Authors: Elena Borzova, Bernhard F. Gibbs
Categories: Review Article
Source: Sports Medicine (Auckland, N.z.)
Authors: Elena Borzova, Bernhard F. Gibbs
Lactate is a ubiquitous and pleiotropic signalling molecule, with important functional effects in tissue and cellular metabolism. As an exerkine, lactate is not only substantially released from tissues during exercise but may also play a role in exercise-related medical conditions. Since exercise is a known co-factor in anaphylaxis, this may suggest a mechanistic relevance for lactate release during anaphylactic events. Here, we evaluated in vitro and in vivo evidence for lactate release from mast cells (MCs) from preclinical microdialysis studies, animal models and clinical data in anaphylaxis. Lactate levels are markedly elevated in both animal models of anaphylaxis and patients with anaphylaxis. Although not causative, lactate is clearly relevant to many different steps in anaphylaxis, including MC activation, vascular permeability and gastrointestinal dysfunction, but currently lacks a comprehensive interpretation framework in anaphylaxis. As a result, lactate cannot be currently considered a biomarker of anaphylaxis per se. However, given its wide dynamic range, a plethora of available lactate biosensors, and the ease of measurement in various biological fluids, lactate may be a potential candidate for biomarker development. At present, lactate’s contribution to anaphylaxis, which was discovered a century ago by Zunz and La Barre, has not been fully elucidated. Unresolved issues in anaphylaxis include the patient’s metabolic state; the kinetics of lactate release and its biological actions; MC bioenergetics and metabolome; activation thresholds; and feedback mechanisms, as well as an expression of lactate-metabolizing enzymes. A closer focus on these known unknowns may demystify the contribution of lactate in anaphylaxis and beyond.
Lactate in anaphylaxis. There are various clinical scenarios for lactate measurements in (1) exercise-induced anaphylaxis, (2) fatal or near-fatal anaphylaxis, (3) anaphylaxis in mastocytosis and (4) epinephrine-induced lactic acidosis. First, there is likely to be an overlap in early signalling events and pre- and post-translational processes mediated by lactate in the context of exercise in healthy subjects and in patients with exercise-induced urticaria/anaphylaxis, which may well be further complicated by abnormal MC reactivity, activation threshold and, possibly, feedback mechanisms in the latter. This underlines a commonality in metabolic pathways that may involve, at least in part, MC-derived histamine and its subsequent hemodynamic effects involved in anaphylaxis. Second, elevated serum lactate was demonstrated to be associated with anaphylaxis severity [54], especially in relation to fatal anaphylaxis in critical care settings [31]. This is in keeping with circumstantial evidence from a variety of previous reports from case studies and animal models. Furthermore, lactate release parallels histamine release in a MC activation event in a patient with mastocytosis [147]. Finally, lactate acidosis may rarely occur following multiple epinephrine injections in patients with anaphylaxis.
The online version contains supplementary material available at 10.1007/s40279-025-02273-8.
Lactate, albeit not causal, may be associated with the severity of anaphylactic reactions due to upregulated glycolytic pathways.Glycolytic pathways play a pivotal role in endothelial hyperpermeability and are triggered by histamine, which is released both physiologically during exercise as well as by allergic mechanisms.There is a need for further metabolomic studies in human and murine anaphylaxis.
Anaphylaxis is the most severe sudden-onset systemic allergic reaction which is unpredictable in severity [1] and is potentially life-threatening [2]. Owing to a spectrum of clinical manifestations with multisystem organ involvement [3], anaphylaxis has various definitions [4]. The annual incidence of anaphylaxis has substantially increased worldwide over the past decades [5, 6], raising concerns over an anaphylaxis ‘epidemic’ [7]. Emergency department visits and hospitalizations due to anaphylaxis have been increasing in the UK, the USA [8] and Australia [9].
The mechanisms of anaphylaxis are primarily caused by allergen-mediated crosslinking of immunoglobulin E (IgE) bound to high-affinity IgE receptors (FcεRI) on mast cells and basophils and the resultant release of histamine as well as de novo-generated inflammatory lipid mediators. Histamine and platelet-activating factor (PAF) majorly contribute to vasodilatation, bronchoconstriction and atrial fibrillation, all of which potentially contribute to the severity of systemic anaphylaxis [10–12]. In addition, cysteinyl leukotrienes are also rapidly produced from mast cells and basophils, where they contribute to bronchoconstriction, and have been clearly implicated in anaphylaxis [13].
Although relatively rare, fatalities due to anaphylaxis may occur because of shock, laryngeal angioedema with asphyxia, severe bronchospasm and cardiac arrythmias [14]. Data from the European Anaphylaxis Registry suggests that the rate of fatal drug anaphylaxis has been increasing [15]. Although fatal outcomes are rare, adolescents and young adults are particularly vulnerable to fatal food-induced anaphylaxis [16], whereas fatal anaphylaxis occurs in older adults, with a median age of 49 years [15].
Exercise-induced hypersensitivity disorders, including exercise-induced anaphylaxis (EIA) (Box 1), are also recognized as an important problem in recreational and competitive athletes [17]. Cold-induced anaphylaxis occurs in 37% of patients with typical cold urticaria according to the international COLD-CE study [18]. Anaphylaxis is thus an area of unmet clinical need, requiring prompt recognition, immediate management and more effective preventive strategies.Box 1Exercise and anaphylaxisThe relationship between exercise and anaphylaxis can be divided into three 1. Classical anaphylaxisAt least in some individuals, it can be affected by exercise2. Food-dependent exercise-induced anaphylaxisFood-induced reactions occur in the context of exercise. Typically, food ingestion is followed by exercise3. Exercise-induced anaphylaxisExercise is thought to trigger the anaphylactic episode, independent of an exogenous allergen
Biomarker development in anaphylaxis is intended to aid with the retrospective diagnosis in patients with ambiguous presentations or in cases of idiopathic anaphylaxis. In allergy practice, some patients with a history of anaphylaxis may present with a paucity of the data regarding the index episode [19]. Importantly, there is a need for risk stratification to identify the patients at risk of severe anaphylaxis [20]. In post-mortem examinations of patients with sudden death, biomarkers could help identify the cases with fatal anaphylaxis [19]. Perioperative anaphylaxis needs to be confirmed and followed up with a detailed allergy work-up for suspected drug allergies. There is also a need for prediction and early diagnosis of prolonged, refractory or biphasic anaphylaxis [20]. EIA needs to be differentiated from exercise-induced hypotension in collapsed endurance athletes, highlighting the need for reliable biomarkers in various clinical contexts where exercise can play a role in anaphylaxis [21, 22].
Multiple biomarkers have been in development to address these needs, but their performance in anaphylaxis depends on multiple factors, including testing systems, clinical settings, sampling time and causative allergens [19]. Tryptase is a useful biomarker of anaphylaxis, with a plasma half-life of approximately 2 h, which may remain elevated within 24–48 h of its onset, characterized by high specificity but variable sensitivity, depending on the trigger [23]. Individuals with hereditary α-tryptasemia, with increased α-tryptase-encoding TPSAB1 copy number, may be at increased risk of severe anaphylaxis [24, 25], especially in patients with systemic mastocytosis [25, 26].
Urine biomarkers, including N-methyl histamine, prostaglandins (PGD2 and its metabolite PGF2α) and leukotrienes (LTE4) [27] are subject to wide inter-individual variability. Other biomarkers, such as chymase, carboxypeptidase A, platelet-activating factor, dipeptidyl peptidase I, basogranulin and CCL2, are currently in development [19]. Skin tests are important diagnostic tools which are usually carried out within 6 months of an anaphylaxis episode [28] but, as with assessing allergen-specific IgE, they do not serve as biomarkers for anaphylaxis. Cytokines such as TNF-α, IL-6 and IL-1β are also thought to play a role in anaphylaxis [23]. However, existing biomarkers of anaphylaxis have known limitations [29] and are either not commercially available or not available at the point-of-care [30]. The search for biomarkers of anaphylaxis is an ongoing issue [7], highlighting an important knowledge gap in anaphylaxis research [20]. Recent work from France suggested an association between lactate and fatal anaphylaxis in critical care settings [31], suggesting its potential utility as a biomarker to guide the management of severe anaphylaxis.
Lactate is a ubiquitous messenger, regulating metabolism and physiology [32]. It is produced from the glycolytic intermediate, pyruvate, due to the actions of lactate dehydrogenase (LDH). Under aerobic conditions, pyruvate is usually converted to acetyl CoA and enters the Kreb’s cycle to produce NADH and FADH2, which are then used in oxidative phosphorylation to generate adenosine triphosphate (ATP). However, under anaerobic or high oxygen demand conditions (such as during exercise or inflammatory immune responses), there is a risk of hypoxia which disrupts mitochondrial function, potentially leading to cell death. To guard against this, metabolic adaptations shift from deriving ATP from oxidative phosphorylation to glycolysis alone, which increases lactate levels. As a major myokine and exerkine [32], lactate exerts diverse regulatory effects on redox biology, mitochondrial biogenesis and energy substrate utilization, lipolysis, and histone lactylation in healthy subjects.
Moreover, Zunz and La Barre (Fig. 1) showed that lactate (lactic acid) is centrally involved in anaphylactic shock in guinea pigs, thus marking 100 years of research in this area [33]. In the 1920s, Nobel Prize winners Otto Meyerhof [34] and Archibald Hill [35] demonstrated the role of lactate (lactic acid) in anaerobic conditions. During this period, Otto Warburg discovered that glycolytic activity, and subsequent lactate production, in cancer cells increases despite normoxic conditions, which is called the Warburg effect [36, 37]; it is still not fully understood a century later [38]. George Brooks [39] developed a lactate shuttle theory, demonstrating that lactate links glycolytic and oxidative metabolism [40]. Recognition of lactate shuttling came from physical exercise studies but now is being extended to other research areas. Over the last two decades, lactate has been increasingly recognized as a signalling molecule in various biological contexts [41], including chronic inflammation [42] and cancer [43].Fig. 1Prof. Edgard Zunz (1874–1939). Prof. Edgard Zunz was a prominent Belgian pharmacologist and the Director of the Laboratory of Pharmacodynamics and Therapeutics at the University of Brussels. Anaphylactic shock was one of Prof. Zunz’ research interests. In 1924, Prof. Zunz and his coworker Jean La Barre first reported lactate release during anaphylactic shock in their experiments with guinea pigs. In 1934, Prof. Zunz served as the President of the Belgian Royal Academy of Medicine. The portrait of Prof. Edgard Zunz was kindly provided by the Belgian Royal Academy of Medicine
Our interest stemmed from several mechanistic findings in lactate metabolism in sports immunology, intensive care science and immune reprogramming, pointing towards a role for lactate in different contexts, beyond cancer [42], especially in anaphylaxis. Since lactate is significantly associated with fatal anaphylaxis [31], it is crucial to determine whether its release fulfils the unmet need for more efficient biomarkers in the precision management of anaphylaxis [28] and other mast cell (MC)-dependent diseases [44].
Insights about lactate in anaphylaxis lie at the intersection of exercise immunology, critical care and allergy metabolomics. Lactate release is substantially, both locally and systemically, elevated during acute exercise and adaptations to chronic exercise, including increasingly popular endurance exercise. Lactate shuttles, described by George Brooks [39], highlighted lactate-mediated cell-to-cell crosstalk during exercise in healthy individuals. Since exercise is a known trigger or co-factor in anaphylaxis, this suggests a mechanistic relevance for lactate and associated metabolic changes during anaphylactic events, particularly in EIA.
In critical care settings, most evidence on lactate metabolism has come from studies in patients with various states of shock [45, 46], including a small number of studies on anaphylaxis [31, 47]. Higher lactate levels are associated with worse outcomes from anaphylaxis in a critical care setting [31]. Hence, lessons learned regarding lactate in critical care medicine may help predict and prevent fatal anaphylaxis. In allergy research, metabolic studies have focused mostly on lactate metabolism in asthma [48] and food allergy [49], including food allergic children with or without history of anaphylaxis [50]. In this regard, metabolic profiling of anaphylaxis is an area of considerable interest, though currently under-researched.
It is high time to shed light on these lactate research intersections between exercise biology, allergy metabolomics and shock pathophysiology and apply important lessons derived from them to anaphylaxis. Arguably, sufficient evidence has accumulated to evaluate the role of lactate in anaphylaxis. Therefore, in this review, we aimed to evaluate in vitro and in vivo evidence for lactate release from MCs, preclinical microdialysis studies, animal models and clinical data in anaphylaxis to glean novel insights, highlight clinical needs and inform the research agenda in this area.
MCs are key players in anaphylaxis owing to their capacity to release histamine and other vasoactive mediators following allergen provocation or via IgE-independent triggers such as anaphylatoxins [51] and Mas-related G-protein coupled receptor member X2 (MRGPRX2) [52, 53]. Detection of the MC-specific protease, tryptase, is an established indicator of systemic anaphylaxis [54], although its contribution in acute allergic reactions is poorly understood. Tryptase is often used as a surrogate for MC-specific activation where it is released in close correlation to histamine [54], elevations of which were also long known to be associated with EIA [55].
Interestingly, MCs also produce lactate in parallel to histamine release (HR) under normoxic conditions [56–72] (Supplementary Table S1). However, this has only been shown in vitro in rodent mast cells and we simply do not know the proportions of lactate from MC and other sources contributing to its systemic release in humans. MCs depend on glycolytic and oxidative pathways to mitigate their energetic expenditure during degranulation [73, 74]. The signalling pathways underlying lactate release during MC degranulation involve hypoxia-inducible factor-1α (HIF-1α) stabilization, which crucially upregulates glycolytic enzyme expressions (e.g. LDH-A), and suppresses the tricarboxylic acid (Krebs) cycle. HIF-1α expression was shown to increase following FcεRI-mediated stimulation of human MCs as well as basophils, where it plays a crucial role in enabling these cells to generate inflammatory and immunomodulatory cytokines within hours following degranulation [75]. HIF-1α stabilization is a critical step in enhancing glycolytic pathways, which prevent potential adenosine trisphosphate (ATP) depletion, in stimulating angiogenesis, including the production of vascular endothelial growth factor (VEGF), and in the subsequent formation of lactate. HIF-1α accumulation was further shown to be dependent on the mammalian target of rapamycin (mTOR) kinase [76], a central regulator of myeloid cell growth and metabolism, which was recently shown to play a vital role in the ability of MCs to re-granulate following activation [77].
The immunometabolism of allergic effector cells, including mast cells and basophils, relies on glycolysis upon acute activation (the Warburg effect) to address a high energy demand for their activation [75, 78, 79]. Their rapid release of preformed mediators, such as histamine, as well as de novo*-*generated lipid and cytokine mediators, increased demands in ATP generation (used for the phosphorylation of kinases and other signalling proteins). These cells shift towards producing lactate from pyruvate, which is mediated via HIF-α-dependent upregulation of different pyruvate dehydrogenase kinases. Although aerobic glycolysis is less energetically efficient than oxidative phosphorylation, the former allows a faster energy generation under the circumstances of rapidly increased energy demands for immune cell activation. Indeed, IgE-mediated activation of basophils was shown in vitro to dose-dependently decrease ATP levels while increasing HIF-1α accumulation [75, 79]. The resulting induction of glycolysis and glucose transporters subsequently protects the cells against ATP depletion and allows them to fulfil their effector functions.
The energetics of MC degranulation are incompletely understood [74]. Early studies suggested a link between ATP levels and HR, where inhibition of glycolysis blocked HR but did not affect ATP production [66, 80]. Being an energy source [39], lactate may be required for MC energetics since lactate production increases when ATP and oxygen demands exceed supply [81]. Whether lactate contributes to energy metabolism during MC degranulation can be studied by isotope-tracer studies in animal models of anaphylaxis. Furthermore, genetically encoded fluorescent biosensors for extracellular [82] and intracellular lactate [83] and single-cell metabolomics [84] may address these questions in MC lines in future studies.
Net lactate production increases under various conditions, including exercise or inflammation, and elevated lactate concentrations may affect immune cell functions, including MCs [85]. Extracellular lactate is transported across the plasma membrane by four l-lactate-transporting monocarboxylate transporters (MCTs) [86]. In MCs, extracellular lactate may enter MCs by the ubiquitously expressed MCT1 (also known as SLC16a1 [86]), which has a high affinity for lactate (Km = 3.5–10 mM) [42]. CD147, a transmembrane glycoprotein which co-localizes with lactate transporters MCT1, MCT3 and MCT4 [86], was reported in skin MCs [87], although lactate transporters and CD147 expressions have not been evaluated in anaphylaxis.
Functional studies primarily focused on lactic acid (2-hydroxypropionic acid, C3H6O3) rather than lactate (2-hydroxypropanoate, C3H5O3^−^), where inhibitory effects on MCs have been demonstrated in mechanistic studies [68–72]. Syed and coworkers [72] reported that lactic acid suppressed MRGPRX2-mediated MC activation in LAD2 MCs, human skin MCs and mouse peritoneal MCs. Caslin and coauthors [70] demonstrated that lactic acid inhibits LPS-induced MC function by limiting glycolysis and ATP availability. Lactic acid suppressed IgE-mediated mast cell responses in vitro and in vivo, suggesting a role for lactate as a negative feedback loop which limits MC activation (Fig. 2) [69]. However, only moderate inhibitory effects were observed with lactate compared with lactic acid [69, 70, 72], suggesting an essential role of pH; it remains uncertain whether these effects can be induced by lactate in vivo [88]. Despite this, Abebayehu et al. [69] showed that the inhibitory actions of lactic acid on MC function were dependent on MCT1, underlining a role for a lactate/lactic acid-specific effect rather than H^+^ generated from other sources.Fig. 2Overview of the HIF-1α-mediated production of lactate in mast cells. Activation of MCs and related allergic effector cells (e.g. basophils) leads to HIF-1α stabilization which regulates the production of VEGF and induces glycolysis. Glycolytic pathways generate lactate as well as preventing ATP depletion in activated MCs, thereby facilitating de novo-generated cytokine production. Lactate is subsequently released from mast cells and may affect MC responses, suggesting a potential negative feedback loop which remains to be elucidated in anaphylaxis
The potential role of lactate as a signalling molecule in MCs clearly requires further study. One could speculate that lactate signalling in MCs may be abnormal in MC-dependent conditions, including chronic spontaneous urticaria, chronic inducible urticarias (CINDU) or EIA, especially in terms of potential inhibitory feedback loops as implied by previous in vitro studies [69, 70, 72]. However, the notion that lactate has such inhibitory effects on MCs is largely based on observations using lactic acid rather than lactate per se. Whether lactate accumulation in reported patients [31] is due to excessive production or impaired oxidative metabolism also remains to be elucidated.
MC activation is central to anaphylaxis [51]. However, other effector cells (neutrophils, platelets, basophils, macrophages and monocytes) also contribute to its pathophysiology [89]. Importantly, MC activation may indirectly increase lactate levels owing to the actions of histamine on the endothelium. Ziogas et al. recently demonstrated that histamine stimulates hyperpermeability in human microvascular endothelial cells (H1-receptor mediated) by triggering phospholipase C and glycolysis, subsequently significantly enhancing lactate levels [90]. Furthermore, these histamine-induced effects were abrogated by the glycolytic inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), which in vivo crucially protected mice from developing passive cutaneous as well as active systemic anaphylaxis.
The above clearly provides a plausible explanation regarding the association between increased lactate levels in MC-related diseases, due to their histamine-releasing capacity. The release of this biogenic amine from basophils in the circulation is also implicated. Moreover, increased glycolysis associated with ongoing inflammation or exercise may reduce the threshold and subsequently potentiate the severity of histamine-induced vascular permeability. If this is the case, then histamine releasability and/or the polymorphisms and expression levels of H1 receptors on endothelial cells of, for example, patients with anaphylaxis, may be important. Finally, tentative evidence suggests that MC-derived histamine plays a physiological role in optimizing muscle perfusion via H1 and H2 receptors [91, 92]. While MC activation is clearly associated with acute aerobic exercise (as determined by elevated tryptase levels) [91], an important known unknown is how MCs are activated in exercise per se.
There is, therefore, a commonality of MC activation in both exercise and anaphylaxis, which, though orchestrated by different stimuli, results in increased MC mediators and lactate. This notion is further supported by the findings of Parsons et al. [93], showing that post‑exercise hypotension and exercise-associated collapse is also dependent on MC degranulation in marathon runners. The severity of anaphylaxis and other reactions related to exercise hypersensitivity is thus likely to involve thresholds of sensitivity to histamine, and other MC-derived mediators, which are released both physiologically and due to allergic mechanisms, both of which are associated with elevated lactate (summarized in Fig. 3). It remains to be established whether endurance exercise, which is a known hyperglycolytic state, induces glycolytic processes in MCs, vascular endothelium and intestinal epithelial cells, thus affecting the end-organs of immune mediators in anaphylaxis. These aspects, together with other diverse signalling contributions of lactate in health and disease [42, 43], highlight the need to understand this important metabolic messenger, a ‘lactormone’ [39, 94], in the context of anaphylaxis in greater detail.Fig. 3Overview of the differential sources and role of lactate in exercise and anaphylaxis. In addition to its release from skeletal muscles during exercise, lactate is also released from mast cells potentially both during exercise (through yet unknown mechanisms) and in anaphylaxis (following activation by allergens or anaphylatoxins). Histamine is also released from mast cells and stimulates endothelial cells, which results in further lactate release due to the activation of glycolytic pathways. The resulting increased vasodilatation, vascular permeability and subsequent fluid caused by the effects of histamine on the endothelium substantially contributes to the signs and symptoms of anaphylactic shock. The association with lactate release in limited clinical data and activated mast cells in in vitro data suggests that lactate may be a potential indicator or biomarker of mast cell activation. However, lactate may also have regulatory effects on mast cells in some settings, which needs to be further investigated
Since the seminal work by Paul Portier (1866–1962) and Charles Richet (1850–1935) first on the effects of Physalia physalis (Portuguese man-of-war) toxins on various small animals during a cruise on the yacht Princesse Alice II of Prince Albert of Monaco in the summer of 1901, and then their definitive experiments with dogs sensitized with Actinia extracts [95], there have been numerous animal models of anaphylaxis [96]. Lactate release was reported within 30–60 min in anaphylaxis in dogs [97], rabbits [98] and mice [99, 100]. Despite limitations related to species-specific differences and animal genetic backgrounds [96, 101], these animal models may provide further insights into lactate metabolism in anaphylaxis.
Many currently unresolved questions about lactate in anaphylaxis, such as the cellular sources, the kinetics and the catabolism in anaphylaxis, may be, at least partly, answered in isotope studies, with or without exercise or allergen challenges, in mouse or rodent models of food-induced anaphylaxis, including a humanized mouse model of peanut anaphylaxis [102–104].
Microdialysis [105, 106] has been used in metabolic studies [107] in the skin and skeletal muscles in humans to study lactate metabolism at the tissue level. Except the study by Rosdahl et al. [108], baseline lactate concentrations in healthy subjects were two- to threefold higher in the skin and skeletal muscles than those in venous blood [107, 109, 110], underlining that local lactate release can be a promising readout for microneedles and wearables. Importantly, lactate–pyruvate ratios in dermal dialysates indicated normoxic conditions [109, 110], which is in keeping with a contemporary view of lactate production under fully aerobic conditions [39]. Although the skin, particularly the epidermis [111], produces large amounts of lactate on a par with resting skeletal muscles in humans [46, 112], cellular sources of dermal lactate release are unknown [107]. Recent metabolomic study of skin dialysates in healthy subjects demonstrated that lactate levels were fourfold higher in skin dialysates compared with peripheral blood [113]. Further metabolomic cutaneous microdialysis studies in exercise are underway in Japan.
Interstitial lactate levels in skeletal muscles were shown to rise during intermittent static [108] or dynamic exercise [114], consistent with the lactate shuttle hypothesis [39]. Kinetic studies in healthy subjects demonstrated that tissue lactate concentrations remain elevated for an hour (skeletal muscles) following exercise [108] and for 90 min in the skin following oral glucose tolerance tests [107]. Such mechanistic studies now need to be applied to patients with anaphylaxis, using microneedles and wearable biosensors [115] to monitor cutaneous lactate levels in the context of controlled challenges (exercise, allergen or both).
The time course of exercise-induced molecular events is of particular interest given that most EIA cases occur within 1 h (mostly 10–30 min) after exercise [116, 117]. Lactate is known to mediate acute response and long-term adaptations to exercise [118]. Lactate production occurs in fast-twitch white skeletal fibres and in populations of red fibres at the start of exercise [119]. In 30-min endurance tests, there was a significant increase in blood lactate concentration for both trained and untrained individuals [120]. A recent systematic review highlighted increased MCT1 and, to a lesser extent, MCT4 expressions in skeletal muscles following a training program [121].
In skeletal muscles, the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) alters the LDH complex, thereby controlling lactate homeostasis and skeletal muscle metabolic adaptations in response to exercise. In a meta-analysis of human transcriptomic studies, PPARGC1A expression, a central transcriptional regulator of skeletal muscle adaptation to exercise, was upregulated in skeletal muscle biopsies after acute aerobic and resistance exercise [122]. In a human exercise transcriptome study [123], NR4A1 mRNA was increased after aerobic exercise (1 h), whereas mRNA for transcription factors HIF1A and PRARGC1A was increased at 3 h post exercise. Therefore, in healthy individuals, adaptive responses of lactate metabolism to exercise comprise increased lactate in both blood and skeletal muscles, followed by upregulated signalling pathways (NR4A1, HIFα, and PGC-1α) and altered LDH complex and lactate transporter expressions.
Adaptive metabolic responses to acute exercise in humans also include HR [124] as was first reported in healthy subjects following physical exercise on a bicycle ergometer in the 1950s [125]. HR is detected at 30–60 min during exercise. Although histamine is usually associated with allergic and anaphylactic responses, this mediator is also released in the context of exercise adaptations. In healthy subjects, acute aerobic exercise for 1 h induces a twofold upregulation of histidine decarboxylase (HDC) mRNA 3 h following exercise [123]. Aerobic exercise also induces a post-exercise activation of histamine H1 and H2 receptors [123], and these receptors were shown to mediate vasodilatation associated with post-exercise hypotension [126].
The involvement of MCs is further supported by the findings of Parsons et al. [93], showing that post‑exercise hypotension and exercise-associated collapse is also dependent on MC degranulation in marathon runners. In the study by Parsons et al. [93], marathon runners with or without exercise-induced hypotension or exercise-associated collapse demonstrated tryptase release following a marathon race, clearly indicating MC involvement in exercise-induced hypotension per se. Runners with a history of exercise-induced hypersensitivity syndromes were excluded, and a personal or family history of atopy was not evaluated in this study. Therefore, exercise adaptations of histamine metabolism include HR in skeletal muscles and, variably, in the circulation, as well as upregulation of HDC and activation of histamine receptors, all of which are important in anaphylaxis.
In a clinical context, multiple lines of evidence suggest that exercise is a common trigger in anaphylaxis, including food-dependent exercise-induced anaphylaxis (FDEIA) [22]. On the basis of the data of 7316 patients from the Anaphylaxis Registry, patients who reported vigorous exercise during (or prior to) a given reaction had a higher risk [odds ratio (OR) 1.5, 95% confidence interval (CI) 1.3–1.7] of severe anaphylaxis compared with those not physically active [127]. Exercise may also trigger certain chronic inducible urticarias (CINDUs), such as cholinergic urticaria [128], which can be associated with anaphylaxis. Moreover, in adults allergic to peanuts, exercise has been shown to reduce threshold reactivities to oral challenge [21], suggesting that exercise may play a role in conventional anaphylaxis too, at least in certain individuals. Exercise is known to increase allergen absorption in the gut [129] which, at least in part, offers a credible explanation for reduced reactivity thresholds to allergens exposed via the gastrointestinal tract as is the case with FDEIA and other severe food allergies. However, the physiological release of histamine in exercise may serve as an additional parameter for reduced symptom severity thresholds by acting in concert with allergen-induced HR and its downstream actions. This, for example, could further enhance endothelial permeability and therefore exacerbate crucial mechanisms which govern anaphylaxis severity.
EIA is a rare and potentially fatal condition in which anaphylaxis occurs during or after exercise, without exogenous allergen stimulation [130]. Importantly, various CINDUs were reported in athletes, mostly in those practicing field and track sports [131]. Potential mechanisms underlying EIA include altered gastrointestinal permeability, increased transglutaminase activity in the gut mucosa, blood flow redistribution, changes in plasma osmolality and subsequent basophil HR, as well as cellular pH changes leading to MC degranulation [130].
Since its description in an endurance runner in 1979 [116], there have been up to 800 cases reported in literature [127], with many patients being established athletes [132]. Exercise-induced cutaneous MC degranulation was reported in patients with EIA [133]. Laboratory treadmill challenges can provoke the symptoms in patients with EIA, although negative challenges were also reported [134]. Of interest, responders to exercise challenge had a statistically high mean increase from baseline levels of histamine (tenfold) compared with non-responders [134]. In EIA responders undergoing exercise challenges, HR was noted to increase within 10 min [135] and to subside within 20–60 min after cessation of exercise [136, 137]. Exercise-induced tryptase release was demonstrated in an 18-year-old football player with EIA [137]. The mechanisms of MC activation in EIA are unknown. The data on systemic HR in exercise challenges were rather inconsistent in patients with EIA [138], possibly due to its short half-life and technical issues with detection techniques [139]. The latter are likely to be resolved with the advent of metabolomics and biosensing. Anaphylactic responses to acute exercise in patients with EIA during a controlled challenge are known to be linked to MC degranulation and systemic histamine/tryptase release [133, 134, 137]. EIA pathophysiology is likely to result from interplay between the type and intensity of exercise, the athletic history of the patients, adaptations of lactate and histamine metabolisms, and activation thresholds for basophils and MCs, which are the main sources of histamine.
As an important exerkine [32, 140], lactate may play a role in exercise-related, MC-dependent conditions, such as in EIA, which commonly occurs in atopic patients [134] and/or athletes, including endurance athletes [141, 142]. Clinical evidence of exercise-induced lactate release in MC-dependent diseases is limited to a case report with exercise-induced urticaria/angioedema [136]. In a 21-year-old patient with exercise-induced urticaria and angioedema, lactate concentrations rose to high levels (13 mmol/L), accompanied by HR, following treadmill challenge [136]. Further studies are needed to elucidate whether metabolic exercise adaptations, including lactate and HR, augment the pathophysiological mechanisms of EIA.
The tissue crosstalk between the skin and exercising muscles mediated by lactate, as proposed by Brooks [143], indicates that lactate may mediate tissue-to-tissue communication during exercise in health and in MC-dependent conditions. However, the contribution of lactate, released during physical exercise, to the pathophysiology of EIA has been given insufficient attention. There is a need for comparative metabolomic studies in healthy subjects and patients with EIA since it is unclear whether hyperlactatemia enhances HR from MCs in exercise-induced hypersensitivity syndromes as suggested by Tse and co-workers [136]. Whether adaptive and anaphylactic responses to exercise overlap in EIA or whether exercise adaptations create permissive conditions for EIA is also unclear.
Interestingly, in 1949 Herlitz [144] reported that lactic acid produced a wheal-and-flare response in two patients with exercise-induced urticaria. These reactions were transferable by the Prausnitz–Küstner test, suggesting that, in rare cases, the lactate molecule itself may either activate MCs or affect MC activation thresholds in urticaria. However, this observation of potential stimulatory effects of lactic acid contrasts with more recent findings regarding an inhibitory action of lactic acid on MCs [69, 70, 72], underlining an urgent need for further studies.
Patients with mastocytosis are at high risk of severe anaphylaxis [145]. Anaphylaxis can occur in 20–56% of adult patients with mastocytosis owing to excessive MC mediator release [146]. Preventive management of anaphylaxis in mastocytosis includes antihistamines, MC stabilizers, life-long immunotherapy in patients allergic to Hymenoptera venom, cytoreductive therapies for patients with an excessive MC burden [145] and targeted therapies for patients with frequent recurrent anaphylaxis [146].
In mastocytosis, maximal clinical symptoms during a severe MC activation event were strongly associated with both lactate and histamine levels (Supplementary Table S2) [147], supporting previous observations of MC lactate release (Supplementary Table S1). Here, lactate rose to 7 mM at the peak of the attack, with a rapid decline at 1.1 mM/h with a half-life of 153 min [147], exceeding the usual half-life of lactate post-exercise. Future studies need to establish whether metabolomic measurements, including lactate, and using wearable biosensors (Graphical Abstract) can help diagnose and manage such recurrent anaphylactic events.
In a multi-centre French study of 339 patients with anaphylaxis in an intensive care setting, lactate release was shown to be associated with fatal outcome by multivariate analysis [31]. Although not specific to anaphylaxis, the levels of lactate in non-survivors of anaphylaxis were higher than those observed in septic or cardiogenic shocks [148, 149]. Importantly, future studies need to evaluate changes in lactate concentrations from the onset of symptoms rather than from the time of admission to a critical care unit to truly assess how lactate levels evolve in anaphylaxis. Although this may be challenging for food-induced anaphylaxis in an out-of-hospital setting, this should be imminently possible for perioperative anaphylaxis.
In the study by Crestani et al. [50], non-targeted global metabolomics revealed significantly different lactate levels in food-allergic children with (n = 19) or without (n = 51) a history of anaphylaxis, requiring intramuscular epinephrine injection. Using plasma metabolomics, altered carbohydrate metabolism, including decreased levels of pyruvate together with increased levels of lactate, was observed in patients with severe food allergy to profilins, including three patients who required administration of epinephrine [150]. In addition, on the basis of gene set enrichment analysis (GSEA), oxidative phosphorylation was reduced in profilin-allergic patients with severe manifestations on oral challenge, thus suggesting a switch to Warburg metabolism [150].
Metabolomic profiling (Supplementary Table S2) demonstrated metabolic differences during the acute reaction (< 2 h) and following clinical recovery (2–4 h later) in anaphylaxis [47]. In the acute phase, 32.62% patients with moderate anaphylaxis had increased lactate levels, compared with a recovery phase, demonstrating a decline in lactate concentrations in these patients following a recovery. The present evidence supports a role for elevated lactate levels in predicting anaphylaxis severity. Interestingly, patients with severe anaphylaxis had higher lactate levels 2–3 months later compared with those with moderate anaphylaxis [47]. Whether this reflects hyperglycolytic changes and/or MC hyperreleasability associated with severe anaphylaxis is currently unknown.
Under physiological conditions, elevations in lactate production are a known metabolic effect of epinephrine in healthy individuals during exercise [151]. Previously, metabolic effects on lactate levels associated with epinephrine (epinephrine-induced hyperlactatemia) were shown to be mediated via β2 adrenergic stimulation of muscle tissue Na^+^/K^+^-ATPase-activity [152].
Raised lactic acid to high lactate-to-pyruvate ratios in arterial blood and elevated serum lactate dehydrogenase (LDH) levels were described in two patients with anaphylaxis, both treated with epinephrine [153]. Lactic acidosis was also reported following epinephrine injections in a patient with anaphylaxis [154]. Given that around one in ten anaphylactic episodes are treated with multiple epinephrine doses [155], epinephrine-induced lactic acidosis may present a clinical challenge, and an unmet need for therapeutic strategies, requiring serum lactate monitoring during critical care. If epinephrine-induced lactic acidosis is suspected, alternative vasopressors should be considered.
Existing biomarkers, e.g. serum tryptase, histamine, and prostaglandins in urine or skin testing, may be used in clinical practice but not as bedside biomarkers [30]. Since anaphylaxis severity is impossible to predict [156], lactate and associated metabolic changes may unlock this present impasse, where lactate measurements, using disposable biosensors and wearables, offer potential point-of-care testing (Box 2) [157–161]. Understanding the advantages and pitfalls of lactate as a putative anaphylaxis biomarker holds a promise for personalized anaphylaxis management (Supplementary Table S2).Box 2Clinical lactate measurementsHealthy subjects at restLactate concentrations in peripheral blood and dermal interstitial fluid (ISF) in healthy individuals are within the range of 1–2 mMHyperlactatemia is defined as serum lactate level of 2 mM or greater [140]Healthy subjects during exerciseAt sea level, lactate levels > 4 mM are frequently detected in training [137] and can increase up to ≈ 15–25 mM in intense exercise [138]Critically ill patientsLactic acidosis is characterized by elevated lactate levels (> 5 mM) and pH < 7.35 [132–140, 142]In patients with severe sepsis and septic shock, hyperlactataemia can raise up to 15 mMPatients with anaphylaxisEpinephrine-induced lactic acidosis may occur [134]Lactate biosensingMultiple biosensors have been developed for lactate measurements in peripheral blood and dermal interstitial fluid, with a low limit of detection (< 0.1 mM) and a wide linear range (0.1–100 mM). A clinical trial of a lactate biosensor is ongoing (ClinicalTrials.gov no. NCT04238611)
Lactate is an easy-to-measure parameter, thus fulfilling a requirement that biomarkers must be measurable [162, 163]. However, several limitations may hinder its development as a biomarker. The main challenge is the lack of an interpretation framework of lactate concentrations in anaphylaxis. Lactate is reflective of complex metabolic changes and can be elevated in the context of any critical illness but not specifically in anaphylaxis.
Lactate metabolism not only plays a role in anaphylaxis but also in atopic diseases such as atopic dermatitis (AD) and asthma. LDH activity (Supplementary Table S3) is substantially upregulated in in AD [164, 165]. Likewise, elevated lactate was reported in patients with asthma, including those with status asthmaticus [166]. A more recent study underlined that increased lactate is associated with asthma pathogenesis and is crucially associated with increased glycolysis [48], suggesting that it could serve as a biomarker for asthma severity. In the study by Ruman-Colombier and co-workers [167], 87% of patients hospitalized with moderate and severe asthma had hyperlactatemia, with lactate concentrations exceeding 5 mmol/L in 26% of patients. This indicates that lactate is already involved in these atopic diseases; hence, the diagnostic value of lactate measurements in patients with anaphylaxis with comorbid atopic diseases needs further research.
On balance, lactate may be an attractive candidate for biomarker development in anaphylaxis. Although histamine and lactate are both released from MCs, histamine is known to induce a hyperglycolytic state in vascular endothelium which, in turn, leads to further lactate release [88]. Thus, its significance as biomarker, especially as an indicator of vascular involvement in EIA remains to be proven. Whether lactate measurements may offer advantages over the established biomarker tryptase are yet to be demonstrated. In the prospect, this may lead to a development of an integral biomarker signature in anaphylaxis, including lactate, reflecting different pathways and pathogenic steps in anaphylaxis.
While not causative or specific to anaphylaxis per se, lactate is involved in all steps of anaphylaxis, including MC degranulation and vasodilatation. However, lactate may be considered a potential candidate for biomarker development in anaphylaxis, in combination with other known biomarkers. The overarching notion that lactate is involved in anaphylaxis, and especially its severity, is supported by decades of evidence indicating its mechanistic and clinical relevance, albeit one that has not been systematically addressed or fully understood. Lactate may emerge as a potential missing link between anaphylaxis, MC function, and exercise, underlining an intriguing commonality of mechanisms which have so far been largely overlooked.
This perspective raises the question whether the release of lactate and histamine in anaphylaxis is entirely independent or a one-directional event, reflective of hyperglycolytic states and MC degranulation and whether there are amplifying or inhibitory relationships between these mediators. In our opinion, the most relevant in vitro finding is that histamine induces lactate release from endothelial cells, suggesting that lactate release in anaphylaxis can be induced, at least in part, by histamine. Another important question is whether hyperglycolytic states (Supplementary Box S1) in anaphylaxis and other allergic or urticarial diseases may open new therapeutic possibilities. However, many crucial questions regarding the role of lactate in anaphylaxis remain to be addressed (summarised in Table 1).Table 1Unanswered questions in lactate research in anaphylaxisCategoryUnanswered questions1AetiologyDo lactate levels differ depending on the aetiological factor of anaphylaxis?What are the lactate levels in (food-dependent) exercise-induced anaphylaxis or anaphylaxis associated with CINDUs?What are the lactate levels in anaphylaxis with exercise as a cofactor?2EpidemiologyCan lactate measurements at rest or during exercise detect individuals who are at risk of anaphylaxis?Are endurance athletes more likely to develop urticaria/anaphylaxis?3PathophysiologyWhat is the role and relevance of lactate in the pathogenesis of anaphylaxis?Do lactate levels and release kinetics differ depending on the anaphylaxis endotypes?Does lactate release differ in IgE-dependent and non-IgE-dependent anaphylaxis?Does lactate contribute to MC regulation in anaphylaxis? If so, how?Is the MC lactate signalling dysregulated in anaphylaxis?What is the expression level of lactate receptors on MCs in patients with anaphylaxis?Are MCs, endothelial cells and gastrointestinal epithelium in a hyperglycolytic state in endurance athletes?What are the overlap mechanisms between exercise adaptations and priming in atopic diseases?What are the local events in the skin underlying lactate release in healthy subjects and in patients with anaphylaxis?4Clinical heterogeneityDo metabolic signatures differ between anaphylaxis phenotypes?What are the lactate levels in different anaphylaxis phenotypes?Is there a difference in lactate release between exercise-induced anaphylaxis and other exercise-induced urticaria/angioedema?At what lactate levels does fatal or near-fatal anaphylaxis occur?What is the lactate release pattern in anaphylaxis associated with CINDUs?5ComorbiditiesWhat is the shared lactate pathophysiology of anaphylaxis with comorbid atopic diseases?What are the characteristics of lactate metabolism in patients with anaphylaxis with comorbid skin diseases?What are the characteristics of lactate release in patients with anaphylaxis with or without comorbid atopic diseases?What are the mechanisms underlying lactate release in atopic and non-atopic patients with anaphylaxis?6Clinical courseWhat are the lactate levels in patients with severe anaphylaxis?What are the lactate levels and kinetics in patients with exercise-induced anaphylaxis?What is the metabolomic signature of life-threatening or fatal anaphylaxis?What are the predictive models for the risk of anaphylaxis and for the disease severity in anaphylaxis associated with CINDUs?What is the accuracy of lactate as the prognostic biomarker in exercise-induced anaphylaxis?7DiagnosisCan lactate release pattern be useful for severity grading in anaphylaxis?What are the local events in the skin underlying lactate release in atopic and non-atopic endurance athletes?Can the local lactate release in the skin be measured in individuals with a history of anaphylaxis using wearables?Can the measurements of skin lactate release, using wearables, detect early signs of anaphylaxis?8Laboratory testingWhat is the clinical relevance of lactate measurements in patients with anaphylaxis?9Differential diagnosisWhat is the impact of metabolomics on the differential diagnosis of anaphylaxis?Can we differentiate anaphylaxis and exercise-induced hypotension using lactate and metabolomic signature?10TreatmentCan lactate levels guide the treatment of anaphylaxis?Can lactate levels inform clinicians about the efficacy of epinephrine?What is the lactate release pattern following epinephrine injection in patients with anaphylaxis with or without lactic acidosis?Can lactate be a predictive biomarker for treatment efficacy in anaphylaxis?Can lactate be a novel therapeutic target in anaphylaxis?What are the risk factors for epinephrine-induced lactic acidosis in patients with anaphylaxis?Are patients with multiple epinephrine injections at risk of lactic acidosis?What is the optimal management of patients with anaphylaxis with epinephrine-induced lactic acidosis?CINDU, chronic inducible urticarias
Finally, exercise is associated with both lactate and HR, posing novel questions as to how physiological and anaphylactic responses to exercise can be bridged in EIA. These questions have been in the field for a hundred years and have not been resolved. Yet, they must be resolved given the mechanistic plausibility, expanded knowledge of lactate metabolism, advent of lactate biosensors and accumulation of clinical evidence regarding the life-threatening condition of anaphylaxis.
Aerobic under aerobic conditions, 1 mole of glucose is metabolized to pyruvate, which, in turn, is converted to acetyl-coenzyme A, which, via tricarboxylic acid (Krebs) cycle, is oxidized to carbon dioxide, with a production of 38 moles of ATP [159].Anaerobic glycolysis (Embden–Meyerhof pathway): under anaerobic conditions, pyruvate is converted to lactate via the Embden–Meyerhof (glycolytic) pathway with a production of only 2 moles of ATP per mole of glucose [159].Anaphylaxis: a serious allergic reaction that is rapid in onset and potentially life-threatening. Anaphylaxis is highly likely when any of the following three criteria are Acute onset of illness within minutes to hours, with involvement of the skin or mucosal tissue and at least one of the respiratory compromise, reduced blood pressure, or symptoms of end-organ dysfunction; orTwo or more of the following that occur rapidly (minutes to hours) after exposure to a likely allergen or other trigger for that skin or mucosal tissue involvement, respiratory compromise, reduced blood pressure or associated symptoms, or gastrointestinal symptoms; orReduced blood pressure^^ that occurs within minutes to hours after exposure to a known allergen for that patient [3, 7].^^Low systolic blood pressure (age-specific) or greater than 30% decrease in systolic blood pressure in infants and children, whereas the systolic blood pressure is less than 90 mm Hg or there is a greater than 30% decrease from the patient’s baseline.Biomarker: a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, or pharmacologic response to a therapeutic intervention (National Institutes of Health Biomarkers Definitions Working Group [162]). For a biomarker, the relation to clinical indices or outcomes is important.Biosensor: an analytical device that uses a biological sensing element and a physical transducer to produce an electrochemical, optical, mass or other signals, which together relates the concentration of an analyte to a measurable electrical signal.CD147 (also known as Basigin, neurothelin or EMMPRIN (extracellular matrix metalloproteinase-inducer)): a transmembrane glycoprotein which co-localizes with lactate transporters MCT1, MCT3 and MCT4 and enhances their activities.Cori a metabolic pathway, named after Carl Ferdinand Cori and Gerty Cori, that generates glucose (gluconeogenesis) from lactate in liver and kidney.Exerkines: a broad variety of signalling moieties that are released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways [140].HIF-1α: the inducible subunit of hypoxia-inducible factor 1 (HIF-1α) transcription factor, which crucially stimulates glycolysis, angiogenesis and cell adhesion.Histamine: inflammatory mediator which plays a crucial role in eliciting the major signs and symptoms of acute allergic reactions, including anaphylaxis. Mast cells and basophils (which share many functional properties with mast cells but are fewer in number) are the principal sources of this biogenic amine. Its contribution to anaphylaxis includes stimulation of H1 receptors, which are involved in bronchoconstriction, vasodilatation, increasing vascular permeability and itch. H1 and H2 receptors are also expressed in the heart and play a major role in cardiac arrhythmias associated with anaphylactic shock. H4 receptors are also involved in pruritus (together with H1).Histidine an enzyme primarily expressed in mast cells and basophils involved in the generation of histamine by catalysing the decarboxylation of histidine.Hyperlactatemia: elevated blood lactate concentration (> 2 mmol/L).Krebs cycle (the tricarboxylic acid cycle): an aerobic metabolic pathway that produces 36 molecules of ATP for 1 molecule of pyruvate.Lactate: a hydroxy monocarboxylic acid anion (the conjugate base of lactic acid), with two stereoisomers, produced during glycolysisLactate a function of production and uptake of lactate, mostly by liver and kidney, followed by metabolism that leads to a given serum lactate concentration. In clinical practice, lactate clearance refers to the changes in lactate concentrations over time.Lactate dehydrogenase (EC 1.1.1.27): a tetrameric enzyme, with five isoforms, that acts as a catalyst in the pyruvate + NADH + H^+^ ↔ lactate + NAD^+^. LDH is composed of two subunits LDH-A and LDH-B, which belongs to the 2-hydroxyacid oxidoreductase family. LDH-A, characterized by a higher affinity for pyruvate, preferentially converts pyruvate to l-lactate, whereas LDH-B has higher affinity for lactate and catalyzes l-lactate to pyruvate [40]. LDH also regenerates NAD^+^ from its reduced form (NADH).Lactate a concept, developed by George Brooks [40], that describes the role of lactate in delivery of oxidative and gluconeogenic substrates, as well as in cell signalling.Lactate-to-pyruvate a molar ratio that reflects the equilibrium between product and substrate of the reaction catalysed by lactate dehydrogenase.Lactic acid (2-hydroxypropanoic acid): an organic acid belonging to the family of carboxylic acids (lactate is the conjugate base of lactic acid).Lactic a cellular metabolic process characterized by rises in blood lactate (> 5 mmol/L) and decreases in blood pH (< 7.25).Lactylation: a newly discovered lactate-dependent metabolic reprogramming that involves a post-translational modification of histone lysine residues and impacts cell metabolism and function [41].Mast cell process involving the fusion of MC granules and rapid release, withing minutes, of preformed inflammatory meditators (e.g. histamine) and enzymes (e.g. tryptase) following stimulation either by IgE-mediated crosslinking with allergens or IgE-independent triggers (e.g. anaphylatoxins).Mastocytosis: a clonal mast cell disorder, characterised by the proliferation, accumulation and activation of MCs in the skin and/or extracutaneous tissues.Microdialysis: a research sampling technique that allows real-time measurements of extracellular concentrations of soluble endogenous and exogenous molecules from interstitial fluid through a semipermeable membrane [105].Monocarboxylate acid members of the solute carrier (SLC) family of proteinsMRGPRX2 (MAS-related G-protein-coupled receptor member X2): a G-protein coupled receptor expressed in human MCs that is known as a potent activator of MCs [72].Na^+^/K^+^-ATPase: a membrane ion pump system located in the sarcolemma, which requires a continuous source of ATP to function. For every ATP molecule, three NA^+^ ions are pumped out of the cell and two K^+^ ions are pumped into the cell [152].Ovalbumin: a 45 kDa chicken-derived glycoprotein allergen, mostly present in egg white, which is commonly used for sensitization in animal models of anaphylaxis.Prausnitz–Küstner Reaction: a test for type I hypersensitivity where a non-sensitized individual is injected intradermally with serum from an allergen-sensitized individual resulting in a subsequent wheal-and-flare reaction following administration of the causative allergen.Wearable miniaturized electronic device that can be easily donned on and off the body or incorporated into clothing or other body-worn accessories [168].Warburg metabolic phenomenon, originally described in cancer cells, where aerobic glycolysis is favoured over oxidative phosphorylation.
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 478 KB)