Cold urticaria – What we know and what we do not know

Abstract

Cold urticaria (ColdU) is a common form of chronic inducible urticaria characterized by the development of wheals, angioedema or both in response to cold exposure. Recent research and guideline updates have advanced our understanding and management of ColdU. Today, its pathophysiology is thought to involve the cold‐induced formation of autoallergens and IgE to these autoallergens, which provoke a release of proinflammatory mediators from skin mast cells. The classification of ColdU includes typical and atypical subtypes. We know that cold‐induced wheals usually develop on rewarming and resolve within an hour and that anaphylaxis can occur. The diagnosis relies on the patient's history and cold stimulation testing. Additional diagnostic work‐up, including a search for underlying infections, should only be done if indicated by the patient's history. The management of ColdU includes cold avoidance, the regular use of nonsedating antihistamines and the off‐label use of omalizumab. However, many questions regarding ColdU remain unanswered. Here, we review what is known about ColdU, and we present important unanswered questions on the epidemiology, underlying pathomechanisms, clinical heterogeneity and treatment outcomes. Our aim is to guide future efforts that will close these knowledge gaps and advance the management of ColdU.

Cold Agglutinins and Cryoglobulins Associate With Clinical and Laboratory Parameters of Cold Urticaria

“…Cold urticaria (ColdU) is a type of chronic inducible urticaria (CIndU) characterized by the occurrence of wheals and/or angioedema in response to cooling ( 1 , 2 ). It is classified into: (a) cold contact urticaria, which is characterized by whealing in response to local cold stimulation tests (CSTs) on the forearm with an ice cube and/or Temp Test ® technology, and (b) atypical ColdU, in which other provocation methods are needed to produce whealing (e.g., general body cooling) or local CSTs produce atypical responses.…”

“…It is classified into: (a) cold contact urticaria, which is characterized by whealing in response to local cold stimulation tests (CSTs) on the forearm with an ice cube and/or Temp Test ® technology, and (b) atypical ColdU, in which other provocation methods are needed to produce whealing (e.g., general body cooling) or local CSTs produce atypical responses. Cold-induced anaphylaxis may also occur ( 1 ). ColdU is confirmed by provocation testing, and disease activity is measured by trigger threshold(s) ( 3 – 5 ).…”

“…Histamine release in ColdU coincides with the onset of pruritus and swelling ( 10 ). The mast cell-activating signals in ColdU have not yet been well defined and are likely to be heterogeneous ( 1 , 3 ). Autoantibodies are held to play a role in some patients with ColdU ( 1 ), and passive transfer studies found that localized ColdU can be induced in healthy human subjects by injecting them intradermally with serum of some ColdU patients ( 11 ).…”

“…The mast cell-activating signals in ColdU have not yet been well defined and are likely to be heterogeneous ( 1 , 3 ). Autoantibodies are held to play a role in some patients with ColdU ( 1 ), and passive transfer studies found that localized ColdU can be induced in healthy human subjects by injecting them intradermally with serum of some ColdU patients ( 11 ). Further studies found that the serum factors that initiated ColdU depended on immunoglobulin E (IgE) ( 10 , 12 , 13 ), and rarely on immunoglobulin M (IgM) ( 14 ).…”

“…Further studies found that the serum factors that initiated ColdU depended on immunoglobulin E (IgE) ( 10 , 12 , 13 ), and rarely on immunoglobulin M (IgM) ( 14 ). A cold-inducible antigen, however, has not yet been identified ( 1 ).…”