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

WHO A clinical case definition of post COVID-19 condition by a Delphi consensus (6 Oct 2021) WHO reference number: WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1

Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS- CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others* and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.

A separate definition may be applicable for children.


CDC: Symptoms commonly reported among people with post COVID conditions

 
Source: CDC 2021


Dennis A, Wamil M, Alberts J On behalf of COVERSCAN study investigators, et al (30 March 2021) Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study BMJ Open 2021;11:e048391. doi: 10.1136/bmjopen-2020-048391

Conclusions In individuals at low risk of COVID-19 mortality with ongoing symptoms, 70% have impairment in one or more organs 4 months after initial COVID-19 symptoms, with implications for healthcare and public health, which have assumed low risk in young people with no comorbidities.

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

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.

National Institute for Health Research (16 March 2021). NIHR Themed Review: Living with Covid19 – Second review doi: 10.3310/themedreview_45225

National Institute for Health Research (15 October 2020). NIHR Themed Review: Living with Covid19; October 2020; doi:10.3310/themedreview_41169

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

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

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

Deepti Gurdasani (20 July 2021 via Twitter) - Twitter thread summarising long Covid and addressing common myths

Symptom studies and surveys

Aiyegbusi OL, Hughes SE, Turner G, et al. (15 July 2021.) Symptoms, complications and management of long COVID: a review. Journal of the Royal Society of Medicine. doi:10.1177/01410768211032850. Reviewed 27 articles.

The presence of more than five symptoms in the first week of acute infection was significantly associated with the development of long COVID irrespective of age or gender

Davis HE et al. (15 July 2021) Characterizing long COVID in an international cohort: 7 months of symptoms and their impact, EClinicalMedicine (Lancet Journals), 2021, 101019, ISSN 2589-5370, https://doi.org/10.1016/j.eclinm.2021.101019 Science Direct

"For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. During their illness, participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. ... 85.9% of participants (95% CI, 84.8% to 87.0%) experienced relapses, primarily triggered by exercise, physical or mental activity, and stress"

Pre-print of above: Davis et al. (27 Dec 2020) Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact. medRxiv pre-print.

Prevalence of 205 symptoms in 10 organ systems was estimated in this cohort, with 66 symptoms traced over seven months. Respondents experienced symptoms in an average of 9.08 (95% confidence interval 9.04 to 9.13) organ systems. The most frequent symptoms reported after month 6 were: fatigue (77.7%, 74.9% to 80.3%), post-exertional malaise (72.2%, 69.3% to 75.0%), and cognitive dysfunction (55.4%, 52.4% to 58.8%).These three symptoms were also the three most commonly reported overall.

Blomberg, B., Mohn, K.GI., Brokstad, K.A. et al. (23 June 2021) Long COVID in a prospective cohort of home-isolated patients. Nat Med (2021). https://doi.org/10.1038/s41591-021-01433-3. Prospective cohort in Norway

Havervall S, Rosell A, Phillipson M, et al. (7 April 2021) Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers. JAMA. doi:10.1001/jama.2021.5612

Lambert et al. (27 March 2021) COVID-19 Survivors’ Reports of the Timing, Duration, and Health Impacts of Post-Acute Sequelae of SARS-CoV-2 (PASC) Infection. medRxiv 2021.03.22.21254026; doi: https://doi.org/10.1101/2021.03.22.21254026

Sudre et al (October 2020) Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App medRxiv 2020.10.19.20214494 doi: https://doi.org/10.1101/2020.10.19.20214494

Report: What Does COVID-19 Recovery Actually Look Like? Other version: 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

Lambert, N. J. & Survivor Corps. (2020) COVID-19 “Long Hauler” Symptoms Survey Report.

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

Conferences and Webinars

US NIH workshop on long COVID (video)

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

Sapien Care Group (5 February 2021). The Challenge of Long Covid (video)., SimplyCPD "Our experts from academic immunology, Intensive care and general practice will discuss the road ahead." -About Sapien Care

BMJ COVID-19 Grand Round (4 Sep 2020). Long Covid: diagnosis, management, prognosis (video).

Post COVID-19 Condition: Best practices on management for clinicians and patients (video) International Society for Vaccines, 8 September 2021

Prevalence

Sivan M, Rayner C, Delaney B. (1 April 2021) Fresh evidence of the scale and scope of long covid BMJ 2021; 373 :n853 doi:10.1136/bmj.n853

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

Whitaker M, Elliott J, Elliott P et. al. (24 Jun 2021.) Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people Item Type: Working Paper. 24 Jun 2021. URI: http://hdl.handle.net/10044/1/89844 Imperial REACT study

Implications

The scale of morbidity identified in this study presents significant challenges for the affected individuals and their families, and for health services and society more broadly. [...] Given the high potential population health burden, investment is urgently needed to expand the network of services investigating and managing people with Long COVID, to link these services to national research studies and consistent data collection to improve our understanding, and to create the infrastructure for trials in the same way as has been achieved for acute COVID-19.

We identified two clusters of participants based on their symptoms. Individuals with predominantly respiratory symptoms comprised a relatively small proportion of those with persistent symptoms -- a greater proportion comes from a cluster of less organ-specific symptoms, particularly fatigue. Clinicians will need to be aware of the range of presenting symptoms to best support their patients towards recovery and there will need to be education of healthcare professionals to recognise and respect the experiences of people reporting these symptoms. Societal recognition of Long COVID as an important outcome of the pandemic (including as an occupational illness for those acquiring it through work) is needed, including for those who may require benefits as well as rehabilitation. The Long COVID patient groups provide much needed support to those involved, but will require resources if they are to be able to work effectively with health services, especially to reach people in more deprived and marginalised groups.

In summary we have identified significant ongoing morbidity among people post COVID-19, with a substantial proportion experiencing persistent symptoms lasting 12 weeks or more. Managing the long term sequelae of SARS-CoV-2 infection in the population will remain a major challenge for health services in the next stage of the pandemic.

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.

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.

Michelen M, Manoharan L, Elkheir N, et al Characterising long COVID: a living systematic review BMJ Global Health 2021;6:e005427 doi: http://dx.doi.org/10.1136/bmjgh-2021-005427

Abstract

Background While it is now apparent clinical sequelae (long COVID) may persist after acute COVID-19, their nature, frequency and aetiology are poorly characterised. This study aims to regularly synthesise evidence on long COVID characteristics, to help inform clinical management, rehabilitation strategies and interventional studies to improve long-term outcomes.

Methods A living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research on COVID-19 database, LitCovid and Google Scholar were searched till 17 March 2021. Studies including at least 100 people with confirmed or clinically suspected COVID-19 at 12 weeks or more post onset were included. Risk of bias was assessed using the tool produced by Hoy et al. Results were analysed using descriptive statistics and meta-analyses to estimate prevalence.

Results A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case–control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function.

Conclusion Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings.

Diagnosis

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

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.

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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 inflammatory

MCAS/histamine section is below

Gerd Wallukat et al. (April 2021) Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms Journal of Translational Autoimmunity, Volume 4, 2021, 100100, SSN 2589-9090, https://doi.org/10.1016/j.jtauto.2021.100100

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

Cappel MA, Cappel JA, Wetter DA (21 Jan 2021) Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms. Mayo Clinic Proceedings, 96(4):989-1005. DOI: 10.1016/j.mayocp.2021.01.009

Glynne P, Tahmasebi N, Gant V, Gupta R. Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines Journal of Investigative Medicine Published Online First: 05 October 2021. doi: 10.1136/jim-2021-002051

Abstract

Long COVID is characterized by the emergence of multiple debilitating symptoms following SARS-CoV-2 infection. Its etiology is unclear and it often follows a mild acute illness. Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.

Cardiovascular

Emer Joyce European Journal of Heart FailureVolume 22, Issue 12 p. 2187-2189 COVID‐19, myocarditis, and the other side of the bed First published: 22 November 2020 https://doi.org/10.1002/ejhf.2062


Jennifer Abbasi. February 10, 2021. Researchers Investigate What COVID-19 Does to the Heart JAMA. Published online February 10, 2021. doi:10.1001/jama.2021.0107 https://jamanetwork.com/journals/jama/fullarticle/2776538


Allison Bond, Nisha Parikh. (Summer 2020) What is COVID Doing to Our Hearts? UCSF Magazine. Lay audience article.

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. 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

Dixon H. (21 July 2020) Pathophysiology of COVID-19: Myocarditis. Journal of Anaesthesia Practice

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:

Bakker, J.(13 July 2020) Heart scans could lead to better treatment for patients in hospital with coronavirus. British Heart Foundation

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

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.

Schofield JR. Persistent antiphospholipid antibodies, mast cell activation syndrome, postural orthostatic tachycardia syndrome and post COVID syndrome: 1 year on EJCRIM 2021;8 doi:10.12890/2021_002378

Abstract This is the first case report of a patient with post-COVID-19 postural orthostatic tachycardia syndrome (POTS) with multiple persistent antiphospholipid antibody (aPL)-positivity more than a year after illness onset who also meets Global Consensus-2 criteria for mast cell activation syndrome (MCAS), suggesting pathological activation of the acquired and innate immune systems by SARS-CoV-2. While the patient continues to meet criteria for POTS 1 year on, her functional ability has improved significantly with therapy directed at MCAS, POTS and aPL-positivity.

MCAS, Allergy 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.

Valent, P. et al (16 Nov 2020). Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine. International Journal of Molecular Sciences 21, 9030. https://doi.org/10.3390/ijms21239030

Typical manifestations of immediate-type hypersensitivity (allergic) reactions consistent with the diagnosis of systemic MCA (anaphylaxis), include acute urticaria, flushing, pruritus, headache, abdominal cramping, diarrhea, respiratory symptoms, and vascular instability (hypotension) [20,21,22,23]. Although none of these symptoms are absolutely specific for MCA, many are typically found in these patients. Especially, when occurring together in one patient at the same time, these symptoms are suggestive of MCA, although basophil activation is considered to manifest with a similar spectrum of symptoms. The likelihood of MCA is even higher when multiple (two or more) of these symptoms are recorded and are responsive to drugs blocking MC mediator effects, mediator production, or mediator release in MCs. [...]
Minimal diagnostic criteria of MCAS include (i) typical clinical symptoms indicative of multi-organ involvement, usually meeting criteria for anaphylaxis; (ii) an increase in the serum tryptase level above the individual’s baseline serum tryptase (sBT), meeting the 20% + 2 threshold (= sBT × 1.2 + 2) and/or a clear increase in another MC mediator in biological fluids; and (iii) response of the symptoms to drugs targeting MC activation, mediator release from MCs and/or MC mediator effects (Supplemental Table S1). All three criteria must be fulfilled to arrive at the diagnosis MCAS by consensus criteria [20,21,22,23,39].

Endocrinology

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

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

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?

Taquet, Maxime et al. (6 April 2021) 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. The Lancet Psychiatry. “Our study provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection. Risks were greatest in, but not limited to, patients who had severe COVID-19.”

Neurology

Graham EL et al. (23 Mar 2021), Persistent neurologic symptoms and cognitive dysfunction in non‐hospitalized Covid‐19 “long haulers”. Ann Clin Transl Neurol. https://doi.org/10.1002/acn3.51350

Marcel S Woo et al. (23 November 2020) Frequent neurocognitive deficits after recovery from mild COVID-19, Brain Communications, Volume 2, Issue 2, 2020, fcaa205, https://doi.org/10.1093/braincomms/fcaa205

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

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

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 (1 March 2021) 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. (26 Jan 2021) 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

Whyte MB, Kelly PA, Gonzalez E, Arya R, Roberts LN (Nov 2020). Pulmonary embolism in hospitalised patients with COVID-19. Thromb Res. 2020 Nov 1;195:95–9.

The Wells score was no different between those with and without PE

Roubinian NH, Dusendang JR, Mark DG, et al. (05 April 2021) Incidence of 30-Day Venous Thromboembolism in Adults Tested for SARS-CoV-2 Infection in an Integrated Health Care System in Northern California. JAMA Intern Med. doi:10.1001/jamainternmed.2021.0488
Limitations of this study include the follow up is only for 30 days as acknowledged by authors and only a single PCR done therefore risk of false negatives present in controls.


Dermatology

Colmenero, I., Santonja, C., Alonso-Riaño, M. Et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. (2020) Br. J. Dermatol., 183: 729-737. https://doi.org/10.1111/bjd.19327

Summary

Background Chilblains (‘COVID toes’) are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established.

Objectives To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue.

Methods We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one.

Results Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy.

Conclusions

Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage.

Frumholtz, L., Bouaziz, J.-D., Battistella, M. Et al. Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak Br J Dermatol. (2021) https://doi.org/10.1111/bjd.20707

Summary

Background The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear.

Objectives To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus.

Methods This observational study was conducted during 9–16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included.

Results Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic–natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL.

Conclusions

Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.