Sumter Family Medicine: Ingram James R Md Sumter, Sc
Clinical Review State of the Art Review Long covid—mechanisms, take a chance factors, and management
BMJ 2021; 374 doi: https://doi.org/ten.1136/bmj.n1648 (Published 26 July 2021) Cite this as: BMJ 2021;374:n1648 Read our latest coverage of the coronavirus pandemic
- Harry Crook , enquiry assistant1,
- Sanara Raza , enquiry assistantone,
- Joseph Nowell , inquiry assistant1,
- Megan Immature , clinical enquiry officeholder1,
- Paul Edison , clinical senior lecturer , honorary professor12
- aneFaculty of Medicine, Regal College London, London, UK
- 2Cardiff University, Cardiff, United kingdom of great britain and northern ireland
- Correspondence to P Edison paul.edison{at}imperial.air-conditioning.uk
Abstruse
Since its emergence in Wuhan, People's republic of china, covid-xix has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more 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 can remain long subsequently the astute SARS-CoV-ii infection, and this condition is now coined long covid past 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 severe forms. Like acute covid-nineteen, long covid can involve multiple organs and can bear upon many systems including, merely 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 mail-traumatic stress disorder, musculus pain, concentration problems, 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. Adventure factors for astute covid-19 and long covid and possible therapeutic options are also discussed.
Introduction
Coronavirus disease 2019 (covid-19) has spread across the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-xix have been recorded worldwide, and more than 3.97 million deaths have been reported by the World Wellness Organization .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-ii), enters cells via the angiotensin-converting enzyme 2 (ACE2) receptor.4 In one case internalized, the virus undergoes replication and maturation, provoking an inflammatory response that involves the activation and infiltration of allowed cells by various cytokines in some patients.v The ACE2 receptor is present in numerous prison cell types throughout the homo torso, including in the oral and nasal mucosa, lungs, heart, gastrointestinal tract, liver, kidneys, spleen, brain, and arterial and venous endothelial cells, highlighting how SARS-CoV-2 tin can cause damage to multiple organs.67
The bear upon of covid-19 thus far has been unparalleled, and long term symptoms could accept a further devastating effect.8 Contempo show shows that a range of symptoms can remain after the clearance of the acute infection in many people who have had covid-19, and this condition is known every bit long covid. The National Plant for Health and Care Excellence (NICE) defines long covid as the symptoms that continue or develop after astute covid-19 infection and which cannot be explained by an alternative diagnosis. This term includes ongoing symptomatic covid-19, from four to 12 weeks post-infection, and postal service-covid-19 syndrome, beyond 12 weeks post-infection.9 Conversely, The National Institutes of Wellness (NIH) uses the US Centers for Affliction Command and Prevention (CDC) definition of long covid, which describes the condition as sequelae that extend beyond 4 weeks after initial infection.10 People with long covid exhibit interest and impairment in the structure and part of multiple organs.11121314 Numerous symptoms of long covid have been reported and attributed to various organs, an overview of which can be seen in fig 1. Long term symptoms following covid-19 accept been observed across the spectrum of disease severity. This review examines the long term impact of symptoms reported following covid-19 infection and discusses the current epidemiological understanding of long covid, the run a risk factors that may predispose a person to develop the status, and the treatment and management guidelines aimed at treating it.
Fig 1
Multi-organ complications of covid-xix and long covid. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptor. One time these cells take been invaded, the virus can crusade a multitude of harm 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-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 harm" or "mental health" or "depression" or "anxiety" or "psychiatric" or "central nervous system" or "autonomic nervous system" or "isolation" or "loneliness" or "sleeplessness" or "sleep" or "odor" or "taste" or "olfactory" or "gustatory" or "hazard factors" or "handling". To avert unintentionally removing manufactures, no filters were applied. We retrieved 61 881 manufactures in the first case. To screen articles, titles were read by authors showtime, followed past abstracts to further narrow downwardly the number of records considered. To avert unnecessary exclusion of studies, limited 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 chapters were initially included attributable to the novelty of the field. Furthermore, we considered long covid studies regardless of their cohort sizes or study design. We discovered and read fully 227 manufactures on long covid, and we discussed each to determine which would be included in the finalized article. Nosotros performed farther manual searching for additional manufactures and treatment guidelines using relevant databases, including squeamish.org.uk and clinicaltrials.gov. In full, 218 references were included. Studies examining long covid are limited, therefore limited exclusion criteria were applied.
Studies of long covid
Studies have assessed people who have had covid-nineteen to examine the symptoms associated with long covid. These studies are summarized in tabular array ane. The manufactures included throughout this review were selected in favor of quality, with large observational studies of greatest interest. About of the studies included are cross-sectional or cohort observational studies with large cohorts; yet, because of the novelty of the disease and paucity of data, studies involving smaller cohorts and instance serial were also included. Whatever patient with covid-19 may develop long covid, regardless of the severity of their infection and the intensity of the handling they received. Patients treated on wards and intensive intendance units (ICUs) prove picayune difference in incidence of long term symptoms associated with covid-nineteen.17 The proportion of people that develop long covid symptoms, whether they are treated with oxygen lonely, with continuous positive airway pressure, or with invasive ventilation, is like.sixteen 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 betwixt hospitalized and not-hospitalized covid-xix patients.19
Table 1
Summary of studies that accept explored the persisting symptoms post-covid-xix infection, or during long covid
Epidemiology
The reported incidence and mortality rates of covid-19 vary between countries, making information technology difficult 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 information is probable the result 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 verbal epidemiological data of long covid is difficult, this data is needed to inform healthcare systems and governments when developing support and treatment algorithms. The volume of published literature describing cases of patients with covid-nineteen who after develop long covid symptoms is continually growing, which will allow for an improved understanding of its epidemiology.
The current disparities between long covid epidemiology reporting are owing to many reasons, including the length of follow-upward period, population assessed, accurateness of self-reporting, and symptoms examined. Studies effectually the earth have reported various incidence rates for long covid with unlike follow-up examination times later on the acute infection, including 76% of people at 6 months,50 32.half dozen% at 60 days,51 87% at 60 days,15 and 96% at xc days.52 These finding are not fully corroborative, but they prove that a substantial proportion of people who have had covid-nineteen may develop long covid. The Britain Office for National Statistics (ONS) has released data on the prevalence of long covid symptoms.53 They estimated that the five week prevalence of any symptom amidst survey respondents who tested positive for covid-nineteen between 22 April and xiv December 2020 was 22.1%, while the 12 calendar week prevalence was 9.9%. These figures are worrying for patients, service providers, and governments, with many patients likely to develop long covid and require long term back up and treatment. Further studies are required to consolidate our epidemiological understanding of long covid.
Covid-19 variants of concern
Since the start of the pandemic, several covid-19 variants have emerged that have an increased transmissibility and may issue in more severe acute disease. In the United kingdom of great britain and northern ireland, 1 of the first variants of concern to appear was the and so called "Kent variant," from the B.1.1.7 lineage, now termed the Blastoff variant. This variant has approximately 50% increased transmissibility54 and likely increases acute disease severity.55 Equally of xxx June 2021, the Alpha variant has been confirmed in more than than 275 000 cases in the UK56 and spread to at to the lowest degree 136 countries around the earth.57 Other variants of concern or under investigation include the Beta, Gamma, Zeta, Theta, and Kappa variants.56 The CDC reports the emergence of variants of concern and interest in the Usa.58 New covid-xix variants will continue to emerge and spread as we progress through the pandemic, for example, the Eta and Delta variants take arisen, with over 161 000 cases of the rapidly spreading Delta variant confirmed in the UK, as of thirty 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, information technology may be that i variant causes more damaging long term effects than others and, therefore, patients infected with such a variant who keep to develop long covid symptoms may require additional support, as well equally more than rapid and intense treatment strategies to combat their long term symptoms.
Long covid definition
Long covid gained widespread attending following an account published on 5 May 2020 in BMJ Stance where an communicable diseases professor shared his experience of 7 weeks on a "rollercoaster of ill wellness" following covid-nineteen.59 The patient-fabricated term long covid was so made popular post-obit the rise in the use of #LongCovid on Twitter.lx This, plus the growing number of peer reviewed articles published since, has highlighted a post-covid-19 syndrome that tin can last for many weeks later the acute infection. Long covid is at present a recognized term in scientific literature. The NICE guidelines on managing the long term effects of covid-199 and the CDC10 define long covid patients or covid long haulers every bit individuals with ongoing symptoms of covid-19 that persist beyond 4 weeks from initial infection.
Symptoms
Fatigue
Fatigue is more profound than existence overtired; it is unrelenting exhaustion and a constant state of weariness that reduces a person's free energy, motivation, and concentration. Following the SARS outbreak, upward to sixty% 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 exist 11.9% amidst people who accept had covid-19.53 Fatigue is a mutual persisting symptom regardless of severity of the acute stage of covid-xix. One cantankerous-exclusive study found that 92.ix% and 93.5% of hospitalized and not-hospitalized covid-xix patients, respectively, reported ongoing fatigue at 79 days following onset of illness.nineteen Many other cantankerous-sectional and cohort studies report that chronic fatigue is the most frequently reported symptom following recovery from acute covid-nineteen,1517202743 with i showing no association between covid-19 severity and long term fatigue.20 These findings prove that fatigue is a major manifestation of long covid.
Possible mechanisms
Chronic fatigue following viral infection may be the effect of miscommunication in the inflammatory response pathways62; withal, a cantankerous-sectional analytical study found no clan between pro-inflammatory markers and long term fatigue in covid-19 patients with persisting fatigue.20 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-upwards within the central nervous system (CNS), acquired by an increased resistance to cerebrospinal fluid drainage through the cribriform plate as a outcome of olfactory neuron impairment, may contribute to postal service-covid-19 fatigue.63
Hypometabolism in the frontal lobe and cerebellum has also been implicated in covid-19 patients with fatigue and is likely acquired by systemic inflammation and prison 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-xix pandemic have also been linked to chronic fatigue.6667 Lastly, peripheral factors such equally direct SARS-CoV-2 infection of skeletal muscle, resulting in damage, weakness, and inflammation to muscle fibers and neuromuscular junctions may contribute to fatigue.68697071 Overall, information technology is probable that several factors and mechanisms play a role in the evolution of post-covid-19 fatigue. Effigy 2 further outlines these possible mechanisms.
Fig 2
Long term sequalae of covid-19
(one) 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 harm 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 evolution of a prolonged hyperinflammatory and hypercoagulable country, increasing the adventure of thrombosis.
(2) In the heart: (A) chronic inflammation of cardiomyocytes tin can effect in myositis and cause cardiomyocytes death. (B) Dysfunction of the afferent autonomic nervous system tin cause complications such as postural orthostatic tachycardia syndrome. (C) Prolonged inflammation and cellular damage prompts fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis. (D) Fibrotic changes are accompanied past an increase in cardiac fibromyoblasts, while impairment to desmosomal proteins results in reduced cell-to-jail cell adhesion.
(3) In the primal nervous organisation: (A) The long term allowed response activates glial cells which chronically damage neurons. (B) Hyperinflammatory and hypercoagulable states lead to an increased gamble of thrombotic events. (C) Blood-brain bulwark impairment 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 effects of long covid in the brain can lead to cognitive impairment.
(four) Possible mechanisms causing post-covid-nineteen fatigue. A range of central, 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 damage and fiber cloudburst and damage may play a function in fatigue, every bit 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/hurting, neurocognitive/psychiatric, neuroendocrine, autonomic, and allowed 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 agreement of ME/CFS and vice versa.
Dyspnea
Breathlessness is common in people with long covid. The ONS estimates that shortness of jiff has a prevalence of 4.6% at five weeks mail service-covid-19 infection, regardless of presence of astute respiratory symptoms or illness severity.53 Abnormalities in diffusion chapters for carbon monoxide, total lung capacity, forced expiratory volume in the first 2nd, forced vital capacity, and pocket-size airway function, accept been seen in hospitalized covid-nineteen patients at time of discharge, approximately one month following onset of symptoms, showing that lung role in people who take had covid-19 may have time to recover.73 Several studies have plant that dyspnea is a common manifestation following covid-xix infection,1617 and one study reported that 43.four% of 143 patients assessed were withal experiencing dyspnea at sixty days after covid-nineteen onset.xv
Possible mechanisms
As covid-19 is principally a respiratory disease, acute illness can cause substantial impairment to the lungs and respiratory tract via SARS-CoV-two replication inside endothelial cells, resulting in endothelial damage and an intense immune and inflammatory reaction.7475 Those who overcome the acute infection may develop long term lung abnormalities, leading to dyspnea76; however, nigh individuals who develop long term breathing difficulties mail-covid-xix have no signs of permanent or longlasting lung damage.2877 Information technology is likely that only those at high take a chance 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 decumbent to develop fibrotic-like changes to lung tissue.78 The fibrotic state observed in some patients with ongoing dyspnea may be provoked past cytokines such every bit interleukin-6, which is raised in covid-1979 and is involved in the formation 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 ii.
Cardiovascular abnormalities
Cardiac injury and elevated cardiac troponin levels are associated with a significantly increased risk of bloodshed in patients admitted to hospital with astute covid-19 infection.8283 Persisting cardiovascular abnormalities may be burdensome for people with long covid. A cohort study showed cardiac involvement, ongoing myocardial inflammation, and elevated serum troponin levels in many people with covid-19 at 71 days following diagnosis,23 while a big case series showed that chest pain, possibly owing to myocarditis, was a common manifestation in patients 60.3 days following onset of covid-19 symptoms, with 21.vii% of the 143 patient assessed reporting chest hurting.15 Those considered at low risk of astringent covid-19, such equally immature, competitive athletes, take too been found to have residual myocarditis long after recovery from covid-19.84 In addition to cardiac complaints, studies take highlighted an emerging trend in the development of new onset postural orthostatic tachycardia syndrome (POTS) in individuals mail-covid-nineteen infection, because of autonomic dysfunction.8586878889
Possible mechanisms
ACE2 receptors are highly expressed in the heart,xc providing a direct route of infection for SARS-CoV-2. Studies have shown that sarcomere disruption and fragmentation, enucleation, transcriptional changes, and an intense local immune response occurs in cardiomyocytes infected by SARS-CoV-2.9192 Pathological responses to acute cardiac injury and viral myocarditis, such every bit endothelial damage and microthrombosis, can lead to the development of coagulopathy,93 while chronic hypoxia and an increase in pulmonary arterial pressure and ventricular strain may further precipitate the incidence of cardiac injury in people who accept had covid-nineteen.94 Furthermore, sustained immune activation can atomic number 82 to fibrotic changes95 and displacement of desmosomal proteins,96 which could be arrhythmogenic. Viral infection has previously been shown to precede POTS97 and, with the ACE2 receptor expressed on neurons, viral infection by SARS-CoV-2 may have direct negative consequences on the autonomic nervous system.98 A complex combination of infection, an autonomic nervous organization 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.
Noesis and mental health
Studies take explored cognitive office and deficits in patients with covid-19 and suggest that the virus can crusade septic encephalopathy, not-immunological effects such every bit hypotension, hypoxia, and vascular thrombosis, and immunological effects such as adaptive autoimmunity, microglial activation, and a maladaptive cytokine contour.99 Additionally, patients admitted to hospital with covid-19 take presented with a range of complaints including encephalopathy, cognitive harm, cerebrovascular events/disease, seizures, hypoxic encephalon injuries, corticospinal tract signs, dysexecutive syndrome, an altered mental condition, and psychiatric conditions.24100101 These findings reveal that neurological symptoms associated with covid-nineteen are common, diverse, and could pose substantial problems for rehabilitation and ongoing care following recovery from covid-nineteen. Information technology is unknown who is virtually affected past cognitive complaints induced by covid-19 and how long they persist; nonetheless, patient experiences and published summaries of long covid accept described "brain fog" to be a common and debilitating symptom.102103104
Critical disease, astringent acute respiratory syndrome, and long term ventilator support are known to take detrimental effects on long term cognition. Before the covid-xix pandemic, a retrospective report of 1040 ICU treated patients who had respiratory failure, shock, or both during hospital stays, institute that 71% had delirium which lasted around four months following discharge.105 A like report plant that, at 3 months post-belch, twoscore% of ICU treated patients had cognition scores like those of patients with moderate traumatic encephalon injury, while 26% had scores similar to patients with mild Alzheimer'southward disease. Delirium was too 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 likely to pose considerable problems.
Stroke and headache are prevalent in those recovered from astute covid-xix, with the ONS estimating the v week prevalence of headache at 10.one% of all covid-19 survivors.1318344353 Exaggerated levels of systemic inflammation, observed in some patients as a "cytokine tempest," in improver to activation glial cells, poses a substantial gamble to the encephalon and increases the likelihood of neurological manifestations including encephalitis and stroke.74 Hypercoagulability107 and cardio-embolisms, formed because of virus related cardiac injury,108 are manifestations that could result in increased incidences of stroke post-obit covid-19 infection. Covid-19 has also been associated with an increased risk of developing neurological weather condition including Guillain-Barré syndrome,109 and neurodegenerative weather such as Alzheimer's disease.110
The pandemic has had a negative upshot on mental health, with people who have had covid-nineteen exhibiting long term psychiatric symptoms including mail-traumatic stress disorder (PTSD), depression, feet, and obsessive-compulsive symptoms following recovery from the acute infection.3637111112 Quarantine, isolation, and social distancing also accept dissentious effects on mental health and cognition. A rapid review article states that the longer a person is confined to quarantine, the poorer the outcomes for their mental health,67 while periods of isolation and the inability to work can crusade anxiety, loneliness, and financial concerns, and living through a global health crisis tin pb to avoidance behaviors and behavioral changes.113 The mental health of the older population is greatly affected by social distancing and similar measures. By assessing the associations between loneliness, physical activity, and mental health both before and during the pandemic, 1 study found that negative changes of these factors were non solely owing to longitudinal situations earlier 2020, therefore the pandemic exerted extra unfavorable effects on loneliness, physical activeness, 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 become more 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 care abode residents without dementia.116117
Sleeplessness is besides normally reported following recovery from covid-19, with many studies finding poor slumber quality and slumber disturbances to be frequent following recovery from acute disease.16253144118119 Furthermore, a retrospective study of medical records of covid-19 patients treated in Seoul, Republic of korea, institute that after prescriptions to treat fever, cough, and rhinorrhea, medications for sleep problems were the adjacent near prescribed treatments.120 Noesis of the covid-nineteen death toll besides has a negative impact on quality of sleep, stress, anxiety, and other negative emotions,121 and sleep issues take been shown to be associated with covid-19 related loneliness.122 This leads us to question whether post-covid-19 slumber disturbances are a result of covid-nineteen infection, the negative effects of the pandemic, or a combination of both.
Possible mechanisms
Coronaviruses including SARS-CoV-two can infect the central nervous organization (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-xix, 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 blood-brain barrier, which would enable peripheral cytokines and other blood derived substances to enter the CNS and farther bulldoze neuro-inflammation.125 Thrombo-inflammatory pathways may be the crusade of the increased prevalence of stroke in covid-19,126 while "encephalon fog" may evolve from PTSD or deconditioning post-obit critical disease and invasive treatment.127 Prove suggests that a straight viral encephalitis, systemic inflammation, peripheral organ dysfunction, and cerebrovascular changes may contribute to the evolution of long term sequalae following covid-19.128Figure 2 outlines the potential mechanisms occurring inside the CNS.
Olfactory and gustatory dysfunction
Abnormalities of smell and taste have been reported to persist following recovery from covid-xix. The ONS estimated the 5 calendar week prevalence of loss of smell and loss of taste as 7.9% and eight.two% of all people who have had covid-19, respectively.53 Other studies have found varying prevalence of olfactory and gustatory dysfunction, ranging from 11% to 45.i% of cohorts of patients who have recovered from acute covid-19.223947
Possible mechanisms
Non-neuronal expression of the ACE2 receptor may enable entry of the SARS-CoV-2 virus into olfactory support cells, stem cells, and perivascular cells. This local infection could cause an inflammatory response which after reduces the function of olfactory sensory neurons. Additionally, by damaging the support cells responsible for local water and ionic residue, SARS-CoV-2 may indirectly reduce signaling from sensory neurons to the brain,129 resulting in a loss of sense of scent.
ACE2 receptors are also expressed on the mucous membrane of the oral cavity, particularly on the tongue,130 therefore SARS-CoV-2 has a straight road of entry into oral tissue, which may result in cellular injury and dysfunction. Moreover, SARS-CoV-two may bind to sialic acrid receptors,131 causing an increase in gustatory threshold and resulting in degradation of gustatory particles earlier they can be detected.132 Another possible mechanism of gustatory dysfunction in covid-19 and long covid concerns the functional link between taste and smell, whereby gustatory perception is reduced because of antecedent olfactory sensory dysfunction.133
Other ordinarily reported manifestations
Covid-19 infection can result in multi-organ impairment in individuals with low or high risk for astringent acute disease.213 Studies testify the presence of acute kidney injury in discharged patients who have recovered from covid-xix.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-19 found that 35% had decreased kidney office at vi months post-belch.fifty
Acutely, pancreatitis triggered by SARS-CoV-2 has been seen in people with covid-19,6137 while serum amylase and lipase levels have been observed to be higher in people with severe illness compared with balmy cases, and computed tomography images take shown pancreatic injury.138 A cantankerous exclusive written report found that 40% of patients with covid-19 who were at low run a risk 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 decrease in T and B lymphocytes leading to lymphocytopenia, and thrombotic events such equally infarcts.139140141 A cross sectional study found balmy 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, musculus, and blood vessels express the ACE2 receptor and are susceptible to direct damage from SARS-CoV-2 and indirect harm through elevated systemic inflammation.142143144 Alterations in gut microbiota145 and subacute thyroiditis142 have been observed following covid-19 infection.
Possible mechanisms
Kidney injury may occur through several mechanisms associated with covid-xix, including sepsis143 and lung injury leading to hemodynamic changes and hypoxemia.144 The ACE2 receptor is highly expressed in the pancreas,4 perhaps to a greater level than in the lungs138; however, it is unclear whether pancreatic damage is a straight result of viral infection within the pancreas, or caused by the systemic inflammatory response seen during covid-19. 146 The spleen also expresses ACE2 receptors6 and may be directly attacked by the virus, rather than the intense systemic inflammation being the primary cause of splenic damage.139 Chronic systemic inflammation is frequently observed long afterward the clearance of astute covid-xix infection,13 therefore, it is probable that this elevated inflammatory land causes long term complications in multiple organs in people with long covid.
Risk factors
Take chances factors for severe covid-xix and infirmary admission, and run a risk factors for expiry as a result of covid-xix include older age, male person sex, non-white ethnicity, being disabled, and pre-existing comorbidities including obesity, cardiovascular disease, respiratory disease, and hypertension.21319147148 Linked to risk of covid-xix severity and possibly the risk of long covid, the office of immune suppression is nevertheless being debated. Immune suppression may have protective effects against long term furnishings of covid-19 infection149150151; however, these findings are conflicted.152153
The risk factors for developing long covid are less appreciated. To explore the characteristics associated with symptoms of long covid, 274 non-hospitalized patients who had covid-nineteen were interviewed between 14 and 21 days following their positive examination. Risk factors for not 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 condition (P=0.003), with a greater number of conditions associated with a greater odds ratio of non returning to "usual wellness." Of the pre-existing weather condition, having hypertension (odds ratio (OR)=ane.three, P=0.018), obesity (OR=2.31, P=0.002), a psychiatric condition (OR=2.32, P=0.007), or an immunosuppressive condition (OR=two.33, P=0.047) corresponded with the greatest odds of not returning to "usual health."18
A cross sectional study identified an clan between the severity of acute covid-19 infection and postal service-recovery manifestations in people who take had covid-19, showing that a more than severe astute phase may transform into the evolution of more astringent symptoms of long covid.43 A accomplice study, meanwhile, corroborated this finding, with patients with more than than 5 symptoms during the initial covid-19 infection and those that required hospital admission more probable to experience long covid symptoms.34
Although certain factors may increase the risk of both severe covid-19 and long covid, some factors associated with covid-19 do non likewise 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 higher in women compared with men (23.six% versus 20.7%), while the age group estimated to exist most greatly affected by long covid symptoms is 35-49 years (26.8%), followed by 50-69 years (26.1%), and the ≥70 years group (18%).53 Furthermore, a prospective cohort study assessing recovered patients establish no baseline clinical features associated with the subsequent development of long covid symptoms.154 Male person sex activity, age, and pre-existing conditions including obesity, diabetes, and cardiovascular disease have shown no association with the adventure of developing long covid. However, pre-existence of asthma has been found to be significantly associated with long covid.34
Handling and management of long covid
WHO and the Long Covid Forum Grouping concord that enquiry priorities for long covid include improving clinical characterization and the research and development of therapeutics.155156 Clinical characterization of patients with long covid is essential to provide appropriate handling 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 be four dissimilar 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-xix.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 3. In Jan 2021, WHO updated its covid-nineteen guidance to include a new chapter focused on caring for patients mail service-covid-19.157 These guidelines go into trivial detail almost long covid, however. Similarly, the NIH has released treatment guidelines for covid-19,158 but footling guidance on managing long covid. The CDC is expected to release guidance on long covid direction soon.159 The European Society of Cardiology has besides released guidelines on the diagnosis and direction of cardiovascular disease during the pandemic.160 The guidelines for treating and managing long covid will undoubtedly evolve as new evidence comes to light; however, other full general guidelines, such as Evidence Based Medicine's guidance on mail-infectious syndromes may exist useful for treating long covid.161
Pulmonary symptoms
Pulmonary symptoms are common during long covid. Prissy recommends that breathlessness may be investigated using an practise tolerance examination suited to the person's ability, for example the one minute sit down-to-stand test, and treatment and management should be multidisciplinary, with advice and education given on managing breathlessness. Furthermore, the guidelines recommend offering patients with standing respiratory symptoms a breast radiograph past 12 weeks afterwards infection.9 Claret oxygen levels tin be monitored using a pulse oximeter.
Recommendations from the Mayo Clinic 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 even so, chronic shortness of breath may require further intervention. Recognized non-pharmacological strategies for managing dyspnea include breathing exercises,163 pulmonary rehabilitation,164 and maintaining optimal body positioning for postural relief.165 Meanwhile, a systematic review has institute that oral opioids can be used to care for dyspnea,166 therefore this course of drugs may prove useful for treating the status in people with long covid.
Patients with pulmonary fibrosis resulting from covid-nineteen should be managed in accord 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 Dainty guidelines on long covid country that exercise tolerance tests may be undertaken to measure eye office, while lying and continuing blood pressure level and center rate recordings should exist performed if postural orthostatic tachycardia syndrome (POTS) is suspected.nine Urgent referral should occur for people that have symptoms of a life threating complication, such equally cardiac chest hurting.
The European Guild of Cardiology has released comprehensive guidance for the diagnosis and management of cardiovascular affliction during the covid-xix pandemic.160 The range of cardiovascular weather that can manifest in long covid translates to a wide range of potential therapeutic options, therefore, ongoing investigation and ascertainment of cardiac biomarkers is important. NICE guidelines recommend β blockers for several cardiac complaints, including angina,172 cardiac arrhythmias,173 and acute coronary syndromes,174 therefore, β blockers may be useful in the treatment of cardiovascular manifestations of long covid. Myocarditis may resolve naturally over time; however, supportive and/or immunomodulating therapy may ameliorate recovery, equally a systematic review describes.175 A review has as well suggested that anticoagulants may be used to reduce the risks associated with hypercoagulability.176 Meanwhile, advice and education, agents to maintain vascular tone, and agents to manage palpitations accept 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. Overnice recommends that self-management and back up are important in managing fatigue, owing to the poor availability of covid-19 specific treatment.9 A condition that may overlap with long covid fatigue is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), therefore, the treatment algorithm designed for treating ME/CFS may prove 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 practise therapy (Get).178 Post-obit backfire over these guidelines from the ME Association,179 however, Overnice aims to publish revised guidelines in Baronial 2021.180
Randomized controlled trials have shown that CBT is benign in the handling of chronic fatigue,181 however, this is conflicted past findings from a re-analysis of a Cochrane review which question its effectiveness and show a high incidence of agin events. This re-analysis study states that if a trial of a drug or surgical procedure demonstrated similarly high rates of adverse furnishings, then information technology would not be accepted equally a safe treatment 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. Prissy guidelines for ME/CFS178 describe pacing as a cocky-management strategy, however guidance and instruction from healthcare professionals may exist useful for patients. Prove from randomized controlled trials for the use of pacing in long covid is yet to exist seen.
The implementation of group therapy via videoconferencing in people with early on psychosis during the covid-nineteen pandemic shows promising results, with a pilot report showing improvements in psychotic symptoms and self-esteem,183 still, a review article provides information to suggest that CBT is ineffective in reducing long covid symptoms, including fatigue, with merely 10% of participants achieving clinically meaningful improvements.184
Become is a structured intervention programme consisting of physical activities with a therapeutic goal.185 A systematic review of exercise therapy for CFS concluded that patients with ME/CFS by and large feel less fatigued and have improved sleep and concrete function following completion of practise therapy, to a greater caste than post-obit a program of either adaptive pacing or supportive listening.186 The NICE guidelines on ME/CFS recommend GET; however, in July 2020 NICE released a statement urging caution when implementing GET for people recovering from covid-nineteen, stating that with guidelines currently being updated, these recommendations may alter.187 This statement accompanies concerns over the potential negative furnishings of GET, including post-exertional malaise.188
Evidence specific to covid-19 is lacking, therefore cognitive impairment should be managed with back up, including setting tailored, achievable goals and implementing validated screening tools.9 Managing cognitive impairment will crave a holistic approach, nonetheless, patients should be advised that most people gradually recover from cognitive harm following severe illness.106189 The holistic approach to treatment should extend to the services offered, with professionals including occupational and spoken communication and linguistic communication therapists addressing cerebral changes.190 Cerebral harm in long covid, sometimes called "brain fog," has been compared to "chemobrain."191 The Mayo clinic recommendations propose strategies to manage chemobrain including repeating exercises, tracking what influences deficits, and using stress relief and coping strategies. Furthermore, medications including methylphenidate, donepezil, modafinil, and memantine may be considered.192 These strategies may show useful for long covid. Specific to long covid, luteolin, a natural flavonoid, may convalesce cerebral harm past inhibiting mast jail cell and microglia activation,191 but clinical trials are required.
Slumber disturbances may be managed by following relevant guidelines on insomnia,193 and a range of handling strategies can be considered.194195196197 Patients with mental health bug alongside or equally a result of long covid can be managed following the relevant guidelines: low,198 anxiety,199 PTSD,200 obsessive-compulsive disorder,201 and other mental health problems.202 Care abode residents, including those with dementia, who acquire long covid accept additional needs.116 Discussing mental wellness problems with patients requires pity and agreement.203
Treating other organ impairments
Electric current evidence for the recovery of renal function post-obit covid-19 is lacking. Considering that early and shut follow-ups with nephrologists take previously been benign,204 postal service-covid-19 patients with renal dysfunction may benefit from early and ongoing monitoring. Covid-19 tin can disrupt and alter the microbiome of the gut, which may allow for opportunistic infections.145 Covid-nineteen associated subversive thyroiditis tin can result in incident hyperthyroidism, which can be treated with corticosteroids.142 Overall, close follow-up 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-1 and histamine-2 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 utilise has been associated with reduced risk of intubation or expiry in covid-19,209 while a meta-assay of antidepressant drug treatment for major depressive disorder has shown that use of antidepressants, including serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, results in a reduction in peripheral inflammatory markers.210
Emerging treatments
Clinical trials exploring the efficacy of hyperbaric oxygen (NCT04842448), montelukast (NCT04695704), and deupirfenidone (NCT04652518) to treat respiratory weather condition in long covid are ongoing. A trial of animate exercises and singing is also nether way to appraise their utility in improving breathing abnormalities in patients with long covid (NCT04810065).
A trial to assess the effectiveness of an 8 week practise program in patients with long covid and fatigue is ongoing (NCT04841759). Vitamin C supplementation may prove useful in treating fatigue in patients with long covid, with a systematic review final that loftier dose intravenous vitamin C could be a beneficial treatment 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.
2 trials examining the effects of nicotinamide riboside, a dietary supplement, are ongoing (NCT04809974, NCT04604704) with the expectation that the molecule reduces cerebral symptoms and fatigue past modulating the pro-inflammatory response.212
A clinical trial is currently ongoing assessing the effectiveness of a probiotic supplement to normalize the composition of the gut microbiome and reduce inflammation in long covid (NCT04813718). The understanding of long term sequalae of covid-xix infection in the alimentary canal will evolve, with studies currently ongoing (NCT04691895), which will after affect treatment.
Other potential treatments are molecules that suppress the intense inflammatory response seen in covid-xix. Leronlimab is a monoclonal antibody that blocks the office of CCL-5. Information technology has been shown to be constructive and safety in HIV213 and reduces plasma interleukin-vi levels in covid-19.214 Clinical trials are ongoing to evaluate the efficacy of leronlimab mail service-covid-19 (NCT04343651, NCT04347239, NCT04678830). Another antibody treatment, tocilizumab, blocks interleukin-6 receptors and has shown efficacy in a modest trial of patients with covid-19 patients.215 Trials to explore the effects of tocilizumab are ongoing (NCT04330638). The anti-oxidative and anti-inflammatory role of melatonin may also be useful in treating long covid.216 Lastly, adjuvant treatments, such as adaptogens, are beingness 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, nosotros accept reviewed the studies that have explored the persisting symptoms of long covid, and have addressed the possible chance factors associated with developing long covid and the treatment options that may be useful in alleviating its symptoms. Currently, long covid remains enigmatic and, with the question of the touch that new variants of covid-19 will accept on the incidence and severity of long covid notwithstanding looming large, it is important that enquiry continues to explore post-covid-nineteen syndrome. Greater understanding of the pathogenesis, chance 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 endeavor 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 article. The feedback received assisted in developing and focusing our review towards the experiences of different symptoms experienced by patients with long covid. Cognition and mental health were of particular involvement to patients, which we have addressed in this article.
Enquiry Questions
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What is the precise epidemiology of long covid and how will novel variants of covid-xix touch 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 best reduce an individual'southward hazard of developing long term post-covid-19 symptoms?
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Which symptoms, or ready of symptoms, can nosotros use to classify long covid, clinically and phenotypically, with the aim of improving diagnosis and management?
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What is the optimal treatment and management strategy for long covid and is this strategy non-specific or volition 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 The states 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 primary literature search and drafted parts of the manuscript; HC was the first author of the manuscript who drafted the manuscript and revised it; PE was responsible for the concept and design of the work. PE reviewed and revised the manuscript. PE is the guarantor.
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Competing interests: We have read and understood the BMJ policy on annunciation of interests and declare the following interests: PE was funded by the Medical Enquiry Quango and at present by College Education Funding Council for England (HEFCE). He has besides received grants from Alzheimer's Inquiry, Uk, Alzheimer's Drug Discovery Foundation, Alzheimer'due south Club, UK, Medical Inquiry Council, Alzheimer'due south Association U.s.a., Van-Geest foundation, and Eu grants. PE is a consultant to Roche, Pfizer, and Novo Nordisk. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, 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.
This article is made freely available for use in accord with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You lot may utilise, download and print the commodity for any lawful, not-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
https://bmj.com/coronavirus/usage
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View Abstract
Source: https://www.bmj.com/content/374/bmj.n1648
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