Long COVID: presentation

This wiki is intended for healthcare professionals and should not be considered medical advice.

This page primarily concentrates on the presentation of Long COVID. There is also a Management page.

General
Centers for Disease Control and Prevention (Nov 2020). Late Sequelae of COVID-19

[https://jamanetwork.com/journals/jama/fullarticle/2771581 Long-term Health Consequences of COVID-19. del Rio C, Collins LF, Malani P. JAMA. 2020;324(17):1723–1724. doi:10.1001/jama.2020.19719]

Report: What Does COVID-19 Recovery Actually Look Like? Other version: [https://docs.google.com/document/u/1/d/1KmLkOArlJem-PArnBMbSp-S_E3OozD47UzvRG4qM5Yk/mobilebasic?fbclid=IwAR2stV3rKaXkTm5nLzKR4xSMxJg1rTPg4xexWPOkKoYzts_Amvl-ilTORZY#h.qiq796jt7uug Assaf G. et al. (11 May 2020) '''What Does COVID-19 Recovery Actually Look Like? An Analysis of the Prolonged COVID-19 Symptoms Survey by Patient-Led Research Team'''. COVID-19 Body Politics Slack]

[https://dig.abclocal.go.com/wls/documents/2020/072720-wls-covid-symptom-study-doc.pdf Lambert, N. J. & Survivor Corps. COVID-19 “Long Hauler” Symptoms Survey Report.]

Bishof, K. (2020) COVID-19 Confirmed Case Long-hauler Survey, 1,700 Respondents.

Roberts M. et al. (1 May 2020) Covid-19: a complex multisystem clinical syndrome. BMJ Opinion.

[https://jamanetwork.com/journals/jama/fullarticle/2768351 Carfì A. et al. (9 July 2020) Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020;324(6):603-605. doi:10.1001/jama.2020.12603]

Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App Sudre et al medRxiv 2020.10.19.20214494 doi: https://doi.org/10.1101/2020.10.19.20214494

Cennimo DJ, Bergman SJ and Olsen KM. (Updated 14 Jan 2021 when accessed 19 Jan) Coronavirus Disease 2019 (COVID-19) - Clinical Progression - Long COVID Syndrome. Medscape (website). Log-in required but free registration.

Conferences
US NIH workshop on long COVID (video)

ISARIC and GLOPID-R Long COVID Forum (video). Conference from 9-10 December 2020.

Prevalence
Office of National Statistics ( Jan 2021). Updated estimates of the prevalence of long COVID symptoms (Excel).
 * Prevalence of any symptom at 5 wks after positive test:
 * All: 22.1 % five weeks any symptoms w/c 27 December 2020 (95% CI 21.2 to 23.2%)
 * Gender: Male 20.7% (95% CI 19.3-22.1%), Female 23.6% (95% 22.2-25.0%)
 * Age:
 * 27% at age 35-49
 * 26% at age 50-69
 * 25% at age 25-34
 * 18% at >=70
 * 17% at age 17-24
 * 15% at age 12-16
 * 13% at age 2-10
 * Symptoms lasting 5-12 weeks absolute number 301,000 (95% CI 274,000 to 329,000)

Office of National Statistics (16 Dec 2020). Media statement: The prevalence of long COVID symptoms and COVID-19 complications. (Excel)
 * Symptomatic at 5 weeks post-infection 21%
 * Symptomatic at 12 weeks post-infection 9.9%
 * Median symptom duration 39.5 days

Mandal S, Barnett J, Brill SE, et al‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19 Thorax Published Online First: 10 November 2020. doi: 10.1136/thoraxjnl-2020-215818

Tanner C. (12 August 2020) ‘Long haul’ Covid: With almost 600,000 UK sufferers, the professor studying post-Covid syndrome tells us what we know so far. iNews

DutchNews (12 June 2020) Coronavirus takes ‘shocking’ toll on health: patient survey DutchNews

Dutch Lung foundation (2020) Dutch Lung foundation: Health of Corona patients at home in alarmingly poor health even after months. Publication, based on an Interview with Longfonds Director, Michael Rutgers.

Bishof, K. (2020) COVID-19 Suspected & confirmed cases - no length requirements, 700 respondents.

[https://www.medrxiv.org/content/10.1101/2020.11.24.20238261v2 Walsh-Messinger, J et. al. The Kids Are Not Alright: A Preliminary Report of Post-COVID Syndrome in University Students] medRxiv Posted online: 29 November 2020. doi.org/10.1101/2020.11.24.20238261

Results 51% of participants who contracted COVID-19 (N=43) experienced symptoms ≥28 days and were classified as having post-COVID syndrome [...]

Interpretation Our results contradict the perception that this “yet to be defined” post-COVID syndrome predominantly affects middle-aged adults and suggest that exercise intolerance, dyspnea, chest pain, chemosensory impairment, lymphadenopathy, rhinitis, and appetite loss may differentiate post-COVID syndrome from general symptoms of pandemic, age, and academic related stress. These findings are also consistent with previous reports that females are more vulnerable to this post viral syndrome. Large-scale population-based studies are essential to discerning the magnitude and characterization of post-COVID syndrome in young adults as well as more diverse populations.

Diagnosis
A diagnosis of COVID-19 can either be done on a clinical basis or through positive laboratory findings:


 * WHO COVID-19: Case Definitions


 * ICD-10: The International Classification of Diseases

U07.2 COVID-19, virus not identified

Use this code when COVID-19 is diagnosed clinically or epidemiologically but laboratory testing is inconclusive or not available.


 * NHSE National Guidance for post-COVID syndrome assessment clinics

Page 4:

1. Purpose

The purpose of this document is to provide commissioning guidance on the development of a specification to assist local healthcare systems to establish post-COVID assessment clinics for patients experiencing long-term health effects following COVID-19 infection. Clinics will offer physical, cognitive and psychological assessments with the aim of providing consistent post-COVID syndrome services for all who need them, whether they were hospitalised or not and regardless of whether clinically diagnosed or by a SARS-CoV2 test.

Public Health
Leung TYM, Chan EW, Chan VKY, Chan CSL, Chui BJ et al Short- and potential long-term adverse health outcomes of COVID-19: a rapid review Emerging Microbes & Infections, 2020. 9:1, 2190-2199, DOI: 10.1080/22221751.2020.1825914

Conclusion This review of current evidence on the short-term and potential long-term health outcomes of COVID-19 showed that multiple organ systems as well as mental health are affected by the COVID-19 pandemic. The burden of caring for COVID-19 survivors are likely to be huge. Therefore, it is important for policy makers to develop a comprehensive strategy in providing resources and capacity in the healthcare system. Future epidemiological studies are needed to further investigate the risk factors associated with adverse outcomes in patients with COVID-19 and monitor the long-term health impact.

Autoimmune and allergy
Icenogle, Timothy. COVID-19: Infection or Autoimmunity. Frontiers in immunology vol. 11 2055. 11 Sep. 2020, doi:10.3389/fimmu.2020.02055

Woodruff, M.C., Ramonell, R.P., Nguyen, D.C. et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol 21, 1506–1516 (Oct 2020). https://doi.org/10.1038/s41590-020-00814-z

Rodríguez, Yhojan et al. Autoinflammatory and autoimmune conditions at the crossroad of COVID-19. Journal of autoimmunity vol. 114 (Jun 2020): 102506. doi:10.1016/j.jaut.2020.102506

Cardiovascular
Christine A’Court, Mayooran Shanmuganathan, Juan Carlos Leoni-Moreno. COVID-19 and cardiac considerations in the community. British Journal of General Practice 2020; 70 (700): 524-525. DOI: 10.3399/bjgp20X713141

Pugh R. (12 August 2020) Long COVID and Inflammation: A Cardiologist's Expert View. Medscape. Available from: https://www.medscape.com/viewarticle/935488

Puntmann V. O. et al. (2020) Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19).JAMA Cardiologydoi:10.1001/jamacardio.2020.3557 Available from: https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916

Dixon H. (21 July 2020) Pathophysiology of COVID-19: Myocarditis. Journal of Anaesthesia Practice Available from: http://japractice.co.uk/2020/07/pathophysiology-of-covid-19-myocarditis/13680

Dweck, M. R. et al. (18 June 2020) Global evaluation of echocardiography in patients with COVID-19.EuropeanHeart Journal –Cardiovascular Imaging; 2020,21,9 pg949-958 doi: https://doi.org/10.1093/ehjci/jeaa178Available from: https://academic.oup.com/ehjcimaging/article/21/9/949/5859292

Bakker, J.(13 July 2020) Heart scans could lead to better treatment for patients in hospital with coronavirus. British Heart FoundationAvailable from: https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2020/july/heart-scans-abnormal-in-covid-19

Akhmerov, A. Marbán, E. (7 April 2020) COVID-19 and the Heart. Circulation Research; 2020;126 pg 1443-1455 doi: https://doi.org/10.1161/CIRCRESAHA.120.317055 Available from: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.317055

Anastasia Shchedrygina, Eike Nagel, Valentina O. Puntmann & Silvia Valbuena-Lopez COVID-19 myocarditis and prospective heart failure burden Expert Review of Cardiovascular Therapy, 2020 DOI: 10.1080/14779072.2021.1844005

Abstract Introduction COVID-19 is causing considerable morbidity and mortality worldwide. Serious respiratory complications aside, the heart is also frequently involved. The mechanisms and the extent of the myocardial injury, along with the short and long-term cardiovascular (CV) outcomes in COVID-19 survivors remain unclear.

Areas covered Myocardial injury has been found in a considerable proportion of hospitalized COVID-19 patients and is associated with a worse prognosis. The late onset of CV complications with myocarditis-like changes revealed by CMR has been reported in COVID-19 survivors. Previous observational studies on viral myocarditis provide evidence of a significant incomplete recovery with residual dysfunction and remodeling of left ventricle. Incomplete recovery is thought to be the result of persistent myocardial inflammation due to a post-viral autoimmune response. Considering the significant inflammatory nature of COVID-19, COVID-19 survivors may be at risk of developing persistent residual myocardial injury, the sequelae of which are unclear.

Expert commentary COVID-19 is an emerging threat for the heart. The extent of CV injury, along with the short and long-term sequelae, requires further investigation. The early detection of residual myocardial changes in COVID-19 survivors is of utmost importance in order to identify those patients at risk of CV complication development.

Rajpal S, Tong MS, Borchers J, et al. Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering From COVID-19 Infection JAMA Cardiol. September 11, 2020. 2021;6(1):116–118. doi:10.1001/jamacardio.2020.4916

Abstract Myocarditis is a significant cause of sudden cardiac death in competitive athletes and can occur with normal ventricular function. Recent studies have raised concerns of myocardial inflammation after recovery from coronavirus disease 2019 (COVID-19), even in asymptomatic or mildly symptomatic patients. Our objective was to investigate the use of cardiac magnetic resonance (CMR) imaging in competitive athletes recovered from COVID-19 to detect myocardial inflammation that would identify high-risk athletes for return to competitive play.

Dysautonomia
Click here for Dysautonomia resources

Kanjwal K, Jamal S, Kichloo A, Grubb BP. New-onset Postural Orthostatic Tachycardia Syndrome Following Coronavirus Disease 2019 Infection J Innov Card Rhythm Manag. 2020 Nov; 11(11): 4302–4304 doi: 10.19102/icrm.2020.111102

Abstract Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. We report a case of new-onset postural orthostatic tachycardia syndrome in an otherwise healthy female patient following COVID-19 infection. The patient presented with fatigue, orthostatic palpitations, dizziness, and presyncope. She underwent head-up tilt-table testing and the findings were suggestive of postural orthostatic tachycardia syndrome.

Conclusion ''Autonomic dysfunction presenting as POTS can be a delayed manifestation of COVID-19 infection. A high index of suspicion in post–COVID-19 patients who present with orthostatic symptoms may lead to proper diagnosis and treatment in such patients.''

Dani, M. et. al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies Clinical Medicine 2020, Vol 21 No 1 January 2021 Published ahead of Print, published on November 26, 2020 doi:10.7861/clinmed.2020-0896

Abstract The SARS-CoV-2 (COVID-19) pandemic has caused unprecedented morbidity, mortality and global disruption. Following the initial surge of infections, focus shifted to managing the longer-term sequelae of illness in survivors. ''‘Post-acute COVID’ (known colloquially as ‘long COVID’) is emerging as a prevalent syndrome. It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance) which can last for weeks or more following mild illness. We describe a series of individuals with symptoms of ‘long COVID’, and we posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. We suggest that all physicians should be equipped to recognise such cases, appreciate the symptom burden and provide supportive management. We present our rationale for an underlying impaired autonomic physiology post-COVID-19 and suggest means of management.''

MCAS and histamine intolerance
Lawrence B. Afrin, Leonard B. Weinstock, Gerhard J. Molderings Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome International Journal of Infectious Diseases, Volume 100, 2020, Pg 327-332, ISSN 1201-9712. doi: 10.1016/j.ijid.2020.09.016

Highlights
 * Much of Covid-19 hyperinflammation is consistent with mast-cell-driven inflammation.
 * Prevalence of severe Covid-19 is similar to that of mast cell activation syndrome (MCAS).
 * Drugs inhibiting mast cells (MCs) and their mediators show promise in Covid-19.
 * None of the authors currently treated MCAS patients with Covid-19 had severe forms or mortality.
 * The dysfunctional MCs of MCAS may underlie severe acute and chronic Covid-19 illness.

Abstract

Objectives: One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses.

Methods: Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS.

Results: The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19’s hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors’ treated MCAS patients with Covid-19 suffered severe infection, let alone mortality.

Conclusions: Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.

Endocrinology
[https://pmj.bmj.com/content/96/1137/412 Agarwal S., Agarwal S.K. (11 June 2020) Endocrine changes in SARS-CoV-2 patients and lessons from SARS-CoV. Postgraduate Medical Journal 2020;96:412-416. doi: http://dx.doi.org/10.1136/postgradmedj-2020-137934]

Rubino, F. et al. (12 June 2020) New-Onset Diabetes in Covid-19. N Engl J Med 2020; 383:789-790 doi: 10.1056/NEJMc2018688

Palmer, C. (27 May 2020) COVID-19 May Cause Subacute Thyroiditis. Medscape

Brancatella, A. et al. (21 May 2020) Subacute Thyroiditis After Sars-COV-2 Infection. The Journal of Clinical Endocrinology & Metabolism; 2020,105,7 pg 2367-2370 doi: https://doi.org/10.1210/clinem/dgaa276

Gastrointestinal
[https://gut.bmj.com/content/69/6/973 Ng, S. C. Tilg, H. (9 April 2020) COVID-19 and the gastrointestinal tract: more than meets the eye. BMJ Gut; 2020, 69 pg. 973-974 doi: http://dx.doi.org/10.1136/gutjnl-2020-321195 ]

Gaebler C et. al. Evolution of Antibody Immunity to SARS-CoV-2 bioRxiv Posted November 05, 2020 doi.org/10.1101/2020.11.03.367391

Analysis of intestinal biopsies obtained from asymptomatic individuals 3 months after COVID-19 onset, using immunofluorescence, electron tomography or polymerase chain reaction, revealed persistence of SARS-CoV-2 in the small bowel of 7 out of 14 volunteers.

Yeoh YK, Zuo T, Lui GC, et al Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19 BMJ Gut Published Online First: 11 January 2021. doi: 10.1136/gutjnl-2020-323020

Abstract

Objective Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus.

Methods In this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma.

Results Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase.

Conclusion Associations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Mental health
[https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30462-4/fulltext Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA Taquet et al. 2020. The Lancet. DOI:https://doi.org/10.1016/S2215-0366(20)30462-4] Criticisms of the paper: - Not controlled for multiple potential confounding factors - Refers to COVID-19 in general not long COVID specifically, includes intensive care patients?

Neurology
Avindra Nath, Bryan Smith Neurological issues during COVID-19: An Overview, Neuroscience Letters,2020, 135533, ISSN 0304-3940. https://doi.org/10.1016/j.neulet.2020.135533.

R. W. et al. (8 July 2020) The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain; awaa240 doi: https://doi.org/10.1093/brain/awaa240

[https://www.nature.com/articles/s41582-020-0368-9 Hartung, H-P. Aktas, O. (22 May 2020) COVID-19 and management of neuroimmunological disorders. Nature Reviews Neurology; 16, pg 347–348(2020)] doi: https://doi.org/10.1038/s41582-020-0368-9

[https://www.theguardian.com/world/2020/jul/08/warning-of-serious-brain-disorders-in-people-with-mild-covid-symptoms Sample, I. (8 July 2020) '''Warning of serious brain disorders in people with mild coronavirus symptoms. The Guardian''' ]

Ellul, M. A. et al. (2 July 2020) Neurological associations of COVID-19 The Lancet Neurology; 19,9 pg 767-783 doi: https://doi.org/10.1016/S1474-4422(20)30221-0

Eric Song, Ce Zhang, Benjamin Israelow et al Neuroinvasion of SARS-CoV-2 in human and mouse brain J Exp Med 1 March 2021; 218 (3): e20202135. doi: https://doi.org/10.1084/jem.20202135

Abstract Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

Guedj E, Campion JY, Dudouet P et al. 18F-FDG brain PET hypometabolism in patients with long COVID Eur J Nucl Med Mol Imaging, 26 Jan 2021. doi: https://doi.org/10.1007/s00259-021-05215-4

Conclusion On the whole, this study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 infection and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. This hypometabolic profile had an individual relevance to classify patients and healthy subjects, suggesting value as a biomarker to identify and follow these patients. The rationale for the affected brain substrate of these functional complaints is strengthened by the relationships found with the hypometabolic clusters. Finally, the hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.

Thromboembolic
Dhawan, Ranju T et al. Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19 The Lancet Respiratory Medicine, Volume 0, Issue 0