Mercy Clinic Family Medicine Piper Hill Drive St. Peters Mo
Clinical Review State of the Art Review Long covid—mechanisms, adventure factors, and management
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1648 (Published 26 July 2021) Cite this every bit: BMJ 2021;374:n1648 Read our latest coverage of the coronavirus pandemic
- Harry Crook , research assistant1,
- Sanara Raza , research banana1,
- Joseph Nowell , inquiry bananaane,
- Megan Young , clinical research officerane,
- Paul Edison , clinical senior lecturer , honorary professor12
- 1Faculty of Medicine, Purple College London, London, UK
- 2Cardiff University, Cardiff, Great britain
- Correspondence to P Edison paul.edison{at}royal.ac.uk
Abstract
Since its emergence in Wuhan, China, covid-nineteen has spread and had a profound outcome 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 one thousand thousand deaths. Recent testify has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this status is at present coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute illness to the most astringent forms. Similar astute covid-19, long covid can involve multiple organs and can impact many systems including, but non limited 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 pain, concentration issues, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and not-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.
Introduction
Coronavirus illness 2019 (covid-19) has spread beyond the world. Equally of 4 July 2021, more than 183 one thousand thousand confirmed cases of covid-19 accept been recorded worldwide, and more than than 3.97 million deaths accept been reported past the World Health Organization .one The clinical spectrum of covid-19 ranges from asymptomatic infection to fatal disease.23 The virus responsible for causing covid-nineteen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor.4 Once internalized, the virus undergoes replication and maturation, provoking an inflammatory response that involves the activation and infiltration of immune cells by various cytokines in some patients.five The ACE2 receptor is nowadays in numerous cell types throughout the man body, including in the oral and nasal mucosa, lungs, eye, gastrointestinal tract, liver, kidneys, spleen, brain, and arterial and venous endothelial cells, highlighting how SARS-CoV-two can cause harm to multiple organs.67
The impact of covid-xix thus far has been unparalleled, and long term symptoms could have a further devastating effect.viii Recent prove shows that a range of symptoms can remain after the clearance of the acute infection in many people who take had covid-nineteen, and this condition is known equally long covid. The National Constitute for Health and Care Excellence (Prissy) defines long covid as the symptoms that go along or develop after acute covid-xix infection and which cannot be explained by an alternative diagnosis. This term includes ongoing symptomatic covid-xix, from four to 12 weeks post-infection, and post-covid-19 syndrome, across 12 weeks post-infection.nine Conversely, The National Institutes of Health (NIH) uses the Usa Centers for Disease Command and Prevention (CDC) definition of long covid, which describes the condition as sequelae that extend beyond 4 weeks afterwards initial infection.ten People with long covid exhibit interest and impairment in the structure and office of multiple organs.11121314 Numerous symptoms of long covid have been reported and attributed to various organs, an overview of which tin can be seen in fig i. Long term symptoms following covid-19 have been observed across the spectrum of disease severity. This review examines the long term impact of symptoms reported post-obit covid-nineteen infection and discusses the current epidemiological understanding of long covid, the take chances factors that may predispose a person to develop the status, and the treatment and direction guidelines aimed at treating it.
Fig 1
Multi-organ complications of covid-19 and long covid. The SARS-CoV-ii virus gains entry into the cells of multiple organs via the ACE2 receptor. One time 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
We searched PubMed and Embase databases for articles published between January 2020 and May 2021. Our search terms were "long covid" or "post-covid-19" or "COVID long-haulers" or "SARS-CoV-ii" and "epidemiology" or "fatigue" or "fatigue syndrome" or "dyspnoea" or "breathlessness" or "shortness of breath" or "cardiac" or "cardiovascular" or "heart" or "cognition" or "cerebral impairment" or "mental wellness" or "low" or "anxiety" or "psychiatric" or "central nervous organization" or "autonomic nervous organisation" or "isolation" or "loneliness" or "sleeplessness" or "sleep" or "smell" or "taste" or "olfactory" or "gustatory" or "take chances factors" or "handling". To avoid unintentionally removing articles, no filters were applied. Nosotros retrieved 61 881 articles in the outset instance. To screen articles, titles were read past authors first, followed by abstracts to farther narrow down the number of records considered. To avoid unnecessary exclusion of studies, limited exclusion and inclusion criteria were practical. We excluded papers that were non relevant to or did not mention long covid, while studies mentioning long covid in whatsoever capacity were initially included owing to the novelty of the field. Furthermore, we considered long covid studies regardless of their cohort sizes or written report design. Nosotros discovered and read fully 227 articles on long covid, and we discussed each to determine which would be included in the finalized commodity. We performed further manual searching for additional manufactures and treatment guidelines using relevant databases, including squeamish.org.u.k. and clinicaltrials.gov. In total, 218 references were included. Studies examining long covid are express, therefore limited exclusion criteria were practical.
Studies of long covid
Studies accept assessed people who take had covid-19 to examine the symptoms associated with long covid. These studies are summarized in table 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-exclusive or cohort observational studies with large cohorts; nevertheless, because of the novelty of the disease and paucity of data, studies involving smaller cohorts and case series were besides included. Whatever patient with covid-19 may develop long covid, regardless of the severity of their infection and the intensity of the treatment they received. Patients treated on wards and intensive care units (ICUs) show little difference in incidence of long term symptoms associated with covid-19.17 The proportion of people that develop long covid symptoms, whether they are treated with oxygen lonely, with continuous positive airway pressure, or with invasive ventilation, is similar.xvi Many patients with balmy acute symptoms also develop long covid symptoms,13 in fact, studies show minimal differences between the prevalence of long covid symptoms between hospitalized and non-hospitalized covid-xix patients.19
Table 1
Summary of studies that have explored the persisting symptoms mail-covid-19 infection, or during long covid
Epidemiology
The reported incidence and mortality rates of covid-19 vary between countries, making it hard 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 data is likely the result of several factors, including differences in the base population, the accuracy of diagnosis, the reporting systems, and the adequacy 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 understanding of its epidemiology.
The electric current disparities between long covid epidemiology reporting are owing to many reasons, including the length of follow-up menstruation, population assessed, accuracy of self-reporting, and symptoms examined. Studies around the world take reported diverse incidence rates for long covid with different follow-upward examination times afterward the acute infection, including 76% of people at vi months,50 32.half-dozen% at 60 days,51 87% at 60 days,15 and 96% at ninety days.52 These finding are not fully corroborative, but they show that a substantial proportion of people who have had covid-19 may develop long covid. The UK Function for National Statistics (ONS) has released information on the prevalence of long covid symptoms.53 They estimated that the five calendar week prevalence of whatever symptom amid survey respondents who tested positive for covid-nineteen between 22 Apr and 14 Dec 2020 was 22.ane%, while the 12 week prevalence was 9.9%. These figures are worrying for patients, service providers, and governments, with many patients likely to develop long covid and require long term support and treatment. Further studies are required to consolidate our epidemiological understanding of long covid.
Covid-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 than astringent astute disease. In the UK, 1 of the kickoff variants of business organization to appear was the so called "Kent variant," from the B.1.one.7 lineage, now termed the Alpha variant. This variant has approximately 50% increased transmissibility54 and likely increases acute illness severity.55 As 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 organisation or under investigation include the Beta, Gamma, Zeta, Theta, and Kappa variants.56 The CDC reports the emergence of variants of business and interest in the US.58 New covid-19 variants will continue to sally and spread as we progress through the pandemic, for example, the Eta and Delta variants accept arisen, with over 161 000 cases of the speedily spreading Delta variant confirmed in the United kingdom of great britain and northern ireland, as of 30 June 2021.56 Recently, the Lambda variant has emerged, which volition require close monitoring. The ability of these viral strains to inflict long term complications needs to be examined fully. To speculate, it may be that i variant causes more damaging long term effects than others and, therefore, patients infected with such a variant who become on to develop long covid symptoms may crave additional support, equally well as more than 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 Opinion where an infectious illness professor shared his feel of seven weeks on a "rollercoaster of ill health" following covid-19.59 The patient-fabricated term long covid was so made popular post-obit the rise in the employ of #LongCovid on Twitter.threescore This, plus the growing number of peer reviewed manufactures published since, has highlighted a mail-covid-xix syndrome that tin last for many weeks afterwards the acute infection. Long covid is now a recognized term in scientific literature. The Nice guidelines on managing the long term effects of covid-199 and the CDC10 define long covid patients or covid long haulers as individuals with ongoing symptoms of covid-19 that persist beyond four weeks from initial infection.
Symptoms
Fatigue
Fatigue is more profound than being overtired; it is unrelenting exhaustion and a constant state of weariness that reduces a person's energy, motivation, and concentration. Post-obit 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 five week prevalence of fatigue to be eleven.9% among people who have had covid-nineteen.53 Fatigue is a mutual persisting symptom regardless of severity of the acute phase of covid-19. One cantankerous-sectional study found that 92.nine% and 93.5% of hospitalized and non-hospitalized covid-19 patients, respectively, reported ongoing fatigue at 79 days post-obit onset of illness.19 Many other cross-sectional and cohort studies report that chronic fatigue is the near often reported symptom post-obit recovery from acute covid-19,1517202743 with 1 showing no association between covid-19 severity and long term fatigue.xx 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; nonetheless, a cross-sectional belittling study found no clan betwixt pro-inflammatory markers and long term fatigue in covid-nineteen patients with persisting fatigue.twenty It is likely that a range of central, peripheral, and psychological factors play a role in the development of mail-covid-19 fatigue. A narrative review explains that congestion of the glymphatic system and the subsequent toxic build-up within the key nervous organization (CNS), caused past an increased resistance to cerebrospinal fluid drainage through the cribriform plate as a effect of olfactory neuron impairment, may contribute to post-covid-19 fatigue.63
Hypometabolism in the frontal lobe and cerebellum has also been implicated in covid-19 patients with fatigue and is likely caused by systemic inflammation and jail cell mediated immune mechanisms, rather than straight viral neuro-invasion.6465 It is unknown whether this finding continues into long covid.
Negative psychological and social factors associated with the covid-19 pandemic accept also been linked to chronic fatigue.6667 Lastly, peripheral factors such every bit directly SARS-CoV-2 infection of skeletal musculus, resulting in damage, weakness, and inflammation to muscle fibers and neuromuscular junctions may contribute to fatigue.68697071 Overall, it is probable that several factors and mechanisms play a function in the development of post-covid-19 fatigue. Figure 2 further outlines these possible mechanisms.
Fig 2
Long term sequalae of covid-nineteen
(i) 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 eolith collagen and fibronectin resulting in fibrotic changes. (C) Endothelial injury, complement activation, platelet activation, and platelet-leukocyte interactions, release of pro-inflammatory cytokines, disruption of normal coagulant pathways, and hypoxia may result in the development of a prolonged hyperinflammatory and hypercoagulable state, increasing the take chances of thrombosis.
(2) In the heart: (A) chronic inflammation of cardiomyocytes can upshot in myositis and crusade cardiomyocytes death. (B) Dysfunction of the afferent autonomic nervous organization can cause complications such every bit 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.
(3) In the central 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 bulwark harm and dysregulation results in pathological permeability, allowing 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 encephalon can atomic number 82 to cognitive impairment.
(four) Possible mechanisms causing mail service-covid-19 fatigue. A range of fundamental, peripheral, and psychological factors may cause chronic fatigue in long covid. Chronic inflammation in the brain, besides as at the neuromuscular junctions, may result in long term fatigue. In skeletal muscle, sarcolemma impairment and fiber cloudburst and damage may play a role in fatigue, every bit might a number of psychological and social factors
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Post-COVID-nineteen fatigue has been compared with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with many overlaps between the two.72 Symptoms common to both ME/CFS and long covid include fatigue, neurological/hurting, 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 help in developing agreement 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.half-dozen% at five weeks mail-covid-nineteen infection, regardless of presence of acute respiratory symptoms or affliction severity.53 Abnormalities in diffusion capacity for carbon monoxide, total lung capacity, forced expiratory volume in the kickoff second, forced vital capacity, and small airway role, have been seen in hospitalized covid-xix patients at time of discharge, approximately one calendar month following onset of symptoms, showing that lung office in people who accept had covid-xix may take fourth dimension to recover.73 Several studies have found that dyspnea is a mutual manifestation following covid-nineteen infection,1617 and i report reported that 43.iv% of 143 patients assessed were still experiencing dyspnea at 60 days later covid-19 onset.fifteen
Possible mechanisms
As covid-19 is principally a respiratory affliction, acute illness can cause substantial harm to the lungs and respiratory tract via SARS-CoV-ii replication inside endothelial cells, resulting in endothelial impairment and an intense allowed and inflammatory reaction.7475 Those who overcome the acute infection may develop long term lung abnormalities, leading to dyspnea76; withal, most individuals who develop long term breathing difficulties post-covid-19 have no signs of permanent or longlasting lung impairment.2877 It is likely that only those at high risk of developing breathing difficulties, including older people, those who endure acute respiratory distress syndrome, those who have extended hospital stays, and those with pre-existing lung abnormalities, are prone to develop fibrotic-like changes to lung tissue.78 The fibrotic state observed in some patients with ongoing dyspnea may exist provoked past cytokines such as interleukin-6, which is raised in covid-1979 and is involved in the germination of pulmonary fibrosis.80 Pulmonary vascular thromboembolisms have been observed in patients with covid-1981 and may take detrimental consequences in patients with long covid. An overview of the possible machinery causing dyspnea is outlined in fig 2.
Cardiovascular abnormalities
Cardiac injury and elevated cardiac troponin levels are associated with a significantly increased risk of mortality in patients admitted to hospital with astute covid-19 infection.8283 Persisting cardiovascular abnormalities may be crushing for people with long covid. A cohort study showed cardiac involvement, ongoing myocardial inflammation, and elevated serum troponin levels in many people with covid-19 at 71 days following diagnosis,23 while a large case series showed that chest pain, possibly owing to myocarditis, was a common manifestation in patients lx.3 days post-obit onset of covid-19 symptoms, with 21.7% of the 143 patient assessed reporting chest pain.15 Those considered at depression adventure of severe covid-xix, such as young, competitive athletes, have also been constitute to take residual myocarditis long after recovery from covid-19.84 In addition to cardiac complaints, studies have highlighted an emerging tendency 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 middle,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 by SARS-CoV-ii.9192 Pathological responses to acute cardiac injury and viral myocarditis, such as endothelial impairment and microthrombosis, can atomic number 82 to the development of coagulopathy,93 while chronic hypoxia and an increase in pulmonary arterial pressure and ventricular strain may farther precipitate the incidence of cardiac injury in people who have had covid-xix.94 Furthermore, sustained immune activation tin pb 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 directly negative consequences on the autonomic nervous system.98 A complex combination of infection, an autonomic nervous system induced pro-inflammatory response, and a level of autoimmunity may all contribute to the institution of autonomic dysfunction and POTS.89Figure 2 depicts these mechanisms.
Knowledge and mental wellness
Studies take explored cognitive office and deficits in patients with covid-nineteen and suggest that the virus can crusade septic encephalopathy, non-immunological effects such as hypotension, hypoxia, and vascular thrombosis, and immunological furnishings such as adaptive autoimmunity, microglial activation, and a maladaptive cytokine contour.99 Additionally, patients admitted to hospital with covid-xix take presented with a range of complaints including encephalopathy, cognitive impairment, cerebrovascular events/disease, seizures, hypoxic brain injuries, corticospinal tract signs, dysexecutive syndrome, an altered mental status, and psychiatric weather.24100101 These findings reveal that neurological symptoms associated with covid-nineteen are mutual, diverse, and could pose substantial problems for rehabilitation and ongoing care post-obit recovery from covid-19. It is unknown who is most afflicted by cerebral complaints induced by covid-19 and how long they persist; however, patient experiences and published summaries of long covid have described "encephalon fog" to be a common and debilitating symptom.102103104
Critical disease, severe astute respiratory syndrome, and long term ventilator support 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, daze, or both during hospital stays, found that 71% had delirium which lasted around four months following discharge.105 A like report found that, at 3 months post-belch, 40% of ICU treated patients had cognition scores like those of patients with moderate traumatic brain injury, while 26% had scores like to patients with mild Alzheimer'south disease. Delirium was also widely reported, with a longer duration 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 astute covid-xix, with the ONS estimating the 5 week prevalence of headache at x.1% of all covid-19 survivors.1318344353 Exaggerated levels of systemic inflammation, observed in some patients as a "cytokine storm," in addition to activation glial cells, poses a substantial gamble to the brain 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 upshot in increased incidences of stroke post-obit covid-19 infection. Covid-19 has also been associated with an increased risk of developing neurological conditions including Guillain-Barré syndrome,109 and neurodegenerative conditions such as Alzheimer's illness.110
The pandemic has had a negative upshot on mental health, with people who take had covid-xix exhibiting long term psychiatric symptoms including mail service-traumatic stress disorder (PTSD), depression, feet, and obsessive-compulsive symptoms following recovery from the acute infection.3637111112 Quarantine, isolation, and social distancing too accept damaging effects on mental health and knowledge. A rapid review commodity states that the longer a person is confined to quarantine, the poorer the outcomes for their mental health,67 while periods of isolation and the inability to work can cause anxiety, loneliness, and financial concerns, and living through a global health crunch can lead to avoidance behaviors and behavioral changes.113 The mental wellness of the older population is greatly affected past social distancing and like measures. By assessing the associations between loneliness, concrete activity, and mental health both before and during the pandemic, one study found that negative changes of these factors were not solely owing to longitudinal situations earlier 2020, therefore the pandemic exerted actress unfavorable effects on loneliness, physical activity, and mental health.114 People living in intendance homes, including people with dementia, are vulnerable to covid-xix and to other impacts of the pandemic. Those with dementia in intendance homes have been observed to go more than depressed, anxious, agitated, and lonely.115 Protracted social isolation has resulted in exacerbation of neuropsychiatric and behavioral disturbances, including apathy, anxiety, agitation, boredom, and confusion in dementia patients living in care homes, to a greater degree than for intendance habitation residents without dementia.116117
Sleeplessness is besides ordinarily reported post-obit recovery from covid-19, with many studies finding poor slumber quality and sleep disturbances to exist frequent following recovery from acute illness.16253144118119 Furthermore, a retrospective study of medical records of covid-nineteen patients treated in Seoul, South korea, institute that subsequently prescriptions to treat fever, coughing, and rhinorrhea, medications for sleep issues were the next most prescribed treatments.120 Knowledge of the covid-xix expiry toll also has a negative bear on on quality of slumber, stress, anxiety, and other negative emotions,121 and sleep problems have been shown to exist associated with covid-xix related loneliness.122 This leads united states of america to question whether post-covid-xix sleep disturbances are a result of covid-xix infection, the negative furnishings of the pandemic, or a combination of both.
Possible mechanisms
Coronaviruses including SARS-CoV-2 tin infect the cardinal nervous system (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-nineteen, and may result in damaging long term effects, with associations of viral infections and chronic neuro-inflammation with neurodegenerative and psychiatric disorders already elucidated.123124 SARS-CoV-2 may also affect the permeability of the blood-encephalon bulwark, which would enable peripheral cytokines and other claret derived substances to enter the CNS and further drive neuro-inflammation.125 Thrombo-inflammatory pathways may exist the cause of the increased prevalence of stroke in covid-xix,126 while "brain fog" may evolve from PTSD or deconditioning following critical illness and invasive treatment.127 Testify suggests that a directly viral encephalitis, systemic inflammation, peripheral organ dysfunction, and cerebrovascular changes may contribute to the development of long term sequalae post-obit covid-xix.128Figure ii outlines the potential mechanisms occurring within the CNS.
Olfactory and gustatory dysfunction
Abnormalities of olfactory property and gustatory modality have been reported to persist following recovery from covid-19. The ONS estimated the five calendar week prevalence of loss of smell and loss of taste as 7.9% and 8.ii% of all people who have had covid-19, respectively.53 Other studies have found varying prevalence of olfactory and gustatory dysfunction, ranging from xi% to 45.1% of cohorts of patients who have recovered from acute covid-19.223947
Possible mechanisms
Not-neuronal expression of the ACE2 receptor may enable entry of the SARS-CoV-2 virus into olfactory support cells, stem cells, and perivascular cells. This local infection could cause an inflammatory response which subsequently reduces the function of olfactory sensory neurons. Additionally, by damaging the support 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 besides expressed on the mucous membrane of the mouth, particularly on the tongue,130 therefore SARS-CoV-2 has a straight route of entry into oral tissue, which may issue in cellular injury and dysfunction. Moreover, SARS-CoV-two may bind to sialic acid receptors,131 causing an increase in gustatory threshold and resulting in degradation of gustatory particles before they can be detected.132 Some other possible mechanism of gustatory dysfunction in covid-19 and long covid concerns the functional link between gustatory modality and odour, whereby gustatory perception is reduced because of ancestor olfactory sensory dysfunction.133
Other commonly reported manifestations
Covid-xix infection can result in multi-organ harm in individuals with low or high run a risk for severe acute disease.213 Studies testify the presence of acute kidney injury in discharged patients who take recovered from covid-nineteen.134135136 Although the long term furnishings of covid-19 on the kidneys are not fully elucidated, a report assessing kidney office in patients with covid-19 found that 35% had decreased kidney office at 6 months mail-discharge.50
Acutely, pancreatitis triggered past SARS-CoV-2 has been seen in people with covid-nineteen,6137 while serum amylase and lipase levels take been observed to exist college in people with severe illness compared with mild cases, and computed tomography images take shown pancreatic injury.138 A cross sectional study found that xl% of patients with covid-nineteen who were at low chance of severe disease, assessed 141 days following infection, had mild impairment of the pancreas. This impairment was associated with diarrhea, fever, headache, and dyspnea.13 Postmortem and case studies have highlighted the impact that covid-19 has on the spleen, including atrophy of lymphoid follicles, a subtract in T and B lymphocytes leading to lymphocytopenia, and thrombotic events such as infarcts.139140141 A cross exclusive study constitute mild harm of the spleen in 4% of those assessed at 141 days following clearance of covid-xix.13 Other organs and tissues, such as the liver, gastrointestinal tract, muscle, 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-nineteen, including sepsis143 and lung injury leading to hemodynamic changes and hypoxemia.144 The ACE2 receptor is highly expressed in the pancreas,4 perhaps to a greater level than in the lungs138; however, it is unclear whether pancreatic damage is a direct result of viral infection within the pancreas, or caused by the systemic inflammatory response seen during covid-19. 146 The spleen as well expresses ACE2 receptors6 and may exist direct attacked past the virus, rather than the intense systemic inflammation existence the primary cause of splenic damage.139 Chronic systemic inflammation is frequently observed long later on the clearance of acute covid-19 infection,13 therefore, it is likely that this elevated inflammatory state causes long term complications in multiple organs in people with long covid.
Risk factors
Risk factors for severe covid-19 and hospital admission, and risk factors for death every bit a issue of covid-19 include older age, male person sexual activity, non-white ethnicity, being disabled, and pre-existing comorbidities including obesity, cardiovascular disease, respiratory disease, and hypertension.21319147148 Linked to chance of covid-19 severity and mayhap the adventure of long covid, the office of immune suppression is still being debated. Immune suppression may have protective effects against long term effects of covid-19 infection149150151; however, these findings are conflicted.152153
The gamble factors for developing long covid are less appreciated. To explore the characteristics associated with symptoms of long covid, 274 non-hospitalized patients who had covid-nineteen were interviewed betwixt 14 and 21 days post-obit their positive test. Take a chance factors for non returning to "usual health" included age (P=0.01), with the ≥l years age group having the greatest odds ratio, and number of pre-existing medical weather (P=0.003), with a greater number of conditions associated with a greater odds ratio of not returning to "usual health." Of the pre-existing atmospheric condition, having hypertension (odds ratio (OR)=i.3, P=0.018), obesity (OR=2.31, P=0.002), a psychiatric condition (OR=2.32, P=0.007), or an immunosuppressive status (OR=2.33, P=0.047) corresponded with the greatest odds of not returning to "usual health."xviii
A cantankerous sectional written report identified an association between the severity of astute covid-19 infection and post-recovery manifestations in people who have had covid-19, showing that a more than astringent acute stage may transform into the development of more severe symptoms of long covid.43 A cohort study, meanwhile, corroborated this finding, with patients with more than five symptoms during the initial covid-nineteen infection and those that required hospital admission more likely to feel long covid symptoms.34
Although sure factors may increment the risk of both severe covid-19 and long covid, some factors associated with covid-19 practice non too increase risk for long covid. Male sex and older age are associated with an increased take chances of severe covid-19, however, the ONS reported that the prevalence of whatsoever long covid symptoms is higher in women compared with men (23.6% versus 20.vii%), while the age group estimated to exist well-nigh greatly afflicted by long covid symptoms is 35-49 years (26.eight%), followed past 50-69 years (26.1%), and the ≥seventy years group (18%).53 Furthermore, a prospective cohort written report assessing recovered patients institute 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 accept shown no association with the risk of developing long covid. However, pre-existence of asthma has been constitute to be significantly associated with long covid.34
Treatment and management of long covid
WHO and the Long Covid Forum Group agree that research priorities for long covid include improving clinical characterization and the enquiry and development of therapeutics.155156 Clinical characterization of patients with long covid is essential to provide advisable handling options. Gaining an agreement of why certain affliction phenotypes ascend 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 four different syndromes.102 Recognizing which patients belong to which subgroup of long covid, and understanding the pathophysiology, will be important 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-19.9 Guidelines recommend how to identify, refer, and treat patients with long covid. The holistic assessment, investigation, and management approaches suggested by NICE9 are outlined in fig three. 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 go into little particular about long covid, however. Similarly, the NIH has released treatment guidelines for covid-nineteen,158 merely picayune guidance on managing long covid. The CDC is expected to release guidance on long covid management shortly.159 The European Society of Cardiology has also 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 bear witness comes to light; however, other general guidelines, such as Show Based Medicine's guidance on post-infectious syndromes may be useful for treating long covid.161
Pulmonary symptoms
Pulmonary symptoms are common during long covid. NICE recommends that breathlessness may be investigated using an exercise tolerance test suited to the person'southward ability, for example the one minute sit-to-stand up test, and treatment and management should be multidisciplinary, with communication and education given on managing breathlessness. Furthermore, the guidelines recommend offering patients with continuing respiratory symptoms a breast radiograph by 12 weeks after infection.9 Blood oxygen levels tin be monitored using a pulse oximeter.
Recommendations from the Mayo Dispensary suggest that shortness of breath can be self-managed past limiting factors that exacerbate dyspnea, including stopping smoking, avoiding pollutants, avoiding extremes in temperature, and exercising,162 notwithstanding, chronic shortness of jiff may require further intervention. Recognized not-pharmacological strategies for managing dyspnea include breathing exercises,163 pulmonary rehabilitation,164 and maintaining optimal body positioning for postural relief.165 Meanwhile, a systematic review has institute that oral opioids can be used to treat dyspnea,166 therefore this course 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 be considered.170 Modified rehabilitation practices, including stretching, body rotations, acupressure, and massage have shown beneficial long term effects on respiratory symptoms in mild covid-xix patients in a pocket-size trial.171
Cardiovascular symptoms
The NICE guidelines on long covid country that practice tolerance tests may be undertaken to mensurate heart office, while lying and standing blood pressure and centre rate recordings should be performed if postural orthostatic tachycardia syndrome (POTS) is suspected.ix Urgent referral should occur for people that take symptoms of a life threating complication, such as cardiac breast hurting.
The European Society of Cardiology has released comprehensive guidance for the diagnosis and management of cardiovascular disease during the covid-19 pandemic.160 The range of cardiovascular atmospheric condition that can manifest in long covid translates to a wide range of potential therapeutic options, therefore, ongoing investigation and observation of cardiac biomarkers is of import. 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 handling of cardiovascular manifestations of long covid. Myocarditis may resolve naturally over time; still, 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, communication and education, agents to maintain vascular tone, and agents to manage palpitations have been shown by a randomized controlled trial and discussed in a review to be advantageous in the handling of POTS.89177
Treating fatigue, cognitive, and neuropsychiatric symptoms
Chronic fatigue is a common manifestation of long covid. NICE recommends that self-management and support are of import in managing fatigue, owing to the poor availability of covid-19 specific treatment.nine 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 show useful in treating post-covid-19 fatigue. NICE has specific guidelines that outline how to refer and care for ME/CFS patients; these include cognitive behavioral therapy (CBT) and graded exercise therapy (Go).178 Following backlash over these guidelines from the ME Association,179 however, NICE aims to publish revised guidelines in August 2021.180
Randomized controlled trials accept shown that CBT is beneficial in the treatment of chronic fatigue,181 still, this is conflicted by findings from a re-assay of a Cochrane review which question its effectiveness and show a loftier incidence of adverse events. This re-assay study states that if a trial of a drug or surgical procedure demonstrated similarly high rates of agin effects, and then information technology would not be accustomed as a safe treatment option, therefore CBT should have to adhere to the same level of scrutiny.182
Some other management 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 self-direction strategy, however guidance and didactics from healthcare professionals may be useful for patients. Prove from randomized controlled trials for the use 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 airplane pilot report showing improvements in psychotic symptoms and self-esteem,183 however, a review article provides information to suggest that CBT is ineffective in reducing long covid symptoms, including fatigue, with only 10% of participants achieving clinically meaningful improvements.184
GET is a structured intervention plan consisting of physical activities with a therapeutic goal.185 A systematic review of practice therapy for CFS concluded that patients with ME/CFS generally feel less fatigued and take improved slumber and physical function following completion of exercise therapy, to a greater degree than following a program of either adaptive pacing or supportive listening.186 The Dainty guidelines on ME/CFS recommend GET; withal, in July 2020 Dainty released a statement urging caution when implementing Become for people recovering from covid-nineteen, stating that with guidelines currently existence updated, these recommendations may modify.187 This argument accompanies concerns over the potential negative effects of Go, including mail service-exertional angst.188
Evidence specific to covid-19 is lacking, therefore cognitive harm should be managed with support, including setting tailored, achievable goals and implementing validated screening tools.9 Managing cognitive harm will require a holistic approach, nonetheless, patients should exist brash that about people gradually recover from cognitive impairment post-obit severe disease.106189 The holistic approach to treatment should extend to the services offered, with professionals including occupational and speech and linguistic communication therapists addressing cognitive changes.190 Cognitive impairment in long covid, sometimes chosen "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 alleviate cognitive impairment by inhibiting mast cell and microglia activation,191 but clinical trials are required.
Sleep disturbances may be managed past post-obit relevant guidelines on insomnia,193 and a range of treatment strategies can be considered.194195196197 Patients with mental wellness bug alongside or every bit a result of long covid can be managed post-obit the relevant guidelines: depression,198 feet,199 PTSD,200 obsessive-compulsive disorder,201 and other mental health bug.202 Care dwelling residents, including those with dementia, who acquire long covid have boosted 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 defective. Considering that early and close follow-ups with nephrologists accept previously been benign,204 mail-covid-19 patients with renal dysfunction may benefit from early and ongoing monitoring. Covid-19 tin disrupt and alter the microbiome of the gut, which may allow for opportunistic infections.145 Covid-19 associated destructive thyroiditis can event in incident hyperthyroidism, which tin can be treated with corticosteroids.142 Overall, close follow-upward of patients with long covid and adequate investigative procedures should be kept up to accurately diagnose and treat specific symptoms.
Repurposing drugs for long covid
Antihistamines have been implicated as a possible treatment for covid-19, with a study that employed cellular experiments suggesting that histamine-1 antagonists may be able to reduce the covid-19 infection rate by inhibiting SARS-CoV-2 from inbound ACE2 expressing cells.205 Systematic reviews and molecular studies have suggested that histamine-one and histamine-two antagonists are viable candidates for further clinical trials in covid-xix.206207208 Information technology remains to be seen whether antihistamines have potential for treating long covid. Antidepressants accept been proposed to reduce the furnishings of long covid. Antidepressant use has been associated with reduced gamble of intubation or death in covid-19,209 while a meta-analysis of antidepressant drug treatment for major depressive disorder has shown that use of antidepressants, including serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, results in a reduction in peripheral inflammatory markers.210
Emerging treatments
Clinical trials exploring the efficacy of hyperbaric oxygen (NCT04842448), montelukast (NCT04695704), and deupirfenidone (NCT04652518) to care for respiratory conditions in long covid are ongoing. A trial of breathing exercises and singing is likewise under mode to assess their utility in improving breathing abnormalities in patients with long covid (NCT04810065).
A trial to assess the effectiveness of an viii week exercise 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 benign treatment option.211 LOVIT-COVID (NCT04401150) is an ongoing clinical trial aimed at assessing the furnishings 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 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 agreement of long term sequalae of covid-xix infection in the gastrointestinal tract will evolve, with studies currently ongoing (NCT04691895), which volition later on impact handling.
Other potential treatments are molecules that suppress the intense inflammatory response seen in covid-19. Leronlimab is a monoclonal antibiotic that blocks the function of CCL-5. It has been shown to be effective and safety in HIV213 and reduces plasma interleukin-six levels in covid-nineteen.214 Clinical trials are ongoing to evaluate the efficacy of leronlimab mail service-covid-nineteen (NCT04343651, NCT04347239, NCT04678830). Another antibiotic handling, tocilizumab, blocks interleukin-6 receptors and has shown efficacy in a small trial of patients with covid-nineteen patients.215 Trials to explore the effects of tocilizumab are ongoing (NCT04330638). The anti-oxidative and anti-inflammatory function of melatonin may 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-xix, the long term implications are of increasing 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 handling options that may be useful in alleviating its symptoms. Currently, long covid remains enigmatic and, with the question of the affect that new variants of covid-19 volition take on the incidence and severity of long covid still looming big, it is important that enquiry continues to explore mail-covid-19 syndrome. Greater understanding of the pathogenesis, 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 volition effort to support them.
How patients were involved in the cosmos of this article
Members of a long covid focus group were contacted and requested to review the initial drafts of this commodity. 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 we have addressed in this commodity.
Enquiry 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 postal service-covid-xix symptoms?
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Which symptoms, or set of symptoms, tin nosotros utilize to classify long covid, clinically and phenotypically, with the aim of improving diagnosis and direction?
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What is the optimal handling and direction strategy for long covid and is this strategy non-specific or will it require targeting and tailoring to specific patients?
Footnotes
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State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the United states and internationally. For this reason they are written predominantly by 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 start author of the manuscript who drafted the manuscript and revised information technology; 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: We have read and understood the BMJ policy on annunciation of interests and declare the post-obit interests: PE was funded by the Medical Research Council and now past Higher Education Funding Quango for England (HEFCE). He has too received grants from Alzheimer's Research, UK, Alzheimer's Drug Discovery Foundation, Alzheimer'south Club, Britain, Medical Research Council, Alzheimer'south Association US, Van-Geest foundation, and European Matrimony grants. PE is a consultant to Roche, Pfizer, and Novo Nordisk. He has received educational and enquiry grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He is a member of the Scientific Informational Lath at Novo Nordisk.
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Provenance and peer review: commissioned; externally peer reviewed.
This article is made freely bachelor for use in accord with BMJ's website terms and weather condition for the elapsing of the covid-nineteen pandemic or until otherwise adamant past BMJ. You may use, download and print the article for any lawful, not-commercial purpose (including text and information mining) provided that all copyright notices and trade marks are retained.
https://bmj.com/coronavirus/usage
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Source: https://www.bmj.com/content/374/bmj.n1648
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