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Long covid—mechanisms, risk factors, and direction

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

Read our latest coverage of the coronavirus pandemic

1. Harry Crook , research banana1,
2. Sanara Raza , inquiry assistant1,
3. Joseph Nowell , research assistantone,
4. Megan Immature , clinical research officer1,
5. Paul Edison , clinical senior lecturer , honorary professor12

1. ^oneKinesthesia of Medicine, Imperial College London, London, U.k.
2. ²Cardiff Academy, Cardiff, UK

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

Abstract

Since its emergence in Wuhan, China, covid-19 has spread and had a profound upshot on the lives and health of people effectually the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 meg deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-two infection, and this status is at present coined long covid past recognized research institutes. Studies take shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the near astringent forms. Like astute covid-19, long covid tin can involve multiple organs and tin affect many systems including, just not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive harm, slumber disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration bug, and headache. This review summarizes studies of the long term furnishings of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they suffer. Gamble factors for acute covid-19 and long covid and possible therapeutic options are also discussed.

Introduction

Coronavirus disease 2019 (covid-19) has spread beyond the world. As of 4 July 2021, more than 183 one thousand thousand confirmed cases of covid-19 have been recorded worldwide, and more than than 3.97 million deaths have been reported past the World Health System .ane The clinical spectrum of covid-nineteen ranges from asymptomatic infection to fatal affliction.23 The virus responsible for causing covid-nineteen, astringent acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 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 past various cytokines in some patients.5 The ACE2 receptor is present in numerous cell types throughout the homo trunk, including in the oral and nasal mucosa, lungs, heart, gastrointestinal tract, liver, kidneys, spleen, brain, and arterial and venous endothelial cells, highlighting how SARS-CoV-2 can cause damage 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 show shows that a range of symptoms tin remain after the clearance of the acute infection in many people who have had covid-19, and this status is known equally long covid. The National Institute for Health and Care Excellence (NICE) defines long covid as the symptoms that continue or develop afterward acute covid-xix infection and which cannot be explained past an alternative diagnosis. This term includes ongoing symptomatic covid-nineteen, from four to 12 weeks post-infection, and post-covid-xix syndrome, across 12 weeks post-infection.9 Conversely, The National Institutes of Health (NIH) uses the U.s. Centers for Disease Command and Prevention (CDC) definition of long covid, which describes the condition as sequelae that extend beyond 4 weeks later initial infection.10 People with long covid exhibit involvement and impairment in the structure and function of multiple organs.11121314 Numerous symptoms of long covid have been reported and attributed to various organs, an overview of which can exist seen in fig ane. Long term symptoms following covid-19 have been observed across the spectrum of disease severity. This review examines the long term bear upon of symptoms reported post-obit covid-19 infection and discusses the electric current epidemiological understanding of long covid, the chance factors that may predispose a person to develop the status, and the treatment and management guidelines aimed at treating information technology.

Fig 1

Multi-organ complications of covid-19 and long covid. The SARS-CoV-2 virus gains entry into the cells of multiple organs via the ACE2 receptor. Once these cells have been invaded, the virus can cause a multitude of damage ultimately leading to numerous persistent symptoms, some of which are outlined here

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Methods

We searched PubMed and Embase databases for articles published between Jan 2020 and May 2021. Our search terms were "long covid" or "post-covid-19" or "COVID long-haulers" or "SARS-CoV-2" and "epidemiology" or "fatigue" or "fatigue syndrome" or "dyspnoea" or "breathlessness" or "shortness of breath" or "cardiac" or "cardiovascular" or "heart" or "cognition" or "cognitive impairment" 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 "smell" or "taste" or "olfactory" or "gustatory" or "risk factors" or "treatment". To avoid unintentionally removing manufactures, no filters were applied. We retrieved 61 881 manufactures in the first example. To screen articles, titles were read past authors first, followed by abstracts to farther narrow downwardly the number of records considered. To avoid 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 blueprint. We discovered and read fully 227 articles on long covid, and we discussed each to determine which would be included in the finalized article. We performed further manual searching for additional articles and handling guidelines using relevant databases, including nice.org.u.k. and clinicaltrials.gov. In total, 218 references were included. Studies examining long covid are express, therefore express exclusion criteria were applied.

Studies of long covid

Studies take assessed people who have had covid-19 to examine the symptoms associated with long covid. These studies are summarized in tabular array i. The articles included throughout this review were selected in favor of quality, with large observational studies of greatest involvement. Most of the studies included are cross-exclusive or cohort observational studies with big cohorts; however, because of the novelty of the disease and paucity of data, studies involving smaller cohorts and case series were also included. Any patient with covid-xix may develop long covid, regardless of the severity of their infection and the intensity of the treatment they received. Patients treated on wards and intensive care units (ICUs) show footling difference in incidence of long term symptoms associated with covid-xix.17 The proportion of people that develop long covid symptoms, whether they are treated with oxygen alone, with continuous positive airway pressure, or with invasive ventilation, is like.16 Many patients with mild astute symptoms also develop long covid symptoms,13 in fact, studies evidence minimal differences between the prevalence of long covid symptoms between hospitalized and not-hospitalized covid-19 patients.19

Table 1

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

Epidemiology

The reported incidence and mortality rates of covid-19 vary betwixt countries, making it difficult to accurately predict the number of patients who will progress to long covid. Similarly, the authentic reporting of long covid is complicated. The disparity in this epidemiological data is likely the issue 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 information of long covid is difficult, this information is needed to inform healthcare systems and governments when developing support and treatment algorithms. The volume of published literature describing cases of patients with covid-19 who subsequently develop long covid symptoms is continually growing, which will allow for an improved agreement of its epidemiology.

The electric current disparities between long covid epidemiology reporting are owing to many reasons, including the length of follow-upwards period, population assessed, accuracy of self-reporting, and symptoms examined. Studies effectually the world have reported various incidence rates for long covid with unlike follow-up test times after the astute infection, including 76% of people at half-dozen months,fifty 32.6% at threescore days,51 87% at threescore days,15 and 96% at 90 days.52 These finding are not fully corroborative, but they show that a substantial proportion of people who take had covid-19 may develop long covid. The United kingdom of great britain and northern ireland Office for National Statistics (ONS) has released data on the prevalence of long covid symptoms.53 They estimated that the five week prevalence of whatsoever symptom amidst survey respondents who tested positive for covid-19 between 22 April and xiv 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 probable to develop long covid and require long term back up and handling. Further studies are required to consolidate our epidemiological understanding of long covid.

Covid-19 variants of concern

Since the outset of the pandemic, several covid-nineteen variants take emerged that accept an increased transmissibility and may effect in more astringent astute disease. In the Britain, one of the start variants of business concern to appear was the so chosen "Kent variant," from the B.ane.1.seven lineage, now termed the Blastoff variant. This variant has approximately 50% increased transmissibility54 and likely increases astute disease 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 to the lowest degree 136 countries effectually the world.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 involvement in the US.58 New covid-19 variants will go on to emerge and spread as we progress through the pandemic, for example, the Eta and Delta variants have arisen, with over 161 000 cases of the rapidly spreading Delta variant confirmed in the UK, every bit of 30 June 2021.56 Recently, the Lambda variant has emerged, which will require shut monitoring. The ability of these viral strains to inflict long term complications needs to exist 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 continue to develop long covid symptoms may require additional back up, as well as more rapid and intense handling strategies to combat their long term symptoms.

Long covid definition

Long covid gained widespread attending following an account published on 5 May 2020 in BMJ Opinion where an infectious disease professor shared his experience of seven weeks on a "rollercoaster of ill health" following covid-xix.59 The patient-made term long covid was then fabricated popular following the rise in the apply of #LongCovid on Twitter.60 This, plus the growing number of peer reviewed manufactures published since, has highlighted a post-covid-19 syndrome that can last for many weeks after the astute 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 than profound than being overtired; it is unrelenting exhaustion and a constant state of weariness that reduces a person'due south energy, motivation, and concentration. Post-obit the SARS outbreak, upwardly to lx% of patients reported ongoing fatigue at 12 months following recovery from the acute illness.61 In long covid, fatigue is one of the most reported manifestations, with the ONS estimating the v week prevalence of fatigue to exist 11.9% among people who have had covid-19.53 Fatigue is a common persisting symptom regardless of severity of the acute stage of covid-xix. One cantankerous-sectional study found that 92.9% and 93.5% of hospitalized and not-hospitalized covid-xix patients, respectively, reported ongoing fatigue at 79 days following onset of affliction.19 Many other cross-sectional and cohort studies report that chronic fatigue is the most frequently reported symptom following recovery from acute covid-19,1517202743 with one showing no association between covid-19 severity and long term fatigue.20 These findings show that fatigue is a major manifestation of long covid.

Possible mechanisms

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

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

Negative psychological and social factors associated with the covid-19 pandemic have likewise been linked to chronic fatigue.6667 Lastly, peripheral factors such as direct SARS-CoV-2 infection of skeletal muscle, resulting in impairment, weakness, and inflammation to muscle fibers and neuromuscular junctions may contribute to fatigue.68697071 Overall, it is likely that several factors and mechanisms play a part in the development of post-covid-19 fatigue. Figure 2 further outlines these possible mechanisms.

Fig 2

Long term sequalae of covid-19
(1) In the alveoli of the lungs: (A) Chronic inflammation results in the sustained production of pro-inflammatory cytokines and reactive oxygen species (ROS) which are released into the surrounding tissue and bloodstream. (B) Endothelial damage triggers the activation of fibroblasts, which deposit collagen and fibronectin resulting in fibrotic changes. (C) Endothelial injury, complement activation, platelet activation, and platelet-leukocyte interactions, release of pro-inflammatory cytokines, disruption of normal coagulant pathways, and hypoxia may result in the development of a prolonged hyperinflammatory and hypercoagulable state, increasing the risk of thrombosis.
(two) In the center: (A) chronic inflammation of cardiomyocytes can result in myositis and cause cardiomyocytes death. (B) Dysfunction of the afferent autonomic nervous system can cause complications such as postural orthostatic tachycardia syndrome. (C) Prolonged inflammation and cellular damage prompts fibroblasts to secrete extracellular matrix molecules and collagen, resulting in fibrosis. (D) Fibrotic changes are accompanied past an increase in cardiac fibromyoblasts, while harm to desmosomal proteins results in reduced cell-to-prison cell adhesion.
(three) In the fundamental nervous organization: (A) The long term immune response activates glial cells which chronically harm neurons. (B) Hyperinflammatory and hypercoagulable states atomic number 82 to an increased adventure of thrombotic events. (C) Blood-encephalon barrier damage 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 encephalon tin lead to cognitive impairment.
(4) Possible mechanisms causing post-covid-xix fatigue. A range of central, peripheral, and psychological factors may crusade chronic fatigue in long covid. Chronic inflammation in the brain, too as at the neuromuscular junctions, may outcome in long term fatigue. In skeletal musculus, sarcolemma harm and fiber cloudburst and impairment may play a role in fatigue, as might a number of psychological and social factors

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Mail service-COVID-19 fatigue has been compared with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), with many overlaps between the two.72 Symptoms common to both ME/CFS and long covid include fatigue, neurological/pain, neurocognitive/psychiatric, neuroendocrine, autonomic, and immune symptoms, with both ME/CFS and long covid patients having long symptom durations, reduced daily activity, and post-exertional angst.72 ME/CFS remains enigmatic, therefore, research into long covid may aid in developing understanding of ME/CFS and vice versa.

Dyspnea

Breathlessness is common in people with long covid. The ONS estimates that shortness of breath has a prevalence of 4.six% at 5 weeks post-covid-19 infection, regardless of presence of acute respiratory symptoms or disease severity.53 Abnormalities in improvidence capacity for carbon monoxide, total lung capacity, forced expiratory book in the first 2d, forced vital capacity, and pocket-sized airway function, have been seen in hospitalized covid-xix patients at time of discharge, approximately 1 month post-obit onset of symptoms, showing that lung function in people who take had covid-19 may have fourth dimension to recover.73 Several studies take establish that dyspnea is a mutual manifestation following covid-19 infection,1617 and one written report reported that 43.4% of 143 patients assessed were still experiencing dyspnea at 60 days after covid-19 onset.15

Possible mechanisms

As covid-19 is principally a respiratory illness, acute illness tin cause substantial harm to the lungs and respiratory tract via SARS-CoV-2 replication inside endothelial cells, resulting in endothelial impairment and an intense allowed and inflammatory reaction.7475 Those who overcome the astute infection may develop long term lung abnormalities, leading to dyspnea76; however, most individuals who develop long term animate difficulties post-covid-19 have no signs of permanent or longlasting lung damage.2877 Information technology is likely that only those at high risk of developing animate difficulties, including older people, those who endure astute respiratory distress syndrome, those who have extended hospital stays, and those with pre-existing lung abnormalities, are prone to develop fibrotic-like changes to lung tissue.78 The fibrotic state observed in some patients with ongoing dyspnea may be provoked past cytokines such as interleukin-half dozen, 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 have detrimental consequences in patients with long covid. An overview of the possible mechanism causing dyspnea is outlined in fig 2.

Cardiovascular abnormalities

Cardiac injury and elevated cardiac troponin levels are associated with a significantly increased chance of mortality in patients admitted to hospital with acute 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 instance series showed that breast pain, possibly attributable to myocarditis, was a common manifestation in patients 60.3 days post-obit onset of covid-19 symptoms, with 21.seven% of the 143 patient assessed reporting chest pain.15 Those considered at low risk of severe covid-19, such every bit young, competitive athletes, have also been constitute to have residue myocarditis long after recovery from covid-19.84 In addition to cardiac complaints, studies have highlighted an emerging trend in the development of new onset postural orthostatic tachycardia syndrome (POTS) in individuals postal service-covid-xix infection, considering of autonomic dysfunction.8586878889

Possible mechanisms

ACE2 receptors are highly expressed in the centre,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-2.9192 Pathological responses to astute cardiac injury and viral myocarditis, such as endothelial impairment and microthrombosis, can lead to the development of coagulopathy,93 while chronic hypoxia and an increase in pulmonary arterial pressure and ventricular strain may further precipitate the incidence of cardiac injury in people who have had covid-xix.94 Furthermore, sustained allowed activation tin can lead to fibrotic changes95 and displacement of desmosomal proteins,96 which could be arrhythmogenic. Viral infection has previously been shown to precede POTS97 and, with the ACE2 receptor expressed on neurons, viral infection by SARS-CoV-ii may have direct negative consequences on the autonomic nervous system.98 A complex combination of infection, an autonomic nervous arrangement 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 role and deficits in patients with covid-19 and suggest that the virus can cause septic encephalopathy, not-immunological effects such equally hypotension, hypoxia, and vascular thrombosis, and immunological effects such every bit adaptive autoimmunity, microglial activation, and a maladaptive cytokine profile.99 Additionally, patients admitted to hospital with covid-19 have presented with a range of complaints including encephalopathy, cerebral 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 common, diverse, and could pose substantial issues for rehabilitation and ongoing care following recovery from covid-19. It is unknown who is near affected past cognitive complaints induced past covid-nineteen and how long they persist; however, patient experiences and published summaries of long covid accept described "brain fog" to be a common and debilitating symptom.102103104

Critical illness, severe acute respiratory syndrome, and long term ventilator back up are known to take detrimental effects on long term cognition. Before the covid-19 pandemic, a retrospective study of 1040 ICU treated patients who had respiratory failure, stupor, or both during hospital stays, found that 71% had delirium which lasted around four months following belch.105 A like study constitute that, at three months post-belch, twoscore% of ICU treated patients had cognition scores similar those of patients with moderate traumatic brain injury, while 26% had scores similar to patients with mild Alzheimer'southward disease. Delirium was also widely reported, with a longer duration of delirium associated with worse cognition.106 With many covid-xix patients requiring ICU admission and mechanical ventilation, long term cerebral impairment and delirium are likely to pose considerable problems.

Stroke and headache are prevalent in those recovered from acute covid-19, with the ONS estimating the 5 calendar week prevalence of headache at 10.i% of all covid-19 survivors.1318344353 Exaggerated levels of systemic inflammation, observed in some patients every bit a "cytokine storm," in add-on to activation glial cells, poses a substantial chance to the brain and increases the likelihood of neurological manifestations including encephalitis and stroke.74 Hypercoagulability107 and cardio-embolisms, formed considering of virus related cardiac injury,108 are manifestations that could issue in increased incidences of stroke following covid-19 infection. Covid-19 has likewise been associated with an increased take a chance of developing neurological weather including Guillain-Barré syndrome,109 and neurodegenerative weather such every bit Alzheimer's affliction.110

The pandemic has had a negative outcome on mental health, with people who have had covid-19 exhibiting long term psychiatric symptoms including post-traumatic stress disorder (PTSD), depression, feet, and obsessive-compulsive symptoms following recovery from the acute infection.3637111112 Quarantine, isolation, and social distancing too have damaging furnishings on mental health and noesis. 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 crisis tin can lead 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, one study found that negative changes of these factors were non solely owing to longitudinal situations before 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 alone.115 Protracted social isolation has resulted in exacerbation of neuropsychiatric and behavioral disturbances, including apathy, anxiety, agitation, colorlessness, and defoliation in dementia patients living in intendance homes, to a greater degree than for care home residents without dementia.116117

Sleeplessness is also commonly reported following recovery from covid-nineteen, with many studies finding poor sleep quality and sleep disturbances to be frequent following recovery from acute illness.16253144118119 Furthermore, a retrospective report of medical records of covid-19 patients treated in Seoul, South Korea, establish that after prescriptions to care for fever, cough, and rhinorrhea, medications for slumber problems were the adjacent most prescribed treatments.120 Knowledge of the covid-19 decease cost also has a negative impact on quality of sleep, stress, feet, and other negative emotions,121 and sleep problems accept been shown to be associated with covid-nineteen related loneliness.122 This leads us to question whether post-covid-19 sleep disturbances are a result of covid-19 infection, the negative furnishings of the pandemic, or a combination of both.

Possible mechanisms

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

Olfactory and gustatory dysfunction

Abnormalities of olfactory property and gustation have been reported to persist following recovery from covid-xix. The ONS estimated the 5 week prevalence of loss of aroma and loss of taste equally 7.9% and 8.ii% of all people who have had covid-xix, 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

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

ACE2 receptors are too expressed on the mucous membrane of the oral cavity, particularly on the tongue,130 therefore SARS-CoV-2 has a direct road of entry into oral tissue, which may effect in cellular injury and dysfunction. Moreover, SARS-CoV-2 may bind to sialic acid receptors,131 causing an increase in gustatory threshold and resulting in degradation of gustatory particles before they can exist 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 commonly reported manifestations

Covid-19 infection can issue in multi-organ impairment in individuals with low or high adventure for severe acute illness.213 Studies show the presence of acute kidney injury in discharged patients who have recovered from covid-19.134135136 Although the long term effects of covid-xix on the kidneys are not fully elucidated, a study assessing kidney role in patients with covid-19 found that 35% had decreased kidney function at half dozen months postal service-belch.50

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 mild cases, and computed tomography images have shown pancreatic injury.138 A cantankerous exclusive study found that 40% of patients with covid-19 who were at low risk of astringent 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 as infarcts.139140141 A cross exclusive study found balmy damage of the spleen in iv% of those assessed at 141 days following clearance of covid-xix.thirteen Other organs and tissues, such as the liver, gastrointestinal tract, muscle, and blood vessels limited 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-xix infection.

Possible mechanisms

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

Take chances factors

Risk factors for severe covid-xix and infirmary admission, and risk factors for death equally a consequence of covid-19 include older historic period, male person sexual activity, non-white ethnicity, being disabled, and pre-existing comorbidities including obesity, cardiovascular disease, respiratory illness, and hypertension.21319147148 Linked to risk of covid-19 severity and perhaps the risk of long covid, the office of allowed suppression is still being debated. Allowed suppression may have protective effects against long term effects of covid-19 infection149150151; however, these findings are conflicted.152153

The hazard factors for developing long covid are less appreciated. To explore the characteristics associated with symptoms of long covid, 274 non-hospitalized patients who had covid-19 were interviewed between 14 and 21 days following their positive test. Risk factors for not returning to "usual health" included historic period (P=0.01), with the ≥50 years age group having the greatest odds ratio, and number of pre-existing medical atmospheric condition (P=0.003), with a greater number of conditions associated with a greater odds ratio of not returning to "usual wellness." Of the pre-existing weather 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 condition (OR=2.33, P=0.047) corresponded with the greatest odds of not returning to "usual health."18

A cross sectional report identified an association between the severity of astute covid-nineteen infection and post-recovery manifestations in people who have had covid-19, showing that a more than severe astute phase 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-19 infection and those that required infirmary access more likely to experience long covid symptoms.34

Although certain factors may increase the gamble of both astringent covid-19 and long covid, some factors associated with covid-19 do not also increment risk for long covid. Male sex activity and older historic period are associated with an increased gamble of severe covid-nineteen, however, the ONS reported that the prevalence of whatsoever long covid symptoms is higher in women compared with men (23.6% versus twenty.7%), while the historic period group estimated to be almost profoundly afflicted by long covid symptoms is 35-49 years (26.8%), followed by l-69 years (26.1%), and the ≥70 years group (eighteen%).53 Furthermore, a prospective cohort report assessing recovered patients institute no baseline clinical features associated with the subsequent development of long covid symptoms.154 Male sexual activity, historic period, and pre-existing conditions including obesity, diabetes, and cardiovascular illness take shown no association with the risk of developing long covid. Still, pre-existence of asthma has been found to be significantly associated with long covid.34

Treatment and direction of long covid

WHO and the Long Covid Forum Grouping agree that research 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 sure disease phenotypes ascend in different individuals is an of import piece of the puzzle. A review, which included perspectives from patients with long covid, suggested that the status may actually be four dissimilar 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 place, refer, and treat patients with long covid. The holistic assessment, investigation, and management approaches suggested past NICE9 are outlined in fig iii. 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 petty detail about long covid, however. Similarly, the NIH has released treatment guidelines for covid-xix,158 but little guidance on managing long covid. The CDC is expected to release guidance on long covid management before long.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 will undoubtedly evolve as new evidence comes to light; however, other full general guidelines, such as Bear witness 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's ability, for example the one minute sit-to-stand test, and treatment and direction should be multidisciplinary, with advice and educational activity given on managing breathlessness. Furthermore, the guidelines recommend offering patients with continuing respiratory symptoms a chest radiograph by 12 weeks after infection.9 Claret oxygen levels can exist monitored using a pulse oximeter.

Recommendations from the Mayo Dispensary advise that shortness of breath can exist self-managed by limiting factors that exacerbate dyspnea, including stopping smoking, avoiding pollutants, avoiding extremes in temperature, and exercising,162 however, chronic shortness of breath may crave further intervention. Recognized non-pharmacological strategies for managing dyspnea include breathing exercises,163 pulmonary rehabilitation,164 and maintaining optimal trunk positioning for postural relief.165 Meanwhile, a systematic review has plant 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-xix 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 benign long term effects on respiratory symptoms in balmy covid-19 patients in a small trial.171

Cardiovascular symptoms

The Overnice guidelines on long covid state that exercise tolerance tests may be undertaken to measure centre part, while lying and continuing blood pressure and heart rate recordings should be performed if postural orthostatic tachycardia syndrome (POTS) is suspected.9 Urgent referral should occur for people that have symptoms of a life threating complication, such as cardiac breast pain.

The European Order of Cardiology has released comprehensive guidance for the diagnosis and management of cardiovascular illness during the covid-19 pandemic.160 The range of cardiovascular conditions that tin can manifest in long covid translates to a wide range of potential therapeutic options, therefore, ongoing investigation and observation of cardiac biomarkers is important. Squeamish 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; however, supportive and/or immunomodulating therapy may improve recovery, as a systematic review describes.175 A review has also suggested that anticoagulants may exist used to reduce the risks associated with hypercoagulability.176 Meanwhile, advice and didactics, agents to maintain vascular tone, and agents to manage palpitations have been shown by a randomized controlled trial and discussed in a review to be advantageous in the treatment of POTS.89177

Treating fatigue, cognitive, and neuropsychiatric symptoms

Chronic fatigue is a mutual manifestation of long covid. Prissy recommends that cocky-management and support are important in managing fatigue, owing to the poor availability of covid-xix specific treatment.9 A status that may overlap with long covid fatigue is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), therefore, the treatment algorithm designed for treating ME/CFS may prove useful in treating post-covid-xix fatigue. Dainty has specific guidelines that outline how to refer and care for ME/CFS patients; these include cerebral behavioral therapy (CBT) and graded practice therapy (Go).178 Following backlash over these guidelines from the ME Association,179 withal, NICE aims to publish revised guidelines in August 2021.180

Randomized controlled trials accept shown that CBT is benign in the treatment of chronic fatigue,181 withal, this is conflicted by 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 process demonstrated similarly high rates of adverse effects, so information technology would not be accepted every bit a safe treatment option, therefore CBT should take 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. Squeamish guidelines for ME/CFS178 draw pacing equally a self-direction strategy, yet guidance and instruction from healthcare professionals may exist useful for patients. Show from randomized controlled trials for the employ of pacing in long covid is yet to be seen.

The implementation of grouping therapy via videoconferencing in people with early psychosis during the covid-19 pandemic shows promising results, with a 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 ten% of participants achieving clinically meaningful improvements.184

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

Evidence specific to covid-19 is lacking, therefore cognitive impairment should be managed with back up, including setting tailored, achievable goals and implementing validated screening tools.ix Managing cognitive impairment will require a holistic approach, yet, patients should exist brash that most people gradually recover from cerebral impairment following astringent disease.106189 The holistic approach to treatment should extend to the services offered, with professionals including occupational and speech and language therapists addressing cognitive changes.190 Cognitive impairment in long covid, sometimes called "encephalon 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 damage by inhibiting mast cell and microglia activation,191 but clinical trials are required.

Slumber disturbances may exist managed by following relevant guidelines on insomnia,193 and a range of treatment strategies tin can be considered.194195196197 Patients with mental health problems alongside or equally a result of long covid can exist managed following the relevant guidelines: depression,198 anxiety,199 PTSD,200 obsessive-compulsive disorder,201 and other mental health problems.202 Care domicile residents, including those with dementia, who acquire long covid take additional needs.116 Discussing mental health problems with patients requires compassion and understanding.203

Treating other organ impairments

Current evidence for the recovery of renal function following covid-xix is lacking. Considering that early and shut follow-ups with nephrologists take previously been beneficial,204 mail-covid-19 patients with renal dysfunction may do good from early and ongoing monitoring. Covid-19 tin disrupt and alter the microbiome of the gut, which may permit for opportunistic infections.145 Covid-19 associated destructive thyroiditis can upshot in incident hyperthyroidism, which tin exist treated with corticosteroids.142 Overall, shut follow-upwards 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 take been implicated as a possible treatment for covid-19, with a report that employed cellular experiments suggesting that histamine-ane antagonists may be able to reduce the covid-19 infection charge per unit by inhibiting SARS-CoV-2 from inbound ACE2 expressing cells.205 Systematic reviews and molecular studies accept suggested that histamine-i 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 have been proposed to reduce the effects of long covid. Antidepressant utilise has been associated with reduced risk of intubation or death in covid-xix,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 care for respiratory atmospheric condition in long covid are ongoing. A trial of breathing exercises and singing is also under fashion to assess their utility in improving breathing abnormalities in patients with long covid (NCT04810065).

A trial to assess the effectiveness of an 8 week 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 terminal 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 understanding of long term sequalae of covid-19 infection in the gastrointestinal tract will evolve, with studies currently ongoing (NCT04691895), which will subsequently affect handling.

Other potential treatments are molecules that suppress the intense inflammatory response seen in covid-19. Leronlimab is a monoclonal antibody that blocks the function of CCL-v. It has been shown to be effective and condom in HIV213 and reduces plasma interleukin-6 levels in covid-nineteen.214 Clinical trials are ongoing to evaluate the efficacy of leronlimab post-covid-19 (NCT04343651, NCT04347239, NCT04678830). Another antibody handling, tocilizumab, blocks interleukin-six receptors and has shown efficacy in a modest trial of patients with covid-xix patients.215 Trials to explore the effects of tocilizumab are ongoing (NCT04330638). The anti-oxidative and anti-inflammatory function of melatonin may too be useful in treating long covid.216 Lastly, adjuvant treatments, such every bit adaptogens, are being explored for their effectiveness in treating long covid (NCT04795557).

Decision

With many people having been infected and standing to be infected with covid-19, the long term implications are of increasing concern. Here, we have reviewed the studies that take explored the persisting symptoms of long covid, and take addressed the possible risk factors associated with developing long covid and the treatment options that may be useful in alleviating its symptoms. Currently, long covid remains enigmatic and, with the question of the touch on that new variants of covid-19 will accept on the incidence and severity of long covid still looming large, it is of import that research continues to explore post-covid-19 syndrome. Greater agreement 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 will endeavor to support them.

How patients were involved in the cosmos of this commodity

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

Research Questions

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

• What are the major adventure factors for long covid and how practice nosotros best reduce an private'southward run a risk of developing long term mail service-covid-nineteen symptoms?

• Which symptoms, or set of symptoms, can we utilise to classify long covid, clinically and phenotypically, with the aim of improving diagnosis and management?

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

Footnotes

• Country of the Art Reviews are deputed on the footing of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly past US authors

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

• Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: PE was funded by the Medical Research Council and at present past Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer'due south Enquiry, U.k., Alzheimer's Drug Discovery Foundation, Alzheimer's Society, United kingdom, Medical Research Quango, Alzheimer'due south Association US, Van-Geest foundation, and European Wedlock grants. PE is a consultant to Roche, Pfizer, and Novo Nordisk. He has received educational and inquiry 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.

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

This article is fabricated freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined past BMJ. You may use, download and impress the commodity for whatever lawful, not-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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References

1. ↵
2. ↵
3. ↵

   Kim GU, Kim MJ, et al. Clinical characteristics of asymptomatic and symptomatic patients with mild covid-xix. Clin Microbiol Infect 2020;26:948e1-3.

4. ↵
5. ↵
6. ↵
7. ↵
8. ↵
9. ↵
10. ↵
11. ↵
12. ↵
13. ↵

    Dennis A, Wamil Thou, Kapur S, et al. Multi-organ impairment in depression-gamble individuals with long COVID. MedRxiv 2020;x.14.20212555 [preprint] doi:ten.1101/2020.10.14.20212555

14. ↵
15. ↵
16. ↵
17. ↵
18. ↵
19. ↵
20. ↵
22. ↵
23. ↵
24. ↵
25. ↵
27. ↵
28. ↵
31. ↵

    Savarraj JPJ, Burkett AB, Hinds SN, et al. Three-month outcomes in hospitalized COVID-19 patients. MedRxiv 2020 [preprint] 10.16.20211029.

33. Valiente-De Southward, Pérez-Camacho I, Sobrino B, et al. Clinical and immunoserological status 12 weeks after infection with COVID-19: prospective observational study. MedRxiv [preprint] 2020. 2020.10.06.20206060.

34. ↵
36. ↵
37. ↵

38. Klein H, Asseo K, Karni N, et al. Onset, duration, and persistence of gustatory modality and smell changes and other COVID-xix symptoms: longitudinal study in Israeli patients. MedRxiv [preprint] 2020. 2020.09.25.20201343 doi:ten.1101/2020.09.25.20201343.

39. ↵

40. Eiros R, Barreiro-Perez M, Martin-Garcia A, et al. Pericarditis and myocarditis long after SARS-CoV-two infection: a cantankerous-exclusive descriptive study in health-intendance workers. MedRxiv [preprint] 2020. 2020.07.12.20151316.

43. ↵
44. ↵
47. ↵
50. ↵
51. ↵
52. ↵
53. ↵
54. ↵
55. ↵
56. ↵
57. ↵
58. ↵
59. ↵
60. ↵
61. ↵
62. ↵
63. ↵
64. ↵
65. ↵
66. ↵
67. ↵
68. ↵
69. ↵
70. ↵
71. ↵
72. ↵
73. ↵
74. ↵
75. ↵
76. ↵
77. ↵
78. ↵
79. ↵
80. ↵
81. ↵
82. ↵
83. ↵
84. ↵
85. ↵
86. ↵
87. ↵
88. ↵
89. ↵
90. ↵
91. ↵
92. ↵
93. ↵
94. ↵
95. ↵
96. ↵
97. ↵
98. ↵
99. ↵
100. ↵
101. ↵
102. ↵
103. ↵

     Sleat D, Wain R, Miller B. Long covid: reviewing the science and assessing the risk. Tony Blair Institute for Global Change. 2020. https://institute.global/sites/default/files/articles/Long-Covid-Reviewing-the-Science-and-Assessing-the-Take chances.pdf

104. ↵
105. ↵
106. ↵
107. ↵
108. ↵
109. ↵
110. ↵
111. ↵
112. ↵
113. ↵
114. ↵
115. ↵
116. ↵
117. ↵
118. ↵
119. ↵
120. ↵
121. ↵
122. ↵
123. ↵
124. ↵
125. ↵
126. ↵
127. ↵
128. ↵
129. ↵
130. ↵
131. ↵

     Milanetti M, Miotto M, Rienzo LD. Monti Chiliad, Gosti K, Ruocco G. In-silico testify for two receptors based strategy of SARS-CoV-2. bioRxiv [preprint] 2020:11107.

132. ↵
133. ↵
134. ↵
135. ↵
136. ↵
137. ↵
138. ↵
139. ↵
140. ↵
141. ↵
142. ↵
143. ↵
144. ↵
145. ↵
146. ↵
147. ↵
148. ↵
149. ↵
150. ↵
151. ↵
152. ↵
153. ↵
154. ↵
155. ↵
156. ↵
157. ↵
158. ↵
159. ↵
160. ↵
161. ↵
162. ↵
163. ↵
164. ↵
165. ↵
166. ↵
167. ↵
168. ↵
169. ↵

     National Institute for Wellness and Care Excellence. Bronchiectasis (non-cystic fibrosis), acute exacerbation: antimicrobial prescribing NICE guideline. 2018. https://www.nice.org.uk/guidance/ng117

170. ↵
171. ↵
172. ↵
173. ↵
174. ↵
175. ↵
176. ↵
177. ↵
178. ↵

     National Institute for Health and Care Excellence. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and direction clinical guideline. 2007. https://www.nice.org.united kingdom/Guidance/CG53

179. ↵
180. ↵
181. ↵
182. ↵
183. ↵
184. ↵
185. ↵
186. ↵
187. ↵
188. ↵
189. ↵
190. ↵
191. ↵
192. ↵
193. ↵
194. ↵

     National Institute for Health and Care Excellence. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of indisposition. 2004. https://www.nice.org.uk/Guidance/TA77

195. ↵
196. ↵
197. ↵
198. ↵
199. ↵
200. ↵
201. ↵
202. ↵
203. ↵
204. ↵
205. ↵
206. ↵
207. ↵
208. ↵
209. ↵
210. ↵
211. ↵
212. ↵
213. ↵
214. ↵
215. ↵
216. ↵

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