatory response pathways62; however, a cross-exclusive belittling study found no association between pro-inflammatory markers and long term fatigue in covid-19 patients with persisting fatigue.20 It is likely that a range of key, peripheral, and psychological factors play a role in the development of post-covid-19 fatigue. A narrative review explains that congestion of the glymphatic organization and the subsequent toxic build-upwards within the fundamental nervous system (CNS), caused by an increased resistance to cerebrospinal fluid drainage through the cribriform plate as a consequence of olfactory neuron harm, may contribute to mail-covid-nineteen fatigue.63
Hypometabolism in the frontal lobe and cerebellum has besides been implicated in covid-xix patients with fatigue and is probable caused by systemic inflammation and cell mediated immune mechanisms, rather than direct viral neuro-invasion.6465 It is unknown whether this finding continues into long covid.
Negative psychological and social factors associated with the covid-nineteen pandemic have 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 musculus fibers and neuromuscular junctions may contribute to fatigue.68697071 Overall, it is probable that several factors and mechanisms play a role in the development of mail service-covid-nineteen fatigue. Figure 2 further outlines these possible mechanisms.
Fig two
Long term sequalae of covid-nineteen
(1) In the alveoli of the lungs: (A) Chronic inflammation results in the sustained product 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 effect in the development of a prolonged hyperinflammatory and hypercoagulable state, increasing the risk of thrombosis.
(2) In the center: (A) chronic inflammation of cardiomyocytes can result in myositis and cause cardiomyocytes death. (B) Dysfunction of the afferent autonomic nervous organization 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 by an increase in cardiac fibromyoblasts, while damage to desmosomal proteins results in reduced cell-to-cell adhesion.
(iii) In the primal nervous system: (A) The long term immune response activates glial cells which chronically damage neurons. (B) Hyperinflammatory and hypercoagulable states lead to an increased risk of thrombotic events. (C) Blood-encephalon 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. (E) The furnishings of long covid in the brain can lead to cognitive impairment.
(4) Possible mechanisms causing mail-covid-xix fatigue. A range of cardinal, peripheral, and psychological factors may cause chronic fatigue in long covid. Chronic inflammation in the brain, too as at the neuromuscular junctions, may result in long term fatigue. In skeletal muscle, sarcolemma harm and fiber atrophy and damage may play a office in fatigue, as might a number of psychological and social factors
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Mail service-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 immune symptoms, with both ME/CFS and long covid patients having long symptom durations, reduced daily activity, and post-exertional malaise.72 ME/CFS remains enigmatic, therefore, research 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.six% at five weeks postal service-covid-19 infection, regardless of presence of astute respiratory symptoms or affliction severity.53 Abnormalities in improvidence capacity for carbon monoxide, total lung capacity, forced expiratory volume in the showtime second, forced vital capacity, and small airway role, have been seen in hospitalized covid-19 patients at time of belch, approximately one month following onset of symptoms, showing that lung office in people who accept had covid-19 may take time to recover.73 Several studies take found that dyspnea is a mutual manifestation post-obit covid-19 infection,1617 and one study reported that 43.4% of 143 patients assessed were even so experiencing dyspnea at 60 days subsequently covid-19 onset.fifteen
Possible mechanisms
As covid-nineteen is principally a respiratory affliction, acute disease tin can cause substantial harm to the lungs and respiratory tract via SARS-CoV-2 replication inside endothelial cells, resulting in endothelial impairment and an intense immune and inflammatory reaction.7475 Those who overcome the acute infection may develop long term lung abnormalities, leading to dyspnea76; nevertheless, most individuals who develop long term breathing difficulties post-covid-19 have no signs of permanent or longlasting lung harm.2877 It is probable that merely those at high risk of developing breathing difficulties, including older people, those who endure acute respiratory distress syndrome, those who accept extended infirmary stays, and those with pre-existing lung abnormalities, are prone to develop fibrotic-like changes to lung tissue.78 The fibrotic land observed in some patients with ongoing dyspnea may be provoked by cytokines such as interleukin-vi, which is raised in covid-1979 and is involved in the germination of pulmonary fibrosis.fourscore Pulmonary vascular thromboembolisms have been observed in patients with covid-1981 and may accept 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 chance of mortality in patients admitted to hospital with astute covid-nineteen 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 large case series showed that chest pain, possibly owing to myocarditis, was a common manifestation in patients sixty.three days following onset of covid-nineteen symptoms, with 21.7% of the 143 patient assessed reporting breast hurting.15 Those considered at low take chances of severe covid-19, such equally young, competitive athletes, have as well been establish to have rest myocarditis long later recovery from covid-nineteen.84 In improver to cardiac complaints, studies accept highlighted an emerging trend in the development 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 eye,ninety providing a directly route of infection for SARS-CoV-ii. Studies have shown that sarcomere disruption and fragmentation, enucleation, transcriptional changes, and an intense local allowed response occurs in cardiomyocytes infected by SARS-CoV-2.9192 Pathological responses to acute cardiac injury and viral myocarditis, such as endothelial impairment and microthrombosis, can lead to the development of coagulopathy,93 while chronic hypoxia and an increase in pulmonary arterial pressure level and ventricular strain may farther precipitate the incidence of cardiac injury in people who take had covid-19.94 Furthermore, sustained immune activation tin 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 past SARS-CoV-two may accept direct negative consequences on the autonomic nervous system.98 A circuitous 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 two depicts these mechanisms.
Cognition and mental health
Studies have explored cognitive function and deficits in patients with covid-19 and suggest that the virus can cause septic encephalopathy, not-immunological effects such as hypotension, hypoxia, and vascular thrombosis, and immunological effects such as adaptive autoimmunity, microglial activation, and a maladaptive cytokine contour.99 Additionally, patients admitted to infirmary with covid-19 have presented with a range of complaints including encephalopathy, cognitive damage, cerebrovascular events/disease, seizures, hypoxic brain injuries, corticospinal tract signs, dysexecutive syndrome, an altered mental status, and psychiatric conditions.24100101 These findings reveal that neurological symptoms associated with covid-nineteen are common, various, and could pose substantial problems for rehabilitation and ongoing care following recovery from covid-xix. Information technology is unknown who is most affected by cognitive 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 disease, severe astute respiratory syndrome, and long term ventilator back up are known to have detrimental effects on long term noesis. Before the covid-19 pandemic, a retrospective report of 1040 ICU treated patients who had respiratory failure, shock, or both during hospital stays, found that 71% had delirium which lasted around four months following discharge.105 A similar study institute that, at 3 months postal service-discharge, twoscore% of ICU treated patients had knowledge scores similar those of patients with moderate traumatic brain injury, while 26% had scores similar to patients with mild Alzheimer's disease. Delirium was also 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 impairment and delirium are probable to pose considerable problems.
Stroke and headache are prevalent in those recovered from acute covid-19, with the ONS estimating the 5 week prevalence of headache at 10.ane% of all covid-xix 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-19 has as well been associated with an increased risk of developing neurological conditions including Guillain-Barré syndrome,109 and neurodegenerative atmospheric condition such as Alzheimer's illness.110
The pandemic has had a negative effect on mental health, with people who take had covid-19 exhibiting long term psychiatric symptoms including post-traumatic stress disorder (PTSD), depression, anxiety, and obsessive-compulsive symptoms post-obit recovery from the astute infection.3637111112 Quarantine, isolation, and social distancing as well accept dissentious effects on mental wellness 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 lead to avoidance behaviors and behavioral changes.113 The mental health of the older population is greatly afflicted by social distancing and similar measures. Past assessing the associations betwixt loneliness, physical activity, and mental health both before and during the pandemic, one report found that negative changes of these factors were not solely attributable 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-19 and to other impacts of the pandemic. Those with dementia in care homes have been observed to go more than depressed, broken-hearted, agitated, and lone.115 Protracted social isolation has resulted in exacerbation of neuropsychiatric and behavioral disturbances, including aloofness, anxiety, agitation, boredom, and confusion in dementia patients living in care homes, to a greater degree than for intendance dwelling residents without dementia.116117
Sleeplessness is also commonly reported post-obit recovery from covid-19, with many studies finding poor slumber quality and sleep disturbances to be frequent following recovery from acute disease.16253144118119 Furthermore, a retrospective study of medical records of covid-19 patients treated in Seoul, S Korea, found that after prescriptions to treat fever, cough, and rhinorrhea, medications for sleep issues were the adjacent most prescribed treatments.120 Knowledge of the covid-19 death toll also has a negative impact on quality of sleep, stress, anxiety, and other negative emotions,121 and sleep problems accept been shown to be associated with covid-19 related loneliness.122 This leads us to question whether post-covid-19 slumber disturbances are a event of covid-xix infection, the negative furnishings of the pandemic, or a combination of both.
Possible mechanisms
Coronaviruses including SARS-CoV-ii can infect the central nervous organisation (CNS) via hematogenous or neuronal retrograde neuro-invasive routes.123 The entry machinery and subsequent CNS infection may explain the high incidence of neuro-inflammation seen in patients with covid-19, and may event in damaging long term effects, with associations of viral infections and chronic neuro-inflammation with neurodegenerative and psychiatric disorders already elucidated.123124 SARS-CoV-2 may too affect 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 post-obit critical illness and invasive handling.127 Evidence suggests that a directly viral encephalitis, systemic inflammation, peripheral organ dysfunction, and cerebrovascular changes may contribute to the evolution of long term sequalae following covid-19.128Figure ii outlines the potential mechanisms occurring within the CNS.
Olfactory and gustatory dysfunction
Abnormalities of aroma and taste have been reported to persist following recovery from covid-19. The ONS estimated the 5 week prevalence of loss of aroma and loss of taste as seven.9% and 8.2% of all people who have had covid-nineteen, respectively.53 Other studies have institute varying prevalence of olfactory and gustatory dysfunction, ranging from 11% to 45.i% of cohorts of patients who have recovered from acute covid-xix.223947
Possible mechanisms
Non-neuronal expression of the ACE2 receptor may enable entry of the SARS-CoV-two virus into olfactory support cells, stem cells, and perivascular cells. This local infection could cause an inflammatory response which afterwards reduces the office of olfactory sensory neurons. Additionally, by damaging the back up cells responsible for local h2o and ionic balance, SARS-CoV-two may indirectly reduce signaling from sensory neurons to the brain,129 resulting in a loss of sense of smell.
ACE2 receptors are also expressed on the mucous membrane of the oral cavity, particularly on the natural language,130 therefore SARS-CoV-two has a direct route of entry into oral tissue, which may result in cellular injury and dysfunction. Moreover, SARS-CoV-2 may bind 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-nineteen and long covid concerns the functional link between taste and olfactory property, 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 gamble for severe acute illness.213 Studies evidence the presence of acute kidney injury in discharged patients who take recovered from covid-19.134135136 Although the long term effects of covid-nineteen on the kidneys are not 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.50
Acutely, pancreatitis triggered by SARS-CoV-ii has been seen in people with covid-19,6137 while serum amylase and lipase levels take been observed to be higher in people with astringent illness compared with balmy cases, and computed tomography images have shown pancreatic injury.138 A cantankerous exclusive study constitute that twoscore% of patients with covid-19 who were at low take a chance of astringent disease, assessed 141 days post-obit infection, had mild impairment of the pancreas. This harm was associated with diarrhea, fever, headache, and dyspnea.thirteen Postmortem and case studies have highlighted the impact that covid-19 has on the spleen, including cloudburst of lymphoid follicles, a decrease in T and B lymphocytes leading to lymphocytopenia, and thrombotic events such equally infarcts.139140141 A cross exclusive study found mild impairment of the spleen in 4% of those assessed at 141 days following clearance of covid-19.thirteen Other organs and tissues, such equally the liver, alimentary canal, musculus, and blood vessels limited 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-19, 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; even so, it is unclear whether pancreatic impairment is a direct result of viral infection inside the pancreas, or caused by the systemic inflammatory response seen during covid-xix. 146 The spleen also expresses ACE2 receptors6 and may be straight attacked by the virus, rather than the intense systemic inflammation being the primary cause of splenic damage.139 Chronic systemic inflammation is often observed long afterward the clearance of acute covid-19 infection,13 therefore, information technology is likely that this elevated inflammatory state causes long term complications in multiple organs in people with long covid.
Hazard factors
Risk factors for severe covid-19 and hospital access, and risk factors for expiry equally a issue of covid-19 include older age, male sex, non-white ethnicity, being disabled, and pre-existing comorbidities including obesity, cardiovascular affliction, respiratory disease, and hypertension.21319147148 Linked to chance of covid-19 severity and possibly the take chances of long covid, the role of immune suppression is still being debated. Immune suppression may accept protective furnishings against long term effects of covid-xix infection149150151; nonetheless, these findings are conflicted.152153
The run a 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 betwixt fourteen and 21 days following their positive test. Risk factors for non returning to "usual health" included historic period (P=0.01), with the ≥50 years age group having the greatest odds ratio, and number of pre-existing medical conditions (P=0.003), with a greater number of weather associated with a greater odds ratio of non returning to "usual wellness." Of the pre-existing conditions, having hypertension (odds ratio (OR)=1.three, P=0.018), obesity (OR=two.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 cantankerous sectional study identified an association betwixt the severity of astute covid-19 infection and post-recovery manifestations in people who have had covid-xix, showing that a more severe acute stage may transform into the evolution of more severe symptoms of long covid.43 A cohort report, meanwhile, corroborated this finding, with patients with more five symptoms during the initial covid-19 infection and those that required hospital admission more than likely to experience long covid symptoms.34
Although sure factors may increase the risk of both severe covid-nineteen and long covid, some factors associated with covid-19 practice not as well increase risk for long covid. Male sex and older age are associated with an increased risk of astringent covid-19, however, the ONS reported that the prevalence of any long covid symptoms is college in women compared with men (23.6% versus xx.7%), while the historic period group estimated to exist about profoundly affected past long covid symptoms is 35-49 years (26.8%), followed by 50-69 years (26.1%), and the ≥70 years grouping (xviii%).53 Furthermore, a prospective cohort study assessing recovered patients plant no baseline clinical features associated with the subsequent evolution of long covid symptoms.154 Male sex, age, and pre-existing weather condition including obesity, diabetes, and cardiovascular disease have shown no association with the hazard of developing long covid. However, pre-being of asthma has been found to exist significantly associated with long covid.34
Treatment and management of long covid
WHO and the Long Covid Forum Group agree that inquiry 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 advisable 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 condition may actually exist four different syndromes.102 Recognizing which patients belong to which subgroup of long covid, and agreement the pathophysiology, will be important in deciding the handling they receive.
Guidelines
Various guidelines focus on treating and managing long covid, or take included recommendations for long covid in their guidelines for treating covid-19.9 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 January 2021, WHO updated its covid-19 guidance to include a new chapter focused on caring for patients post-covid-19.157 These guidelines get into niggling detail almost long covid, however. Similarly, the NIH has released treatment guidelines for covid-19,158 only little guidance on managing long covid. The CDC is expected to release guidance on long covid management presently.159 The European Society of Cardiology has also released guidelines on the diagnosis and direction of cardiovascular disease during the pandemic.160 The guidelines for treating and managing long covid volition undoubtedly evolve as new testify comes to lite; however, other general guidelines, such equally Evidence Based Medicine'due south guidance on postal service-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 test suited to the person's ability, for instance the ane minute sit-to-stand test, and treatment and management should be multidisciplinary, with communication and educational activity given on managing breathlessness. Furthermore, the guidelines recommend offer patients with continuing respiratory symptoms a breast radiograph by 12 weeks after infection.9 Blood oxygen levels tin can be monitored using a pulse oximeter.
Recommendations from the Mayo Clinic suggest that shortness of breath tin be self-managed past limiting factors that exacerbate dyspnea, including stopping smoking, avoiding pollutants, avoiding extremes in temperature, and exercising,162 nevertheless, chronic shortness of breath may require further intervention. Recognized not-pharmacological strategies for managing dyspnea include breathing exercises,163 pulmonary rehabilitation,164 and maintaining optimal trunk positioning for postural relief.165 Meanwhile, a systematic review has found that oral opioids can exist used to treat dyspnea,166 therefore this class of drugs may prove useful for treating the condition in people with long covid.
Patients with pulmonary fibrosis resulting from covid-19 should be managed in accordance with NICE guidelines on idiopathic pulmonary fibrosis,167 while antifibrotic therapies may be advantageous.168 Exacerbations of bronchiectasis should be treated with antimicrobial prescribing,169 while non-antimicrobial therapies, including airway clearance, may exist considered.170 Modified rehabilitation practices, including stretching, trunk rotations, acupressure, and massage have shown benign long term effects on respiratory symptoms in mild covid-nineteen patients in a small trial.171
Cardiovascular symptoms
The Overnice guidelines on long covid state that exercise tolerance tests may be undertaken to mensurate centre function, while lying and standing blood pressure and heart rate recordings should be performed if postural orthostatic tachycardia syndrome (POTS) is suspected.nine Urgent referral should occur for people that take symptoms of a life threating complexity, such every bit cardiac breast pain.
The European Society of Cardiology has released comprehensive guidance for the diagnosis and management of cardiovascular illness during the covid-19 pandemic.160 The range of cardiovascular conditions that can manifest in long covid translates to a wide range of potential therapeutic options, therefore, ongoing investigation and ascertainment of cardiac biomarkers is of import. Dainty 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 time; nevertheless, supportive and/or immunomodulating therapy may improve recovery, as a systematic review describes.175 A review has also suggested that anticoagulants may be used to reduce the risks associated with hypercoagulability.176 Meanwhile, advice and education, agents to maintain vascular tone, and agents to manage palpitations take been shown by a randomized controlled trial and discussed in a review to be advantageous in the treatment of POTS.89177
Treating fatigue, cerebral, and neuropsychiatric symptoms
Chronic fatigue is a mutual manifestation of long covid. NICE recommends that self-management and support are important in managing fatigue, owing to the poor availability of covid-19 specific treatment.ix A status 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 prove useful in treating postal service-covid-nineteen fatigue. Dainty has specific guidelines that outline how to refer and care for ME/CFS patients; these include cognitive behavioral therapy (CBT) and graded exercise therapy (GET).178 Following backfire over these guidelines from the ME Association,179 however, NICE aims to publish revised guidelines in August 2021.180
Randomized controlled trials have shown that CBT is beneficial in the treatment of chronic fatigue,181 notwithstanding, this is conflicted by findings from a re-analysis of a Cochrane review which question its effectiveness and show a high incidence of adverse events. This re-assay study states that if a trial of a drug or surgical procedure demonstrated similarly high rates of adverse furnishings, and so it would not be accepted as a condom handling option, therefore CBT should have 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. Squeamish guidelines for ME/CFS178 describe pacing equally a cocky-management strategy, even so guidance and education from healthcare professionals may exist useful for patients. Show from randomized controlled trials for the use of pacing in long covid is yet to be seen.
The implementation of grouping therapy via videoconferencing in people with early on psychosis during the covid-xix pandemic shows promising results, with a pilot written report showing improvements in psychotic symptoms and cocky-esteem,183 however, a review article provides information to suggest that CBT is ineffective in reducing long covid symptoms, including fatigue, with only x% 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 ended that patients with ME/CFS mostly feel less fatigued and accept improved slumber and concrete function following completion of practice therapy, to a greater caste than post-obit a programme of either adaptive pacing or supportive listening.186 The Overnice guidelines on ME/CFS recommend GET; however, in July 2020 Prissy released a statement urging caution when implementing Become 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 lacking, therefore cognitive impairment should be managed with support, including setting tailored, achievable goals and implementing validated screening tools.nine Managing cognitive impairment will require a holistic approach, however, patients should be advised that most people gradually recover from cognitive impairment following severe illness.106189 The holistic approach to treatment should extend to the services offered, with professionals including occupational and speech and language therapists addressing cognitive changes.190 Cognitive impairment in long covid, sometimes called "brain fog," has been compared to "chemobrain."191 The Mayo dispensary 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 exist considered.192 These strategies may prove useful for long covid. Specific to long covid, luteolin, a natural flavonoid, may convalesce cerebral damage by inhibiting mast cell and microglia activation,191 simply clinical trials are required.
Sleep disturbances may be managed by post-obit relevant guidelines on insomnia,193 and a range of handling strategies tin be considered.194195196197 Patients with mental wellness issues alongside or equally a result of long covid tin be managed following the relevant guidelines: depression,198 anxiety,199 PTSD,200 obsessive-compulsive disorder,201 and other mental health problems.202 Care home residents, including those with dementia, who acquire long covid take additional needs.116 Discussing mental health issues with patients requires compassion and understanding.203
Treating other organ impairments
Electric current show for the recovery of renal role following covid-19 is lacking. Because that early on and close follow-ups with nephrologists have previously been beneficial,204 post-covid-19 patients with renal dysfunction may benefit from early and ongoing monitoring. Covid-19 can disrupt and alter the microbiome of the gut, which may allow for opportunistic infections.145 Covid-19 associated subversive thyroiditis tin can upshot in incident hyperthyroidism, which can exist treated with corticosteroids.142 Overall, close follow-upwardly of patients with long covid and adequate investigative procedures should be kept upward to accurately diagnose and care for specific symptoms.
Repurposing drugs for long covid
Antihistamines accept been implicated as a possible treatment for covid-19, with a written report that employed cellular experiments suggesting that histamine-i antagonists may be able to reduce the covid-nineteen infection rate by inhibiting SARS-CoV-2 from entering ACE2 expressing cells.205 Systematic reviews and molecular studies accept suggested that histamine-1 and histamine-ii antagonists are viable candidates for further clinical trials in covid-19.206207208 It remains to be seen whether antihistamines have potential for treating long covid. Antidepressants have been proposed to reduce the effects of long covid. Antidepressant use has been associated with reduced risk of intubation or decease in covid-19,209 while a meta-assay of antidepressant drug treatment for major depressive disorder has shown that utilise 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 breathing exercises and singing is besides under fashion to assess their utility in improving breathing abnormalities in patients with long covid (NCT04810065).
A trial to assess the effectiveness of an 8 week practice program in patients with long covid and fatigue is ongoing (NCT04841759). Vitamin C supplementation may bear witness 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.
Ii trials examining the furnishings of nicotinamide riboside, a dietary supplement, are ongoing (NCT04809974, NCT04604704) with the expectation that the molecule reduces cerebral 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-xix infection in the gastrointestinal tract will evolve, with studies currently ongoing (NCT04691895), which volition later on affect handling.
Other potential treatments are molecules that suppress the intense inflammatory response seen in covid-19. Leronlimab is a monoclonal antibiotic that blocks the role of CCL-v. Information technology has been shown to be effective and safe in HIV213 and reduces plasma interleukin-half-dozen levels in covid-nineteen.214 Clinical trials are ongoing to evaluate the efficacy of leronlimab post-covid-xix (NCT04343651, NCT04347239, NCT04678830). Another antibody treatment, tocilizumab, blocks interleukin-6 receptors and has shown efficacy in a minor 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 as well be useful in treating long covid.216 Lastly, adjuvant treatments, such as adaptogens, are being explored for their effectiveness in treating long covid (NCT04795557).
Conclusion
With many people having been infected and continuing to be infected with covid-19, the long term implications are of increasing concern. Hither, we accept reviewed the studies that take explored the persisting symptoms of long covid, and have addressed the possible run a risk factors associated with developing long covid and the handling 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 still looming large, it is important that research continues to explore post-covid-19 syndrome. Greater agreement 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 condition and the healthcare systems that will effort 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 different symptoms experienced by patients with long covid. Cognition and mental health were of item interest to patients, which we have addressed in this article.
Research Questions
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What is the precise epidemiology of long covid and how volition novel variants of covid-19 impact the epidemiology and severity of long covid?
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What are the major risk factors for long covid and how do we best reduce an individual'due south chance of developing long term mail-covid-xix symptoms?
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Which symptoms, or set of symptoms, can we utilize to allocate long covid, clinically and phenotypically, with the aim of improving diagnosis and management?
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What is the optimal treatment and management strategy for long covid and is this strategy not-specific or volition it require targeting and tailoring to specific patients?
Footnotes
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State of the Art Reviews are deputed on the ground of their relevance to academics and specialists in the U.s.a. and internationally. For this reason they are written predominantly by U.s. authors
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Contributors: HC, SR, JN, and MY performed the master 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 piece of work. PE reviewed and revised the manuscript. PE is the guarantor.
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Competing interests: Nosotros have read and understood the BMJ policy on announcement of interests and declare the post-obit interests: PE was funded by the Medical Research Quango and now by Higher Teaching Funding Council for England (HEFCE). He has too received grants from Alzheimer's Research, UK, Alzheimer's Drug Discovery Foundation, Alzheimer'southward Society, United kingdom, Medical Research Quango, Alzheimer's Association US, Van-Geest foundation, and European Marriage 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 Scientific discipline/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He is a member of the Scientific Informational Board at Novo Nordisk.
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Provenance and peer review: commissioned; externally peer reviewed.
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Source: https://www.bmj.com/content/374/bmj.n1648
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