Aquagenic urticaria: presentation, diagnosis and management

Summary

Aquagenic urticaria, a rare dermatological condition characterised by urticarial eruptions following water contact, poses significant diagnostic and therapeutic challenges. This condition, although uncommon, necessitates heightened clinical awareness due to its substantial impact on the patient’s quality of life. We present a comprehensive account of a paediatric case involving a girl in her mid-teens, who developed recurrent wheals post-exposure to water, independent of its temperature or source. Diagnosis hinged on a detailed clinical history and a definitive water provocation test, with routine laboratory assessments yielding no contributory findings. The therapeutic regimen featuring cetirizine yielded significant symptomatic relief. Although antihistamines are the cornerstone of treatment, the differential response among individuals necessitates an individualised approach, considering adjunctive treatments such as omalizumab and ultraviolet therapy. This case reinforces the critical role of clinical acumen in the recognition and diagnosis of aquagenic urticaria and calls for further research into its pathophysiology to refine treatment strategies.

Background

Aquagenic urticaria, a rare and enigmatic form of physical urticaria, is characterised by the rapid onset of urticarial lesions on contact with water, irrespective of its temperature or source. With less than 100 cases documented in the literature, aquagenic urticaria continues to challenge clinicians and researchers due to its elusive pathophysiology and varying clinical presentations. Diagnosis relies heavily on the clinical presentation and history, complemented by provocation tests which are crucial for confirming aquagenic urticaria and distinguishing it from other types of chronic inducible urticaria. The management of aquagenic urticaria, constrained by the impracticality of water avoidance, primarily focuses on providing symptomatic relief which emphasises the need for further investigation into targeted therapeutic interventions.

Here, we present a case of aquagenic urticaria manifesting during early adolescence. This report delves into the clinical manifestations observed, explores the current understanding of the pathogenesis and reviews the diagnostic approaches and treatment modalities available aiming to enhance clinician awareness and improve patient outcomes.

Case presentation

A girl in her early adolescence with no significant medical history other than known allergies to dust, rabbits and cats was referred to our clinic, presenting with an urticarial rash. She presented with a 2-year history, starting around menarche, of multiple pinpoint sized wheals with surrounding 1–3 cm erythematous flares which developed immediately after contact with water. The lesions occurred immediately after water exposure, irrespective of temperature or source including showering/bathing, swimming pools, seawater and getting rain soaked. These symptoms consistently manifested after every instance of water exposure. Each episode typically lasted approximately 30–60 min and would spontaneously resolve without the use of medication. The patient did not experience any symptoms due to exposure to sweat, or tears, however, she reported abdominal discomfort while drinking water and symptomatic episodes when in contact with animal saliva. She had no systemic reactions, such as headache, shortness of breath, wheezing, dizziness or fainting and no family history of urticaria. The individual did not show any other forms of inducible urticaria. There was no recorded family history of atopy, and none of her family members had reported skin reactions when exposed to water. Her symptoms were not linked to consumption of food or medication prior to contact with water. There was no use of estroprogestins or any other hormonal medications.

Investigations

On physical examination, skin appeared clear with a distinct absence of dermographism. A routine laboratory evaluation was performed, encompassing a complete blood count, liver and renal function tests, urine analysis, panels for immunoglobulins, thyroid function tests, all yielding results within normal limits, ruling out any underlying abnormalities. After discontinuing antihistamines for 1 week, a water provocation test was administered. This involved regional contact using a damp cloth on the patient’s trunk, maintained at 35°C (figure 1A). After 20 min, there was a development of urticarial eruption on the trunk, which was consistent with the patient’s natural exposure to water (figure 1B). Given the patient’s history and the results of the water provocation test, a diagnosis of aquagenic urticaria was established.

Figure 1. (A) Urticarial eruption after 20 min of regional contact with wet cloth as a result of water provocation test (35°C). (B) Multiple pinpoint wheals surrounded by erythema prior to diagnosis of aquagenic urticaria.

Treatment

Her mother initially administered montelukast, a leukotriene receptor antagonist, based on her own judgement, which she observed to moderately manage the patient’s symptoms. On evaluation at our clinic, cetirizine, a second-generation H1 antihistamine, was prescribed at 10 mg daily, leading to further symptom relief. Following this, the use of montelukast was discontinued, and the patient continued to experience substantial relief from the wheals.

Outcome and follow-up

At the 8-month follow-up, she did not report any further episodes of symptoms, unless a dosage of cetirizine was missed. At the 14-month follow-up, the patient continued to report further improvement in her condition, which enabled her to participate in daily activities without any restrictions. Additionally, the administration of the Children’s Dermatology Life Quality Index yielded a score of 0, indicating no impairment of quality of life-related to her condition at this time.

Discussion

Aquagenic urticaria, a rare form of physical urticaria, arises when water contacts the skin’s dermis, irrespective of its temperature.¹ Notably, its onset typically coincides with puberty and exhibits a higher prevalence in females.² The typical clinical presentation involves the emergence of hives on the upper limbs and trunk, excluding the palms, within thirty minutes of water exposure. These hives commonly resolve between 30 and 60 min post water removal.^{3 4} Systemic symptoms like wheezing or dyspnoea are infrequent.⁵ To further elucidate the prevalence and characteristics of aquagenic urticaria in the paediatric population, previously reported cases of aquagenic urticaria with reported treatments and outcomes are described in table 1.

Table 1. Reported cases of paediatric aquagenic urticaria.

Study	Gender	Age of onset	Family history	Treatment	Outcome
Napolitano et al18	F	1	–	Desloratadine 5 mg once daily	Remission with treatment
Wasserman et al19	M	3	–	Dimetindene 15 drops 1 hour prior to water contact	Remission with treatment
Park et al11	M	3	–	Ketotifen 5 mL syrup once daily	Remission with treatment
Ercan et al20	M	5	–	Cetirizine once daily	Remission with treatment, and treatment stopped after 4 weeks with no recurrence
Napolitano et al18	F	7	–	Desloratadine 5 mg once daily	Remission with treatment
Arıkan-Ayyıldız et al12	M	8	–	Rupatadine once daily	Symptoms controlled
Fukumoto et al21	F	8	–	Loratadine 10 mg once daily	Remission with treatment
Arıkan-Ayyıldız et al12	M	10	–	Second generation H1-antihistamine once daily	Remission with treatment
Davis et al22	F	10.5	–	Hydroxyzine 25 mg three times per day	Symptoms controlled
Chen et al23	M	12	–	Fexofenadine 60 mg two times per day	Skin lesions continued to develop, however, pruritus improved. Refused to titrate the dose of fexofenadine because of concerns about adverse effects
McGee et al15	M	12	–	Petrolatum-containing cream before showering	Remission with treatment
Rubin and Kabil24	M	12	–	Cetirizine 10 mg three times per day	Cetirizine dosage was increased from once daily, to two times per day, to three times per day, resulting in improvement in disease management
Arıkan-Ayyıldız et al12	M	12	–	Avoidance of hot bath, heavy exercise, emotional strains, with second-generation H1 antihistamines once daily if needed	Symptoms controlled
Muinelo et al25	F	12	–	Symptomatic treatment with antihistamines only if skin lesions worsened	NR
Broderick et al26	M	12	–	Cetirizine 20 mg two times per day	Decreased duration of hives, with urticaria persisting following showers
Treudler et al27	M	13	Mother, grandmother, aunt, cousin	Cetirizine once daily	No prolonged therapeutic effect achieved with antihistamines or with UVB radiation therapy
Hide et al28	M	13	–	Terfenadine 60 mg, mequitazine 6 mg and topical diphenhydramine 1% once daily	Partial improvement (fewer lesions, and less pruritus)
Czarnetzki et al10	F	14	Sister	Terfenadine 60 mg once daily	Remission with treatment
Fukayama et al29	M	14	–	Levocetirizine 5 mg and pregabalin 75 mg once daily	Limited efficacy on lesions and pruritus
Yavuz et al30	M	14	–	Desloratadine prior to water contact	Remission with treatment
Su et al31	F	14	–	Long-acting antihistamine once daily and counselling	Improved symptom control
Shelly and Rawnsley6	F	15	–	Chlorpheniramine maleate once daily	Symptoms controlled
Czarnetzki et al10	F	15	Sister	Terfenadine 60 mg once daily	Remission with treatment
Kai and Flohr32	M	15	Twins	Cetirizine 10 mg once daily	Remission with treatment
Aung et al33	F	15	–	Cetirizine 20 mg two times per day	Did not respond well to cetirizine 20 mg two times per day. Provided a trial of propranolol 20 mg once daily, still not tolerated. Continues to have itching with hives when showering
Carra et al34	F	16	–	Omalizumab 300 mg subcutaneously every 4 weeks	Antihistamine therapy not well tolerated, but good clinical response to omalizumab therapy
Kiliç et al35	F	16	–	Omalizumab 300 mg subcutaneously every 4 weeks	Did not respond to antihistamine therapy, but responded to omalizumab therapy
Yavuz et al30	M	16	–	Desloratadine prior to water contact	Remission with treatment
Park et al11	M	16	–	Fexofenadine 180 mg once daily	Remission with treatment, dosage adjusted to every other day
Seol et al36	M	17	–	Bepotastine 10 mg once daily	Remission with treatment
Mathelier-Fusade et al37	F	17	–	Cetirizine 10 mg once daily	Remission with treatment
Martínez-Escribano et al38	F	18	–	PUVA (1 /week×20)+astemizole 10 mg once daily	Previous treatment with oral antihistamines including hydroxyzine, cetirizine, ebastine, were ineffective, however PUVA+astemizole resulted in complete remission

PUVA, psoralen and ultraviolet A therapy.

The exact pathophysiological underpinnings of aquagenic urticaria remain unclear. Early propositions by Shelly and Rawnsley postulated an interaction between water and sebaceous glands or sebum, leading to mast cell degranulation, histamine release and resultant weal formation.⁶ Supporting this, Tkach hypothesised an increase in water’s passive diffusion due to hair follicles’ altered osmotic pressure, an idea further bolstered by Gallo et al, who observed urticarial occurrences post-hair extraction.7,9 Another theory posits that water-soluble epidermal antigens diffuse through the dermis, triggering histamine release.¹⁰ Contrarily, some researchers argue against the histamine-centric explanation, as they have noted consistent histamine levels in patients post-water exposure.² Given its significant impact on patients’ quality of life, the absence of a universally accepted mechanistic explanation remains problematic.

The diagnosis of aquagenic urticaria primarily relies on the patient’s history of repeated urticarial reactions following water exposure, supplemented by a water provocation test. Though several methods exist for this test, the standard procedure involves application of a 35℃–37℃ water compress to the upper body for 20–30 min. The emergence of an urticarial response signifies a positive result.^{1 11 12} Aquagenic urticaria can be provoked by water at any temperature, however, using a compress at room temperature is essential to eliminate the potential overlap with cold-induced or local heat urticaria. The predominant diagnostic challenge for aquagenic urticaria is its differentiation from other physical inducible urticaria variants like cholinergic, heat, cold, pressure and exercise-induced urticaria.⁴ Hence, patients must undergo specific provocative tests tailored to these conditions (table 2).¹³

Table 2. Common differential diagnosis of aquagenic urticaria and associated diagnostic evaluation tests.

Condition	Characteristics	Diagnostic evaluation
Aquagenic pruritus	Pruritus or burning sensations without visible skin changes, typically occurring after skin contact with water	Water challenge test, where there is an application of a 35°C–37°C water compress to the upper body for 20–30 min
Cholinergic urticaria	Small, widespread itchy papules due to increased body temperature, often triggered by sweating or stress	Two-step testing: (1) Exercise challenge—moderate physical activity until sweating, followed by 15 additional minutes. (2) If positive, perform a passive warming test—full bath at 42°C until body temperature rises more than 1°C
Contact urticaria	Immediate, transient swelling/whealing and erythema on skin contact with an exogenous agent	Perform a sequence of tests if the eliciting factor is unclear: (1) 20 min Patch Test on healthy and damaged skin, with examinations after 30 min and 24 hours. (2) Standard prick or patch test. (3) Controlled exposure to the suspected allergen (eg, latex gloves). (4) Specific IgE measurements for unresolved cases
Cold urticaria	Itchy weal and flare reaction from cold exposure	Cold stimulation test, where an ice cube is placed on the skin for 1–5 min or TempTest device, producing temperatures of 4°C−44°C, applied on the inner forearm to identify individual threshold temperature at which cold-induced wheals occur
Delayed pressure urticaria	Pruritus, swelling and pain hours after pressure exposure, potentially with burning sensations. May exhibit systemic symptoms like fatigue or joint pain	Apply weighted rods (6.5 cm in diameter, weight of 5 kg, exerting a pressure of 14.6 kPa) to the forearm for 15 min, or use a dermographometer to apply 100 g/mm² vertically to the back skin for 5–180 s. A positive reaction is indicated by a delayed red, palpable swelling recorded after 6 hours
Dermatographic urticaria (urticaria factitia)	Linear, pruritic hives from shear force on the skin, often caused by scratching or rubbing, most frequent type of physical urticaria	Dermatographometer or FricTest application at various pressures (20–60 g/m2) or by moderately rubbing the skin with a blunt smooth object, like a closed ballpoint pen tip, on the patient’s back or forearm
Exercise-induced urticaria	Larger hives not induced by passive warming like cholinergic urticaria, often accompanied by systemic symptoms like shortness of breath, headache or nausea	Exercise challenge—moderate physical activity until sweating, followed by 15 additional minutes. A positive test without a reaction during a subsequent passive warming test confirms this condition
Localised heat urticaria	Reaction limited to the area of heat exposure, characterised by a palpable weal and flare type skin reaction, along with itching	Heat provocation testing for 5 min at 45°C–50°C on the volar forearm using warm water in metal or glass cylinders, a warm water bath, or TempTest to identify individual threshold temperature at which heat-induced wheals occur
Solar urticaria	Immediate reaction to UV and visible light, subsides within 24 hours, differentiable from polymorphous light eruption	Exposing skin areas (commonly the buttocks) to UV and visible radiation using UV lamps with filters (UV-A and UV-B). Apply radiation at the following intensities: UV-A at 6 J/cm², UV-B at 60 mJ/cm² and visible light (eg, from a slide projector at a 10 cm distance)
Vibratory urticaria/angioedema	Pruritus, erythema, and swelling localised to the site of the vibratory stimulus	Use a laboratory vortex mixer as a provocation tool. Place the patient’s forearm on a flat plate atop the vortex mixer, running at speeds between 780–1380 rpm for 10 min

Adapted from Komarow et al.39

Given its ambiguous pathogenesis, treatment options for aquagenic urticaria remain limited and often yield varied results.¹⁴ Non-sedating, second-generation H1 antihistamines are commonly the primary line of treatment, with some patients requiring doses up to four times the typical daily amount. Yet, the response to this regimen can differ significantly from one individual to another.^{1 4 11} In cases where standard treatments are ineffective, ultraviolet (UV) monotherapy or UV combined with antihistamines, has demonstrated some efficacy.^{2 15} It is postulated that the UV therapy leads to an enhanced thickness of the epidermis, potentially inhibiting water from penetrating and interacting further within the epidermal environment.¹⁶ Alternative therapeutic measures encompass the use of topical barrier creams and acetylcholine antagonists.¹⁵ Notably, there have also been recent accounts of aquagenic urticaria being successfully managed with omalizumab.¹⁷

Aquagenic urticaria, though rare, presents a diagnostic and therapeutic challenge for clinicians due to its unique water-induced aetiology. Detailed patient history, thorough physical examinations and water provocation tests are invaluable tools in establishing a definitive diagnosis. While the pathogenesis remains enigmatic, the efficacy of treatments such as second-generation H1 antihistamines underscores the strides made in managing this condition. Continued research is vital to deepen our understanding and enhance therapeutic strategies, ensuring the best possible patient outcomes.

Learning points.

• Aquagenic urticaria, although a rare dermatological condition, demands heightened clinical awareness due to its significant impact on patient quality of life, particularly during sensitive developmental periods such as adolescence. Clinicians should consider aquagenic urticaria in the differential diagnosis when patients present with recurrent urticarial lesions triggered by water exposure.

• The diagnosis of aquagenic urticaria relies on a detailed clinical history, ruling out other forms of inducible urticaria and the implementation of water provocation test to assess the skin for an urticarial reaction secondary to water exposure.

• The management of aquagenic urticaria should be individualised, considering the variability in response to treatments. While non-sedating, second-generation H1 antihistamines are the cornerstone of treatment, some patients may require higher doses or adjunctive therapies.

• Continued research and clinical documentation of aquagenic urticaria cases are essential to unravel its pathophysiology and develop more targeted and effective therapeutic interventions, ultimately improving patient outcomes and quality of life.