Jellyfish envenoming syndromes: unknown toxic mechanisms and unproven therapies

Worldwide media attention recently focused on Australia following the first two known human fatalities attributed to the Irukandji syndrome in Queensland in 2002.1 Jellyfish envenoming represents a major cost to northern Australian communities in terms of public health, leisure and tourism. Management of these syndromes depends on improved understanding of venom action and critical analysis of current therapy.

We review the current state of knowledge of envenoming syndromes caused by Australian jellyfish, the mechanisms of venom action and management. We focus on the deadly box jellyfish, Chironex fleckeri, and the array of jellyfish thought to cause the Irukandji syndrome. Information was obtained from a search of MEDLINE, EMBASE and SciFinder Scholar for articles published in English over the period 1966–2002, using the keywords jellyfish, venom, Chironex fleckeri, Irukandji, Carukia barnesi, antivenom, pressure immobilisation bandaging, verapamil and therapy.

The box jellyfish, C. fleckeri, is found in tropical waters of Australia's north, from Gladstone in Queensland to Broome in Western Australia (Box 1 and Box 2). It is most prevalent in summer, although stings have been reported year-round.1 The jellyfish has a transparent box-shaped bell measuring up to 20 cm by 30 cm and weighing up to 6 kg, while the total length of tentacles may exceed 60 m.3 Skin contact with C. fleckeri tentacles can result in dermonecrosis, pain and death, occasionally with alarming speed. Some patients also develop delayed cutaneous hypersensitivity reactions at the sting site.4

There have been 67 human deaths attributed to C. fleckeri, the most recent a six-year-old boy at Yarrabah, near Cairns in Queensland, in 1999.1 However, despite this jellyfish's reputation as the "world's most venomous animal",5 the vast majority of human stings are of little consequence.4 Most are managed with no analgesia, local ice packs or oral analgesia only, and rarely require hospital admission.

The mechanism of action of C. fleckeri venom in severe envenoming remains unclear, but the key events appear to be cardiac or respiratory failure, or both.6,7 Some patients with severe C. fleckeri envenoming have been successfully treated by expired-air resuscitation alone,8,9 but fatalities have also occurred due to cardiac toxicity in mechanically ventilated patients.10

A number of jellyfish can cause the Irukandji syndrome,11 although only Carukia barnesi is conclusively known to do so. C. barnesi is a small carybdeid jellyfish with a transparent bell 1.5–2.5 cm in diameter. The infrequency of sightings or capture of C. barnesi and other small jellyfish that may cause the Irukandji syndrome makes precise knowledge of its geographic distribution problematic. Cases of Irukandji syndrome have occurred from Rockhampton in Queensland to Broome, although prevalence is greatest in the Cairns region. Recently, an Irukandji-like syndrome was reported in Hawaii.12

The Irukandji syndrome most commonly presents with generalised pain, hypertension (often severe), nausea, vomiting, and distress. The similarity of many of these symptoms to decompression sickness can provide a diagnostic challenge in scuba divers. Most patients presenting to emergency departments are treated with opiate analgesia, and about half require admission. A small number require advanced life support, usually because of cardiac failure.13

Catecholamine excess has long been proposed as a significant underlying mechanism in severe Irukandji syndrome.1,3,21 Victims develop symptoms mimicking medical conditions associated with endogenous catecholamine excess, such as phaeochromocytoma. Experiments in ventilated piglets showed a 200-fold increase in serum noradrenalin levels and a 100-fold increase in serum adrenalin levels after injection with crude extract of C. barnesi.22 These experiments quantified for the first time a relationship between experimental envenoming by C. barnesi and a hypercatecholaminergic state. However, there is no evidence of further deterioration in patients with cardiac dysfunction associated with severe Irukandji syndrome treated with adrenalin infusions.11

The mechanism of the cardiac dysfunction is yet to be elucidated. A review of 11 cases of pulmonary oedema developing in patients with Irukandji syndrome suggested that these patients had features of myocarditis.23 In a review of 116 patients with Irukandji syndrome presenting to Cairns Base Hospital in the summer of 2001–2002, 25 had raised serum levels of troponin I.24 Eighteen of these 25 patients had echocardiography, with six showing echocardiographic evidence of cardiac dysfunction. Significantly, no patients developed clinical cardiac failure. It is unclear whether the cardiac dysfunction is caused by a myotoxin or the hypercatecholaminergic state, or a combination.

Jellyfish venom is delivered into prey or victims by millions of microscopic stinging cells, known as nematocysts. Light microscopy examination of nematocysts recovered from victims' skin is used to identify the envenoming jellyfish, particularly in Chironex stings. Two techniques are used to harvest nematocysts — scalpel-blade scraping of the sting site, and sticky-tape sampling. These tests generally demonstrate good specificity (ie, positive nematocyst identification correlates well with observed clinical syndromes).14 Both methods also appear to have similar efficacy in terms of nematocyst retrieval, although, given the low nematocyst identification rates in the Irukandji syndrome, their sensitivity remains unknown.

The rapid onset of systemic symptoms after major jellyfish envenoming by C. fleckeri suggests that venom is "most probably introduced directly into blood vessels".15 Postmortem evidence from the last C. fleckeri fatality demonstrated nematocyst barbs penetrating the vascular dermis.16

C. fleckeri venom has haemolytic, lethal, myotoxic and dermonecrotic effects.17 Current evidence suggests that the venom toxins are proteinaceous and target specific organs. Monoclonal antibodies capable of neutralising C. fleckeri-induced haemolysis did not protect against the lethal effects of venom.18 Several myotoxins, with molecular weights of about 600 kDa and 150 kDa, have been reported in C fleckeri venom.19,20 These toxins showed significant lethality in a mouse model of envenomation and may play a role in human cardiotoxicity.3 We speculate that these and other, as yet unidentified, proteins cause ion flux and transmitter release through altering cell membrane permeability, either through specific interactions with ion-channels or receptors or through non-specific interactions with cell membranes.