Cold UrticariaCascia Day

May 2021

Outline• Definition

• Epidemiology

• Pathophysiology

• Patient cases

• Diagnostic tests

• Treatment

• NB to remember that physical

urticaria disorders often

cluster

• Exercise is a cofactor AND

part of cholinergic urticaria

• Often difficult to tease apart

Definition • The physical urticarias are forms of inducible urticaria, in which there is a

specific and definite stimulus that triggers the development of symptoms.

• Cold urticaria is characterized by: pruritic wheals /or angioedema due to

cutaneous mast cell degranulation and release of proinflammatory

mediators after cold exposure of the skin.

• Triggers include skin contact with cold objects, cold liquids, and cold air.

Maurer et al Up To Date 2020

Epidemiology • Account for 5-34% of physical urticaria

• Incidence 0.05% in Europe

• Dependent on the geographic location: ie cold areas have a higher incidence but unknown if this is related to increased presentation due to cold exposure

• Most commonly affects young adults

• Both sexes affected equally: but some studies show female predominance (small studies)

• ≥ 25% patients have other types of physical urticaria (symptomatic dermatographism and cholinergic urticaria most commonly)

• ≤ 50% atopic

Winter in Canada…

…Winter in Thailand

Pathophysiology• The underlying pathophysiology is largely unknown but is likely to involve

immunoglobulin E (IgE)-mediated mast cell activation

• Activation of cutaneous mast cells and degranulation with release of

histamine and proinflammatory markers

• In small case series and case reports:

• Associated disorders: variety of infections, lyme disease, hepatitis, EBV, acute

toxoplasmosis, H.pylori colonization, HIV

• Elevated levels of mast cell activating anti-IgE antibodies

• Associations: cryoglobulinaemia, cold agglutinins, anti-lamin B antibodies, reduced

C1 esterase and C4, elevated platelet-activating factor and platelet factor 4

Pathophysiology

Meixong et al, Cell Press 2020

Clinical presentationCutaneous signs and symptoms:

• Wheal-and-flare reactions /

angioedema post cold exposure

(objects, liquid, air) develop after a

minutes of exposure

• Usually but not always limited to

cold exposed areas

• Dependent on: humidity, wind chill

factor, temperature

Deza et al, 2018/2016

Clinical presentationSystemic signs and symptoms

• Often after extensive cold contact i.e. cold water emersion

• Generalised urticaria to anaphylaxis, rates of reported anaphylaxis vary 18.9%-30% usually triggered by aquatic activities

• Oropharyngeal and GIT symptoms after consuming cold food/beverages (? How common)

Risk factorsEnvironmental:

• Exposure to lower temperatures

• Duration of cold exposure

• Degree of body surface area exposed

• Exposure to objects or water has worse reaction than exposure to cold air

• Wind chill factor NB

Patient:

• Previous cold induced systemic reaction

• Increased risk in those who have cold induced oropharyngeal symptoms

• Age <30 at onset of diagnosis

Deza et al, 2018/2016

Natural history • Often self-limiting

• Remission or improvement in symptoms occur spontaneously in 50% of

patients within 5-6 years (5.6±3.6 years)

• Variant forms tend to be life long

• Paediatric patients less likely to have resolution

Deza et al, 2018/2016

Testing 1. Ice cube test

• Place 3-4 icecubes in a packet of

water

• Place on volar surface of forearm

for 5 mins

• Check for reaction:

• Reflex erythaema

• Wheal (localized or generalized)

• Cold provocation testing using cold

packs or cold water baths

is not recommended for first-line

screening

Testing 1. Temp test

Testing 1. Temp test

Critical temperature threshold

Critical time threshold

Can monitor both as

response to therapy

(Patient on the left had a

critical temperature threshold

of 27ºC!!)

Variants1. Atypical cold urticaria: history of wheals or angioedema on cold exposure, negative

cold stimulation test

2. Delayed cold urticaria: occurs up to 24hours after cold exposure, often have hyperpigmentation at site

3. Familial atypical cold urticaria: symptoms begin in early childhood and are lifelong, usually have symptoms with ingestion of cold food or beverages, cold stimulation test often negative. Subset have deletions in the gene for phospholipase C (PLC)-gamma-2

4. Cold dependent dermatographism

5. Cold induced cholinergic urticaria: symptoms only when exercising in cold environments (clinical history)

6. Systemic cold urticaria: generalized urticaria on cold exposure, not related to exercise, cold stimulation test negative

7. Localised cold urticaria: only specific body parts affected eg the face or lower limbs, need to do cold test at these sites

8. Food dependent cold urticaria: wheals develop at site of cold stimulation test BUT ONLY AFTER eating food

Differentials 1. Familial cold autoinflammatory syndrome (FCAS)

• Hereditary periodic fever syndrome

• Cold induced abnormal serum proteins

• Cold induced urticarial vasculitis

• Present within first few months of life

• Papular rash after cold exposure is often delayed by up to several hours.

• Associated with systemic inflammatory symptoms, including fever, conjunctival injection, and arthralgias.

• The presence of systemic symptoms distinguishes this disorder from simple cold urticaria.

2. Abnormal cold-dependent immunoglobulins

• cryoglobulinemia, cryofibrinogenemia, cold agglutinin disease, and paroxysmal cold hemoglobinuria

• Do not present with urticaria

• Purpura, systemic vasculitis (e.g. renal failure), haemolysis, MODS

Age Sex BMI Age at

onset

CST Anaphylaxis Oropharyngeal

symptoms

Other medical

disorders

FHx Lifestyle

13 F 17.1 10Prev +

now -

+repeated

- Asthma

Severe peanut allergy

Swimming

39 F 20.2 35 + _ - Childhood asthma

PAR

Hiking

Swimming

31 M 28.7 7(relapsed

age 28)

+ +repeated

- Deep sea diving

Surfing

57 M 22.7 54 + + - Hypothyroidism Swimming

Long distance bike riding

50 M 27.2 40 + +repeated

- Asthma Surfing

22 M 23.5 21 - - -

18 M 25.4 16 + +repeated

- Asthma

PAR

Mother:

dermatographism

Rowing

swimming

63 M 28.7 14 + +repeated

- HPT Long distance cold water

swimming

Surfing

48 F 24.1 31 + +repeated

- Graves disease Daughters:

aquagenic urticaria

Swimming

32 F 42.6 6 - - + Asthma, severe

eczema

Treatment• Education about high-risk activities and cold avoidance

• Swimming: water temp above 25ºC, slow emersion, wetsuits etc

• Cold foods and beverages

• Surgery: NB for neuro and cardiac surgery, premedication with

antihistamines

• Injection of cold IV fluids

• Treatment of acute signs and symptoms

• Epipen

• Antihistamines

• Premedication before risky activities

Treatment• Prophylaxis:

• H1 antihistamines at up to 4x recommended dose (Rupatadine also has effects

on platelet derived factors)

• Refractory symptoms:

• Omeluzimab: some only needed in winter

• Cyclosporin / Monteleukast / steroids (all variable responses)

• Doxycycline

• Topical capsacin

• Etanercept

• Dupilumab

• Cold tolerance induction

• Adjustment and discontinuation of therapy — For patients who have been

entirely protected from cold-induced symptoms for at least six weeks on a

higher than standard dose, the dose is then decreased over several months to

the lowest level that provides complete protection. Patients are continued on a

prophylactic antihistamine until they go into remission.