Recommendations for the recognition, diagnosis, and management of long COVID: a Delphi study

Martine Nurek; Clare Rayner; Anette Freyer; Sharon Taylor; Linn Järte; Nathalie MacDermott; Brendan C Delaney

doi:10.3399/BJGP.2021.0265

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BSACI criticism of our suggestions on Long Covid and mast cells
Brendan C. Delaney, Clare Rayner, Anette Freyer, Sharon Taylor, Linn Järte, Nathalie MacDermott and Martine Nurek

Published on: 25 April 2022
Recommendations for the recognition, diagnosis and management of long COVID
British Society for Allergy and Clinical Immunology (BSACI)

Published on: 12 April 2022

Published on: (25 April 2022)
Page navigation anchor for BSACI criticism of our suggestions on Long Covid and mast cells
BSACI criticism of our suggestions on Long Covid and mast cells
Brendan C. Delaney, GP and Chair in Medical Informatics and Decision Making, Imperial College London
Other Contributors:
Clare Rayner, Occupational physician

Anette Freyer, Consultant in acute and obstetric medicine, Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Nottingham

Sharon Taylor, Consultant child and adolescent psychiatrist, Central and North West London NHS Foundation Trust

Linn Järte, CT2 Anaesthetist, Anaesthetics Department, Morriston Hospital, Swansea Bay University Health Board, Swansea

Nathalie MacDermott, NIHR academic clinical lecturer, St Mary's Hospital, Imperial College NHS Trust, London

Martine Nurek, Postdoctoral research associate, Department of Surgery and Cancer, Imperial College London
In their letter, BSACI, criticise our suggestions on the role of mast cells in managing Long Covid based on lack of evidence, and the risk of triggering unnecessary referrals to immunology and allergy clinics.

Our paper was written over a year ago, before Long Covid clinics and in the face of an urgent need to bridge the gap between evidenced based practice and clinical experience in the face of a widening health emergency. Given the slow pace of research, we are no further on in ‘NICE-standard’ evidence, yet we now have 1.7 million people with long Covid, half of whom with symptoms for over a year and over a million with their working lives significantly impacted.¹ For GPs to sit back and take the stance of the BSACI would be a gross failure to meet the needs of our patients. Our recommendations on treating urticaria do not step beyond the SIGN guidance cited, except in considering it reasonable to extend the symptomatic scope of treatment. Referral in severe cases of angioedema or anaphylaxis is within current guidance.

Ongoing research in Long Covid suggests a complex set of immunological,^2,3 platelet and endothelial abnormalities,⁴ possibly linked to viral persistence.⁵ Testing antihistamine response and being aware of potential dietary triggers are simple, low risk interventions that have support from clinicians treating Long Covid patients. A clinical trial of antihistamines, led by UCLH, is abou...
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In their letter, BSACI, criticise our suggestions on the role of mast cells in managing Long Covid based on lack of evidence, and the risk of triggering unnecessary referrals to immunology and allergy clinics.

Our paper was written over a year ago, before Long Covid clinics and in the face of an urgent need to bridge the gap between evidenced based practice and clinical experience in the face of a widening health emergency. Given the slow pace of research, we are no further on in ‘NICE-standard’ evidence, yet we now have 1.7 million people with long Covid, half of whom with symptoms for over a year and over a million with their working lives significantly impacted.¹ For GPs to sit back and take the stance of the BSACI would be a gross failure to meet the needs of our patients. Our recommendations on treating urticaria do not step beyond the SIGN guidance cited, except in considering it reasonable to extend the symptomatic scope of treatment. Referral in severe cases of angioedema or anaphylaxis is within current guidance.

Ongoing research in Long Covid suggests a complex set of immunological,^2,3 platelet and endothelial abnormalities,⁴ possibly linked to viral persistence.⁵ Testing antihistamine response and being aware of potential dietary triggers are simple, low risk interventions that have support from clinicians treating Long Covid patients. A clinical trial of antihistamines, led by UCLH, is about to start (STIMULATE-ICP), but will be over a year in reporting. We do not consider that mast cell disorder is the cause of Long Covid, but a potential symptom target, alongside POTS, and treating either or both if present is something that GPs can offer now to help many patients with Long Covid.

References

1. Office for National Statistics. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK. Available from: www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/7april2022 [cited 2022 Apr 25].
2. Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Mast cell activation symptoms are prevalent in Long-COVID. Int J Infect Dis 2021; 112:217–26.
3. Kell DB, Laubscher GJ, Pretorius E. A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochem J 2022 ;479(4):537–59.
4. Oikonomou E, Souvaliotis N, Lampsas S, Siasos G, Poulakou G, Theofilis P, et al. Endothelial dysfunction in acute and long standing COVID−19: A prospective cohort study. Vascul Pharmacol 2022; 144:106975.
5. Proal AD, VanElzakker MB. Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front Microbiol 2021;12.
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Competing Interests: None declared.
Published on: (12 April 2022)
Page navigation anchor for Recommendations for the recognition, diagnosis and management of long COVID
Recommendations for the recognition, diagnosis and management of long COVID
British Society for Allergy and Clinical Immunology (BSACI), NA, .
The British Society for Allergy and Clinical Immunology (BSACI) would like to respond to the article by Nurek¹ et al. We appreciate this is a growing area of interest, and that further research is needed, but we feel that this article makes conclusions that are not supported by evidence, and which has the potential to trigger unnecessary referrals to allergy and immunology clinics which are already facing huge pressures.

In Box 1, described as ‘Known examples of conditions associated with long COVID’, included are ‘Mast cell activation, including urticaria, angioedema and histamine intolerance’, along with ‘new-onset allergies and anaphylaxis’. It has been recognised that SARS-CoV-2 infection can be associated with urticaria and angioedema,² as is the case with many infections,³ but there is no evidence to suggest that acute infection or long COVID causes new allergic sensitisation or manifestations of allergic or atopic diseases including anaphylaxis. Similarly, it is not clear that urticaria itself is increased in long COVID, after the initial phase of infection. The term ‘histamine intolerance’ can be misleading in that there is no clear evidence to support a role for ingested histamine in chronic urticaria, a well recognised auto-immune disorder. ^4,5

The authors draw parallels between the symptoms of ‘mast cell activation syndrome (MCAS)’ and th...
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The British Society for Allergy and Clinical Immunology (BSACI) would like to respond to the article by Nurek¹ et al. We appreciate this is a growing area of interest, and that further research is needed, but we feel that this article makes conclusions that are not supported by evidence, and which has the potential to trigger unnecessary referrals to allergy and immunology clinics which are already facing huge pressures.

In Box 1, described as ‘Known examples of conditions associated with long COVID’, included are ‘Mast cell activation, including urticaria, angioedema and histamine intolerance’, along with ‘new-onset allergies and anaphylaxis’. It has been recognised that SARS-CoV-2 infection can be associated with urticaria and angioedema,² as is the case with many infections,³ but there is no evidence to suggest that acute infection or long COVID causes new allergic sensitisation or manifestations of allergic or atopic diseases including anaphylaxis. Similarly, it is not clear that urticaria itself is increased in long COVID, after the initial phase of infection. The term ‘histamine intolerance’ can be misleading in that there is no clear evidence to support a role for ingested histamine in chronic urticaria, a well recognised auto-immune disorder. ^4,5

The authors draw parallels between the symptoms of ‘mast cell activation syndrome (MCAS)’ and those of long COVID, and suggest this this diagnosis should be considered in patients with a broad range of symptoms. They acknowledge as do we that MCAS is a controversial area with no clear diagnostic criteria. An association between autonomic dysfunction and mast cell disorders is suggested, although in fact this remains unproven and based predominantly on symptom reporting.⁶ They then offer recommendations for treatment including low histamine diets, antihistamines and montelukast, and suggest referral to immunology or allergy specialists. No evidence is provided to support the use of low histamine diets, or an association between MCAS and long COVID. This is an interesting area for further research, but the evidence is not there for this to be put forward as a recommendation to family doctors.

We understand that the article represents the lived experience of a number of doctors dealing with long COVID, and is an attempt to shed light on possible mechanisms and treatment approaches. However, the casual reader may assume the recommendations carry the same weight as for instance a NICE guideline.

We are concerned that no specialists the field of allergy or immunology were involved in the publication. We do not feel that referral of patients with non-specific symptoms to allergy/immunology clinics is appropriate, unless there is a clear clinical question requiring assessment of a possible specific allergic trigger.

NICE has published detailed guidance for investigation and management of long COVID.⁷ SIGN guidelines also include specific advice on management of urticaria and angioedema in the context of long COVID, which emphasises that no different management strategies are required.⁸ Considerable investment has been made by NHS England into long COVID services which are now starting to develop across the UK.⁹ We would encourage family doctors to use the published NICE and SIGN guidance when assessing patients and to use approved referral pathways.

References

1. Nurek M, Rayner C, Fryer A et al. Recommendations for the recognition, diagnosis and management of long COVID. Br J Gen Pract 2021; 71: e815-e825.

2. Abuelgasim, E, Dona, ACM, Sondh, RS, Harky, A. Management of urticaria in COVID-19 patients: A systematic review. Dermatologic Therapy 2021; 34:e14328.

3. Wedi B, Raap U, Wieczorek D, Kapp A. Urticaria and infections. Allergy Asthma Clin Immunol 2009;5(1):10.

4. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2017 revision and update. Allergy 2018; 73: 1393–1414.

5. Powell RJ, Leech SC, Till S, Huber PA, Nasser SM, Clark AT; British Society for Allergy and Clinical Immunology. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy 2015; 45(3):547-65.

6. Kohn A and Chang C. The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS). Clin Rev Allergy Immunol 2020; 58(3):273-297.

7. NICE. COVID-19 rapid guideline: managing the longterm effects of COVID-19. 2022. Available at: www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-51035515742.

8. Scottish Government. Managing the long-term effects of COVID-19. 2021. Annex C. Available at: www.sign.ac.uk/media/1931/sg-long-covid-isn-version-20.pdf.

9. NHS. Long COVID: the NHS plan for 2021/2022. 2021. Available at: www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2021/06/C1312-long-covid-plan-june-2021.pdf.

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Competing Interests: None declared.