The most common clinical manifestations of histamine release / mast cell degranulation are acute / episodic urticaria (weals) or skin itch, angioedema; and less commonly acute vomiting, abdominal pain and anaphylaxis. Therefore, the diagnosis of mast cell / histamine release mediated conditions relies primarily around clinical history.

This is a brief guide aimed at primary care providers on the approach to diagnosis and management of patients with symptoms of chronic urticaria (weals) +/- angioedema, occurring daily / almost daily for a period lasting >6 weeks (some patients may be affected by symptoms occurring intermittently over months or years). This brief guide does not replace more detailed guidance issued by NICE and the British Society of Allergists and Clinical Immunologists.

Allergic urticaria and angioedema is usually identified by a clinical history of a temporal relationship of symptoms in relation to a particular food / trigger, by either ingestion or contact. Most episodes of urticaria are not allergic. Allergic urticaria/angioedema; and angioedema due to C1 inhibitor deficiency are outside the scope of this brief guidance note. More information on investigating isolated angioedema (i.e angioedema without weals) symptoms can be found in complement testing section at Immunology (nhslothian.scot) and is not covered in detail here - please also refer to Chronic Urticaria and Angioedema - BSACI.

Anecdotally, many patients with Long Covid have described concomitant symptoms of urticaria and angioedema. It is well recognised that intercurrent infection or post viral illnesses can serve as triggers and exacerbators of urticaria and angioedema symptoms. Understanding the natural course of these symptoms in the context of Long Covid, specifically, requires further research. Currently, there is no evidence to suggest that these symptoms arising in the context of Long Covid should be managed any differently.

This guidance note does not serve to advise around referral pathways for patients requiring secondary care input, which will vary regionally across Scotland.

Urticaria and angioedema are identified clinically. Images of typical appearances are available via the links below:

Angioedema | DermNet NZ
Acute urticaria | DermNet NZ

Chronic urticaria (+/- angioedema) affects 2-3% of the population and significantly reduces quality of life. Early recognition of symptoms and instigating treatment is recommended.

CSUA is not caused by an allergy.

Common recognised triggers of CSUA symptoms include infections (especially viral infection), psychological stress, and NSAIDs medications. There is also an association with hormone fluctuations (eg association with oral contraceptive pill use in some women), and thyroid autoimmune disease. For many individuals, however, symptoms are largely idiopathic. 

The natural history of CSUA is that for most individuals, symptoms ‘burn out’ with time (6-12 months). For ~20% of individuals with CSUA, they remain symptomatic for many years and some may require specialist referral.

Treatment is based around symptom control, mainly by antihistamine therapy which may need to be titrated up to four times the standard recommended doses to achieve symptom control. The figure below is inserted from the BSACI guideline: Chronic Urticaria and Angioedema - BSACI.  Step 4 in the figure would normally be applicable to secondary care management:

Fig 2: General management plan for chronic urticaria (Adults and children). The starting point and the rate of progression between steps depend on clinical severity and response. Short course of corticosteroids (e.g. 1 mg/kg prednisolone twice a day, up to 40 mg total per day, for 3 days) may be used for severe exacerbations , see also section on rescue medication. The treatment should be stepped down once control is achieved. Observations on the mechanism of antihistamine action suggest that it is probably sensible to withdraw such therapy gradually, rather than stopping it abruptly.

© 2015 John Wiley & Sons Ltd, Clinical & Experimental Allergy, Volume: 45, Issue: 3, Pages: 547-565, First published: 25 February 2015, DOI: (10.1111/cea.12494).  Copyright applied for.

Other resources around Treatment

NHS Scotland: www.dermatology.nhs.scot/dermatology-pathways/pathways/urticaria/

Patient information leaflets on CSUA are available at the links below:

British Association of Dermatologists - Patient Information Leaflets (PILs) (bad.org.uk)
Urticaria and Angioedema | Information on Hives | Allergy UK

MCAS has been characterised by episodic signs and symptoms of systemic anaphylaxis / symptoms associated with mast cell degranulation that concurrently affect at least two organ systems.

Due to the broad range of possible symptoms affecting many organs, the MCAS diagnostic label may be used to inappropriately ascribe many symptoms to, eg fatigue, rashes of many sorts, chronic illness, oedema, adenopathy, tinnitus, brain fog and many others – all of which are not associated with mast cell / histamine induced symptoms. In addition, many symptoms which can less commonly be associated with histamine release, eg flushing and diarrhoea may be more chronic rather than episodic, which again would point towards other underlying diagnoses. This can cause marked uncertainty for patients and indeed lead to misdiagnosis. 

In some forums / groups, certain disorders have been used to diagnose MCAS with no scientific basis / evidence for any association with mast cell activation. Such conditions include Ehlers-Danlos syndrome, postural orthostatic tachycardia syndrome (PoTS), sclerosing mediastinitis, psychiatric and other idiopathic disorders and others.

A detailed consensus document on MCAS can be found at AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management (2019).

The clinical characterisation of a patient’s symptoms in terms of urticaria / angioedema / CSUA is much more useful, clinically, and helps tailor effective treatment more specifically for the patient. In the context of Long Covid / the Covid-19 pandemic, it would be reasonable to expect that more individuals will present with symptoms of urticaria, angioedema and idiopathic anaphylaxis – all of which can be precipitated and associated with infections, as well as any other acute or prolonged physiological or psychological stresses.