Jellyfish Stings: A Review of Skin Symptoms, Pathophysiology, and Management

Introduction

The jellyfish, a marine invertebrate zooplankton distributed worldwide, belongs to the phylum Cnidaria, which encompasses various other organisms such as fire coral, stinging hydroids, sea wasps, sea nettle, and anemones [1]. The phylum Cnidaria is classified into 6 classes: Scyphozoa, Hydrozoa, Cubozoa, Anthozoa, Myxozoa, and Staurozoa [2]. Among these classes, only Scyphozoa, Hydrozoa, and Cubozoa contain animals referred to as jellyfish [3]. In recent years there has been an increase in recurrent jellyfish outbreaks observed in the oceans, including the Mediterranean Sea and the North Pacific Ocean, thereby increasing the potential risk of jellyfish stings and associated envenomation [3–5]. The estimated number of jellyfish sting incidents per year is approximately 150 million, with fatalities and hospitalizations occurring annually, particularly in the Indo-Pacific regions [6]. Beyond being a public health issue, jellyfish also pose obstacles to various human activities, including diving, fishing, aquaculture, and tourism [7–9]. However, the precise pathogenic mechanisms and constituents of jellyfish venom remain unclear, and the management of jellyfish stings continues to be an important medical topic [10–13]. This article aims to review the skin symptoms, pathophysiology, and management of jellyfish stings, which could provide comprehensive guidance for healthcare professionals and the general public.

Sting Process

The geographical distribution and skin effects of stinging jellyfish are shown in Table 1. All geographic distribution maps of each jellyfish species are reproduced from the World Register of Marine Species (WoRMS) [2], with permission. However, these distributions may be deemed incomplete and should solely serve as a reference owing to the dynamic fluctuations in the global distribution of jellyfish and the limited data available on the WoRMS website.

The tentacles of jellyfish are densely covered with epidermal cells possessing specialized structures and functions, commonly referred to as cnidocytes [14]. Within the cnidocytes, there is a specialized organelle structure enclosed by a collagenous cystic shell known as the nematocyst [15]. Upon physical or chemical stimulation, the nematocysts undergo a rapid increase in static hydraulic pressure. The significant pressure disparity between the interior and exterior of the nematocysts ultimately propels the thread tube to function as a spring transmitter. Discharge of the tubule is one of nature’s most rapid mechanical events, which effectively penetrates human skin and delivers a substantial dose of jellyfish venom. The patient’s prognosis is contingent upon factors such as the jellyfish species, sting location, and individual characteristics [16,17].

Skin Symptoms

Most cutaneous manifestations and signs caused by jellyfish stings are nonspecific among the various classes. Generally, jellyfish stings start with feeling a prick, followed by subsequent swelling and burning or numbing sensations [16–18]. Subsequently, the sting rapidly induces erythema, papules, wheals, or jellyfish tentacle-like lesions characterized by linear, rope-like or whip-like marks accompanied by significant pain and itching. In severe cases, the skin develops obvious blisters, subcutaneous bleeding, and even ulcers or necrosis [6,16–18]. The local symptoms last 1–2 weeks or even several months. Despite proactive treatment, most stings leave noticeable skin pigmentation changes or scarring [19]. However, certain clinical characteristics of the lesion may raise suspicion regarding which Cnidaria class is responsible. For instance, Scyphozoan stings can cause jellyfish-shaped erythematous lesions, Hydrozoa stings can result in a linear rash with a “string of beads” appearance, and Cubozoan stings can leave whip-like marks that are relatively wide and cross-hatched, accompanied by a “frosted” appearance caused by superficial skin necrosis [3]. Seabather’s eruption (SBE), an acute dermatitis, is noteworthy, especially when caused by the thimble jellyfish Linuche unguiculata, Linuche aquila, and, rarely, the sea anemone Edwardsiella lineata [20–23]. Recurrent eruptions subsequent to the initial stings have been reported to be caused by Pelagia noctiluca, Rhizostoma pulmo, and Aurelia aurita [17].

Immune Responses

The symptoms of jellyfish stings can arise indirectly from the body’s immune responses to toxin molecules and nematocysts, including skin lesions, inflammation, pyrexia, myoclonus, and paresthesia [24,25]. The proteins and polypeptides present in jellyfish venom, along with the collagen, glycoproteins, and polysaccharides found in the nematocysts, all can function as antigens or allergens within the human body, eliciting cellular or humoral immune responses [10,16]. Severe systemic allergic reactions sometimes occur, mainly due to prior exposure to antigenic toxins or similar biological components, and species-specific immunoglobulin antibodies in serum can remain high for several years [16,26]. Moreover, the multiple bioactive constituents within jellyfish venom can elicit immune responses via associated signaling pathways and cellular mechanisms [27,28]. For instance, Yap et al proposed that cnidarian pore-forming toxins (PFTs) exhibit similarities to bacterial PFTs, which can induce K+ efflux by penetrating the plasma membrane. Therefore, the reduction in intracellular K+ concentration activates NLRP3 inflammasome and p38 MAPK signaling pathways, regulating cytokine release and initiating immune responses [29]. Furthermore, mast cells, serving as potent promoters of inflammation, can be directly stimulated or their intrinsic or pattern recognition receptors can be activated by toxic components, resulting in degranulation and prompt release of cytokines such as histamine, prostaglandins, and leukotrienes, ultimately triggering accumulation or extravasation of immune cells at the sting site [30]. Additionally, chitin, collagen, polysaccharides, and other constituents within nematocysts can persistently activate proinflammatory innate immune cells such as Langerhans dendritic cells, macrophages, and mast cells, thereby resulting in persistent and recurrent symptoms of vesicular or pruritic dermatitis [10,16,29,31].

Toxins and Toxicity

Jellyfish toxins are mainly divided into 3 categories: Proteinoid toxins, non-protein toxins, and bioactive enzymes. These bioactive ingredients exhibit various biological toxicities including dermal necrosis, hemolysis, and adverse effects on cardiovascular, nervous, hepatic, and renal systems [11,32–34].

PFTs are a well-characterized group of toxin proteins that can be extracted from cnidarian venoms and are usually soluble in water at their very initial stage [35,36]. Most PFTs have potent cytotoxicity and lethality in mice, crayfish, sheep and humans. PFTs can interact with the cellular membrane, inducing structural and permeability alterations, which disrupts cells’ ion gradient, resulting in cellular infiltration, swelling, rupture, and cell death [29]. Additionally, 5 proteins belonging to the CaTX family of hemolysins, along with toxin components potentially involved in the formation of the membrane attack complex (MAC) such as perforin, have also been identified within the toxins derived from Aurelia aurita [37].

Jellyfish venom can also contain histamine, 5-hydroxytryptamine, and kinin-like substances, which can induce local vasodilation in capillaries and venules [38,39]. Pain is a prevalent and distinctive symptom associated with stings, resulting from the contraction of smooth muscles other than vascular smooth muscles due to the biological impact of kinin and 5-hydroxytryptamines [16,40]. It has also been reported that moderate to severe pain is associated with a 200 μm-length piercing by the jellyfish tubule. In fact, deep penetration not only injects venom into dermal tissue, but also causes acute pain through physical stimulation of Aδ pain receptor fibers surrounding the plexus [41].

The enzymes in jellyfish venom can significantly upregulate the expression of inflammatory factors in dermal cells [42]. The suppressive effect of matrix metalloproteinase (MMP) inhibitors Batimastat, epigallocatechin gallate (EGCG), and ethylenediaminetetraacetic acid (EDTA) on toxic metalloproteinases-mediated skin damage suggested a pivotal role of metalloproteinases in the pathogenesis of jellyfish dermatitis [43]. Phospholipase, which is another prominent enzyme of jellyfish venom, has been identified in Cyanea capillata, Nemopilema nomurai, and Aurelia aurita. Phospholipase A2 induces a diverse range of toxicological effects, including inflammation, pain, hemorrhage, and skin necrosis [17,32,44]. The proteolytic activity of venom-derived proteases leads to degradation of the extracellular matrix and vascular basement membrane layer and also facilitates the penetration, diffusion, and activation of other toxic components [17,45].

Inhibiting Further Discharge of Tubules

Medical management of jellyfish stings is summarized in Figure 1. The primary concern is to promptly rescue the victim from potential drowning, followed by vigilant monitoring of vital signs, particularly for any indications of allergic reactions or systemic manifestations [16,18]. Simultaneously, prompt removal of any remaining tentacles and nematocysts from the skin is crucial to prevent further venom release [46].

Inhibiting further tubule discharge mitigates the influx of venom, but improper treatment can worsen the condition [17]. The recommended method is to delicately extract the tentacles using forceps or similar instruments, rather than the hands [10]. Some propose the application of sand or clothing to envelop the tentacles, followed by gentle wiping; however, this may induce pressure alterations that trigger tubule discharge [17]. Ballesteros et al identified ammonia, barium chloride, bleach, scented ammonia, carbonated cola, lemon juice, sodium chloride, and papain as substances capable of inducing nematocyst discharge, which should be avoided [47]. Rinsing with fresh water should also be avoided due to its lower osmotic pressure [16,48]. The ideal inhibition solution should be able to thoroughly eliminate the tentacles during rinsing and effectively impede or even deactivate the nematocysts [16–18].

The utilization of seawater for emergency treatment offers significant advantages owing to its inherent convenience. Experiments have substantiated that tubules of Chrysaora quinquecirrha, Chiropsalmus quadrumanus, Physalia physalis, Nemopilema nomurai, and Carybdea brevipedalia will not discharge in seawater [49,50]. However, in 1983, Burnett et al demonstrated that seawater stimulation can induce the discharge of tubules and release of toxins in Chrysaora quinquecirrha nematocysts [51]. Additionally, the presence of seawater resulted in an increase in the toxic and hemolytic activity of Cyanea capillata venom [52]. In fact, there is currently insufficient compelling evidence to support the notion that seawater has a superior inhibitory effect on nematocyst discharge. Therefore, it is not advisable to indiscriminately employ seawater [46,52].

Fenner et al reported that vinegar effectively inhibited tubule discharge, including Chironex fleckeri, Carybdea rastoni, and Carukia barnesi [53]. Mianzan et al reported that a concentration of pure acetic acid (99%) induced tubule discharge in Olindias sambaquiensis, while lower concentrations of acetic acid (<10%) effectively suppressed this response [54]. However, Birsa et al introduced a 5% acetic acid solution to the tentacle of Physalia physalis and Chrysaora quinquecirrha, resulting in an immediate and mass tubule discharge [49]. In recent years, an increasing number of experimental studies have provided substantial evidence supporting the efficacy of vinegar [55–57]. Certainly, further investigations are imperative to explore the immediate therapeutic effects of vinegar (acetic acid solution) on jellyfish stings caused by specific species.

Saleratus solution has been proved to be effective in deactivating nematocysts of jellyfish, inhibiting the venom release and alleviating skin erythema [16,58,59]. However, Ballesteros et al observed that nematocysts will discharge in Pelagia noctiluca subsequent to sodium bicarbonate treatment [17,47]. In general, the utilization of saleratus for emergency management is safe in most cases, but further comprehensive investigations are warranted to ascertain the applicability.

An experimental study showed a 92% inhibitory efficacy of 50 mmol/L LaCl3 lotion on nematocyst discharge, and also demonstrated significant inhibition of tubule discharge by other metal cations, including K+, Ca2+, and Mg2+ [60]. Stingose, a commercial product containing 20% aluminum sulfate and 1.1% surfactant, is widely utilized for the treatment of marine life stings and has demonstrated effective relief for stings caused by Chrysaora quinquecirrha and Cyanea capillata [16,18,51]. Another commercial product, named “Sting No More” (containing copper gluconate, magnesium sulfate, vinegar, and urea) has been demonstrated to inhibit nematocyst discharge from Alatina alata, Physalia physalis, and Cyanea capillata [52,55,56]. In conclusion, rinsing with appropriate metal cation solutions is an effective emergency treatment.

Urine, ammonia, 70% ethanol, isopropyl alcohol, and methylated alcohol have limited efficacy against most types of jellyfish stings and may even induce a vigorous discharge of nematocyst tubules [16–18,49]. However, there are exceptions. A 20% ammonia solution and a 70% ethanol solution have been reported to effectively reduce the chemosensory-induced tubule discharge of Pelagia noctiluca [17,18,61]. Additionally, methylated alcohol and proteolytic enzymes such as papain and bromelain exhibit potential therapeutic effects against certain jellyfish stings [17,18].

In brief, there is still no universally applicable rinse solution available for an unidentified jellyfish sting. However, considering their widespread availability and effectiveness against a large number of jellyfish species, vinegar (5% acetic acid) and saleratus are recommended for immediate treatment in emergency situations. Furthermore, depending on the prevalent jellyfish species in specific regions, it is advisable for governmental authorities to proactively provide ready access to vinegar, saleratus, and certain types of metal cation solutions.

Reduction of Local Toxic Symptoms

In addition to removing the tentacles, appropriate measures should be taken to alleviate local pain and inflammation, as well as inactivate the toxin to limit further damage [16,18].

Hot compress or immersion in hot water is a commonly employed therapeutic approach for marine envenomation, but its underlying mechanism of action remains unclear [48]. Additionally, cold compress has demonstrated efficacy in pain reduction through restriction of inflammation and venom dissemination [17,62]. However, Li et al conducted a comprehensive review involving a total of 435 participants to compare the efficacy of hot and cold compresses after stings of Physalia physalis and Alatina alata, revealing that hot compress provides clinically significant pain relief superior to that of cold compresses [12]. Doyle et al demonstrated the efficacy of hot compresses in reducing the hemolytic area and inhibiting toxin activity in a Cyanea capillata sting model, while cold compresses were found to be ineffective. Furthermore, this sting model excluded any potential impact of hot compresses on neurons or neural pathways, confirming its direct inhibitory effect on toxin molecules [52]. Therefore, hot compresses are deemed safer and more effective in alleviating localized pain compared to cold or ice treatment [17,63].

The study conducted by Burnett et al concluded that the sole use of lidocaine as the externally applied agent did not yield sufficient efficacy in pain management [64]. However, Birsa et al demonstrated that solutions containing 10% and 15% lidocaine hydrochloride could promptly alleviate pain induced by Chiropsalmus quadrumanus and Chrysaora quinquecirrha [49]. In a systematic review, the efficacy of lidocaine in pain alleviation was further supported, and the application of lidocaine hydrochloride resulted in a significant reduction in skin redness and swelling, as well as the inhibition of tubule discharge induced by various chemical stimuli [48,55,61]. Furthermore, lidocaine can impede tubule discharge and alleviate sting symptoms through its modulation of sodium or calcium ion channels in nematocyst membranes [65]. PFTs or porins present in jellyfish venom can cause a rapid efflux of potassium from red blood cells (RBCs), resulting in hyperkalemia, formation of large tetrameric hemoglobin, and hemolysis. Zinc and copper gluconate can inhibit potassium efflux from RBCs, thereby influencing the process of hemolysis, and exhibits superior efficacy in mitigating pain at the sting site [55,66,67]. Therefore, zinc and copper gluconate may serve as effective emergency treatment options for jellyfish stings. However, further research is necessary to determine their specific efficacy in various jellyfish species.

Future Directions

Currently, researchers possess a limited comprehension of the clinical effects and mechanisms associated with jellyfish stings, primarily due to their reliance on a small number of cases. Given the extensive biological diversity exhibited by toxic jellyfish species, it is imperative to develop individualized treatment protocols due to the significant variation in symptoms resulting from jellyfish stings. Furthermore, despite the diverse range of symptoms caused by jellyfish stings, there remains insufficient empirical evidence to substantiate the presence of active venom components directly accountable for these clinical manifestations. Therefore, comprehensive analyses of venom components from each jellyfish species are required in the future. In addition, the mechanism of action and cytotoxic signaling pathways of bioactive toxin molecules should be further investigated and elucidated to establish a theoretical foundation for the development of targeted drugs against jellyfish stings. The optimal and effective emergency management of jellyfish stings lacks consensus, highlighting the need for standardized diagnostic criteria and treatment protocols in the near future to reduce mortality rates and improve prognosis.

Conclusions

Jellyfish stings can cause a variety of clinical manifestations, most notably skin lesions, and there is no specific treatment. In this article, we review the skin symptoms, pathophysiology, and management of jellyfish stings to provide guidance to healthcare professionals and the public. Further investigations should be conducted, with a focus on elucidating the pathogenic mechanisms of bioactive components in jellyfish venoms and developing effective control strategies. Additionally, standardized diagnostic criteria and treatment protocols should be established for different species of jellyfish to facilitate the comprehensive management of jellyfish stings.