Introduction

Anaphylaxis is the most severe immediate systemic allergic reaction, usually rapid in onset and sometimes fatal [1]. It generally involves at least two organ systems, including the skin/visible mucosal tissue, cardiovascular, respiratory, or gastrointestinal system. Possible symptoms and clinical signs of anaphylaxis are listed in Table 1 [2,3,4,5, 6••]. Immediate administration of adrenaline (epinephrine) is crucial [2], but often underused [3, 7]. Cold-induced anaphylaxis (ColdA) represents a poorly researched form of anaphylaxis in patients with cold urticaria (ColdU). ColdU, a subset of chronic inducible urticaria (CIndU), has an estimated annual incidence of 0.05% in Europe [8] and is characterized by the development of wheals and/or angioedema upon exposure to cold stimuli followed by rewarming [9,10,11, 12••, 13]. The precise fatality rate associated with ColdA is unknown [9, 12••, 14, 15•]. ColdA remains poorly understood due to the absence of a universally accepted definition and limited knowledge of its pathomechanism. This manuscript aims to review: (a) recent research findings, including those from the large international, cross-sectional COLD-CE study (i.e., comprehensive evaluation of ColdU and other cold-induced reactions, a study within the GA2LEN UCARE network) [12••, 16••, 17], and (b) effective management strategies. Additionally, we discuss the potential involvement of mast cells (MCs) and basophils, along with the role of immunoglobulin E (IgE) to autoallergens, in the pathogenesis of ColdA.

Table 1 Possible symptoms and clinical signs of anaphylaxis [2,3,4,5, 6••]
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Classification of ColdU: distinguishing typical and atypical forms through provocation

Standard methods of local cold provocation (LCP) involve the use of an ice cube melting in a plastic bag or nonlatex glove and/or a thermoelectric device, the TempTest® with a 4 − 44 °C gradient, on the volar forearm [18]. ColdU is clinically categorized into two forms: typical ColdU (ColdUT), characterized by immediate whealing in the area of LCP, and atypical ColdU (ColdUA), with either negative LCP tests or atypical responses, such as delayed whealing. For ColdUA, specific provocation methods tailored to individual patient histories are often necessary to elicit whealing [9, 18, 19]. In ColdUT, provocation thresholds should be determined if possible [18]. The critical stimulation time threshold (CSTT) is the minimum contact time (30 s to 5 min) with an ice cube that induces a wheal, and the critical temperature threshold (CTT) is the highest temperature (4 − 37 °C) at which a wheal is induced by TempTest® [12••, 18]. The prevalence of ColdUT in ColdU studies shows significant variability (59 − 100%), indicating potential differences across various populations and settings [11, 12••, 20,21,22,23,24,25,26,27,28,29,30]. While ColdU is predominantly an acquired condition, rare hereditary forms have been identified [31]. The associated risk of ColdA in these hereditary forms remains unknown.

Variability in the definition and reported prevalence of ColdA

The definition of ColdA lacks consensus. In the COLD-CE study, ColdA was diagnosed in 37% (151/412) of patients with ColdUT. This study defined ColdA as an acute cold-induced involvement of the skin and/or visible mucosal tissue accompanied by at least one of the following: cardiovascular manifestations (i.e., hypotension [RR < 90/60 mmHg] or signs or symptoms suggestive of hypotension [loss of consciousness, dizziness, sensation of fainting, weakness]), breathlessness, or gastrointestinal symptoms [12••, 16••]. Previous smaller-scale studies reported systemic reactions, based on variable definitions, in 4 − 51% of ColdU patients [11, 20,21,22,23,24,25,26,27,28,29,30, 32,33,34,35,36], as indicated in Table 2. There are significant challenges in determining the prevalence of ColdA due to its patient-reported nature (often not formally documented/coded by healthcare providers) and the influence of trigger avoidance. It should also be emphasized that the prevalence of ColdA derives exclusively from individual clinical history as, for ethical reasons, nobody would systematically expose patients with ColdU to a cold environment (e.g., bath, shower, room) to establish whether they develop an anaphylactic reaction. Environmental factors such as geographical characteristics also very likely play a role in the development of ColdU/ColdA [37]. A systematic review and meta-analysis identified a 21% prevalence of ColdA, defined as a systemic reaction involving two organ systems and/or hypotension triggered by cold exposure among ColdU cases [15•]. Additionally, a few studies provided data on individual systemic reactions (Table 2) [11, 12••, 22,23,24, 38]. Comparative studies of ColdA prevalence in ColdUT versus ColdUA are limited. Two studies revealed a higher incidence of ColdA in ColdUT patients (Table 2) [26, 34].

Table 2 Cold-induced systemic reactions and their triggers: a summary of studies (1985 − 2023)
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Underrepresentation of ColdA in anaphylaxis publications

Ring and Behrendt (1999) reported that cold can act as an elicitor of 'pseudoallergic (anaphylactoid) hypersensitivity reactions' [4]. Subsequently, Kemp and Lockey (2002) listed cold temperatures as a cause of 'IgE-independent (anaphylactoid) reactions' [39], and Simons et al. (2007) recognized cold as a non-immunologic trigger or a co-trigger of anaphylaxis [40]. The 2011 World Allergy Organization guidelines also mentioned cold as a non-immunologic trigger of anaphylaxis [5]. Williams and Sharma (2015) further identified cold as one of the non-immunologic triggers of anaphylaxis due to the direct activation of MCs and basophils [41]. In a clinical context, Sala-Cunill et al. (2013) found only one ColdA patient in a cohort of 102 anaphylaxis cases [42], and Yeğit et al. (2023) reported just one ColdA patient among 271 anaphylaxis cases [43]. However, in 2023, the Joint Task Force on Practice Parameters recognized ColdA as a form of anaphylaxis associated with physical stimuli and recommended that patients with ColdU may require adrenaline (epinephrine) autoinjectors (AAIs) [6••]. This represents the first official recognition of ColdA as an indication for AAIs.

Systemic cold exposure as the primary trigger of ColdA

The same type of cold exposure does not uniformly result in the same severity of ColdU in all patients [12••, 21, 22, 24, 28, 44, 45]. The primary exogenous risk factors for ColdA appear to be the extent of skin surface area exposed, the temperature, and the duration of the exposure. This correlation likely explains why complete water immersion is the most frequently reported trigger of ColdA [12••, 16••, 20, 22, 24, 26, 28, 33, 38]. This relationship suggests a dose-dependency in ColdA [9]. Other documented triggers of ColdA include exposure to cold air [12••, 16••, 22, 26, 33, 38], localized contact with cold water [25, 33], limited contact with cold solid surfaces [26], cold provocation in the clinical setting [13], consumption of cold food or drinks [11, 26, 33, 46], and exposure to intravenous or irrigation fluids [33, 47,48,49]. Currently, no cofactors are known that may influence the severity of ColdA.

Key diagnostic indicators for assessing the risk of ColdA

It is essential to take a detailed patient history and perform standard LCP tests in all patients reporting symptoms of ColdU or ColdA. Previous studies identified the following 'endogenous' clinical characteristics of patients with ColdU who have previously experienced ColdA episodes: (a) prolonged duration of ColdU [12••, 26]; (b) cold-induced oropharyngeal/laryngeal signs or symptoms, such as swollen tongue and uvula, difficulty swallowing (dysphagia), or voice changes (dysphonia) [12••, 28]); (c) cold-induced generalized wheals, angioedema, or itchy earlobes [12••]; (d) positive standard LCP, indicating ColdUT [26, 33, 34]; (e) shorter CSTTs [12••, 26, 28, 29] and higher CTTs [26] in LCP; (f) larger wheal diameters in LCP [12••]; (g) pseudopodial whealing in LCP [12••]; and (h) a history of systemic reactions to Hymenoptera stings [12••]. On the other hand, the presence of concomitant chronic spontaneous urticaria was associated with a decreased risk of ColdA in patients with ColdUT [12••].

Pathophysiology of ColdA

The pathomechanism of 'typical' IgE mediated anaphylaxis has been extensively studied. It is known to involve various mediators released from activated MCs and basophils such as histamine, platelet-activating factor, enzymes, cysteinyl leukotrienes, and anaphylatoxins [50, 51]. While ColdU is understood as a MC-driven disease [10, 52,53,54,55], with heterogeneous activating signals [10, 56], the pathophysiology of ColdA remains largely unexplored [57]. We hypothesize that ColdA also predominantly involves MC and basophil activation.

Mature MCs are primarily located in tissues exposed to external pathogens such as the skin, airways, and gastrointestinal tract [58], and are situated around blood vessels and nerves [59, 60]. Unlike MCs, basophils are histamine-containing cells that circulate in the blood and play a central role in many types of allergic reactions [13]. A study by Juhlin and Shelley in 1961 revealed histamine release in two patients with ColdA, with distinctive cytologic changes in tissue MCs and blood basophils. They suggested that cutaneous signs result from histamine release by cold-sensitive MCs in the dermis, and systemic symptoms arise from histamine release by cold-sensitive basophils [13]. Passive serum transfer experiments suggest that IgE plays a role in the pathogenesis of ColdU [31, 61,62,63,64,65]. The hypothesis that cold exposure may trigger the formation of de novo autoallergens and subsequent IgE-mediated responses [9, 31, 66] diverges from traditional views of anaphylaxis but could be crucial in understanding ColdA. A case of a 12-year-old girl with ColdU/ColdA successfully treated with anti-IgE therapy also suggests IgE involvement [67]. TRPM8 (transient receptor potential cation channel subfamily M [melastatin] member 8) proteins, which form Ca2+-conducting cation channels activated by menthol or cold, have also been proposed as mediators of MC activation in ColdU [68].

In cases of Hymenoptera venom-triggered anaphylaxis (HVA), testing for underlying clonal MC disorders (CMCDs) is a well-established practice [69,70,71,72]. Given that HVA was recognized as an independent risk factor for ColdA in the COLD-CE study [12••], further research is needed to determine whether patients with ColdA also need to be tested for CMCDs. Furthermore, a case of severe ColdU with the KIT D816V variant reported in 2021 [11] supports the hypothesis of a connection between ColdA and CMCD. Valent et al. reported 'cold temperature' as one of the factors that can provoke anaphylaxis in patients with mastocytosis, attributing it to a temperature effect on MCs [73]. Akin et al. emphasized that the presence of hypotension during anaphylaxis increases the likelihood of an underlying CMCD [74].

Immediate management strategies for high-risk patients

Patients at high risk for anaphylaxis require provision of AAIs [75]. The COLD-CE study highlighted that only a minority of ColdA patients received adrenaline during their anaphylaxis episode or were prescribed an AAI [16••]. Recommendations for prescribing AAIs vary: Yee et al. and Alangari et al. advised that all pediatric patients with ColdUT should have AAIs [22, 33], while Katsarou-Katsari et al. extended this recommendation to all adult patients with ColdUT [21]. However, this approach may lead to high costs and unnecessary lifestyle restrictions for mildly affected ColdU patients. We propose prescribing AAIs to: (a) all patients with a previous episode of ColdA, especially those with cardiovascular reactions; (b) individuals reporting cold-induced oropharyngeal/laryngeal signs or symptoms; and (c) patients deemed high-risk by physicians, based on other previously discussed clinical features. Furthermore, making AAIs accessible in public areas, particularly at beaches and swimming pools, would be advisable due to the potential for cold exposure in these settings.

It is also crucial to recognize the challenges in applying existing ColdA definitions to certain ColdU cases. For instance, respiratory symptoms in ColdU patients with asthma might be due to an exacerbation of asthma triggered by cold air, rather than ColdA. Gastrointestinal discomfort from cold food or drinks might reflect mucosal cooling rather than ColdA. Ingestion of cold foods or beverages can cause localized angioedema in the oropharyngeal/laryngeal tract, leading to upper airway obstruction, which may not be ColdA per se but a sign of direct, localized mucosal sensitivity to cold.

Educational points for long-term management of high-risk patients

Patients at high risk of ColdA require not only comprehensive education but also regular medical follow-ups. The estimated duration of ColdU ranges from 4.8 to 7.9 years [18], but data on the persistence of ColdA risk are lacking. Education is crucial, as patients who are unaware of their condition's risks are more vulnerable to life-threatening complications. Key educational points include:

  1. 1.

    Trigger avoidance: Patients must be advised to exercise caution during activities involving complete water immersion, such as swimming in the sea, lake or pool. Importantly, avoiding all other cold triggers is often unnecessary; patients should avoid only those triggers that have previously caused reactions. For example, if cold food or drinks do not elicit reactions, there is probably no need for avoidance.

  2. 2.

    Recognition of early signs of ColdA: Patients must learn how to identify early clinical signs of ColdA. They should also be thoroughly instructed on when and how to self-administer an AAI.

  3. 3.

    Understanding of treatment options: High-risk patients should always carry AAIs and wear a medical alert bracelet. While second-generation H1-antihistamines can be effective in managing itch and wheals, they are not substitutes for adrenaline in treating ColdA. Bronchodilators can offer relief from respiratory symptoms, especially for individuals with asthma. Glucocorticosteroids, although not typically used for immediate treatment, can be considered in post-ColdA management to reduce inflammation.

Consistent follow-ups with a specialist are essential for high-risk patients to ensure effective long-term management and monitoring of their condition.

Future research directions in ColdA

ColdA remains an intriguing yet understudied area amongst anaphylactic reactions. To improve our understanding of this unique condition and patient care, the following aspects need further research:

  1. 1.

    ColdA frequency and risk factors: Comparative studies of ColdA prevalence and its associated risk factors in patients with ColdUT versus ColdUA are needed.

  2. 2.

    Cofactors: ColdA is likely influenced by multiple factors, and identifying potential cofactors such as genetic predisposition, comorbidities, and environmental triggers could help understand its speed of onset and severity.

  3. 3.

    Laboratory features: A comparative analysis of laboratory features between ColdU patients who experienced ColdA and those who did not could help identify potential biomarkers and clinical predictors of ColdA.

  4. 4.

    Serum tryptase levels: Measuring serum tryptase levels immediately following ColdA could help establish a baseline for understanding MC and basophil activation in ColdA.

Conclusion

This review offers practical information for routine clinical practice and highlights the urgent need for establishing a universally accepted definition of ColdA. Furthermore, it emphasizes the necessity for further extensive research to elucidate its pathophysiology. Collective effort will be needed to develop effective management strategies and improve clinical outcomes for patients suffering from this challenging condition.