Ciguatera Poisoning: Clinical and Immunological Aspects

Abstract

Ciguatera poisoning refers to a type of fish intoxication following consumption of fishes contaminated with ciguatoxin (CTX). The latter toxin originates in a dinoflagellate designated Gambierdiscus toxicus, passes through herbivorous and then to carnivorous fishes along the food chain, ultimately to man. Ciguatera poisoning is unlike tetrodotoxin or scombroid fish poisonings. The Eormer is due to a toxin isolated From puffer fish and the latter to histamine-like degradation products due to bacterial spoilage of fish fissues. Ten minutes Lo 24 hr after consumption of a CTX contaminated fish, clinical symptoms involving the gastroinlestinal, neurological and cardiovascular systems are manifested. The neurological symptoms may persist for munths in some individuals. Ciguatera poisoning is rarely fatal (less than 0.5%). Therapy at best is symptomatic with no specific drugs. Detection in fisti tissues depends on the mouse test Eollowing extraction of the toxin in organic solvents and more recently an immunological approach using specific anti-CTX monoclonal antibody. The stick test is rapid, simple, and specific and requires nu laboratory equipment. It is hoped to adapt the stick test for wide scale use in screening fishes for markets in the endemic areas of the tropical regions.     

Epidemiology and Clinical Features of Ciguatera Fish Poisoning in Hong Kong

In the present review, the main objective was to describe the epidemiology and clinical features of ciguatera fish poisoning in Hong Kong. From 1989 to 2008, the annual incidence of ciguatera varied between 3.3 and 64.9 (median 10.2) per million people. The groupers have replaced the snappers as the most important cause of ciguatera. Pacific-ciguatoxins (CTX) are most commonly present in reef fish samples implicated in ciguatera outbreaks. In affected subjects, the gastrointestinal symptoms often subside within days, whereas the neurological symptoms can persist for weeks or even months. Bradycardia and hypotension, which can be life-threatening, are common. Treatment of ciguatera is primarily supportive and symptomatic. Intravenous mannitol (1 g/kg) has also been suggested. To prevent ciguatera outbreaks, the public should be educated to avoid eating large coral reef fishes, especially the CTX-rich parts. A Code of Practice on Import and Sale of Live Marine Fish for Human Consumption for Prevention and Control of Ciguatera Fish Poisoning was introduced from 2004 to 2013. The Food Safety Ordinance with a tracing mechanism came into full effect in February 2012. The Government would be able to trace the sources of the fishes more effectively and take prompt action when dealing with ciguatera incidents.     

Screening for Predictors of Chronic Ciguatera Poisoning: An Exploratory Analysis among Hospitalized Cases from French Polynesia

Ciguatera poisoning is a globally occurring seafood disease caused by the ingestion of marine products contaminated with dinoflagellate produced neurotoxins. Persistent forms of ciguatera, which prove to be highly debilitating, are poorly studied and represent a significant medical issue. The present study aims to better understand chronic ciguatera manifestations and identify potential predictive factors for their duration. Medical files of 49 patients were analyzed, and the post-hospitalization evolution of the disease assessed through a follow-up questionnaire. A rigorous logistic lasso regression model was applied to select significant predictors from a list of 37 patient characteristics potentially predictive of having chronic symptoms. Missing data were handled by complete case analysis, and a survival analysis was implemented. All models used standardized variables, and multiple comparisons in the survival analyses were handled by Bonferroni correction. Among all studied variables, five significant predictors of having symptoms lasting ≥3 months were identified: age, tobacco consumption, acute bradycardia, laboratory measures of urea, and neutrophils. This exploratory, hypothesis-generating study contributes to the development of ciguatera epidemiology by narrowing the list from 37 possible predictors to a list of five predictors that seem worth further investigation as candidate risk factors in more targeted studies of ciguatera symptom duration.     

Digital Technologies and Open Data Sources in Marine Biotoxins’ Risk Analysis: The Case of Ciguatera Fish Poisoning

Currently, digital technologies influence information dissemination in all business sectors, with great emphasis put on exploitation strategies. Public administrations often use information systems and establish open data repositories, primarily supporting their operation but also serving as data providers, facilitating decision-making. As such, risk analysis in the public health sector, including food safety authorities, often relies on digital technologies and open data sources. Global food safety challenges include marine biotoxins (MBs), being contaminants whose mitigation largely depends on risk analysis. Ciguatera Fish Poisoning (CFP), in particular, is a MB-related seafood intoxication attributed to the consumption of fish species that are prone to accumulate ciguatoxins. Historically, CFP occurred endemically in tropical/subtropical areas, but has gradually emerged in temperate regions, including European waters, necessitating official policy adoption to manage the potential risks. Researchers and policy-makers highlight scientific data inadequacy, under-reporting of outbreaks and information source fragmentation as major obstacles in developing CFP mitigation strategies. Although digital technologies and open data sources provide exploitable scientific information for MB risk analysis, their utilization in counteracting CFP-related hazards has not been addressed to date. This work thus attempts to answer the question, “What is the current extent of digital technologies’ and open data sources’ utilization within risk analysis tasks in the MBs field, particularly on CFP?”, by conducting a systematic literature review of the available scientific and grey literature. Results indicate that the use of digital technologies and open data sources in CFP is not negligible. However, certain gaps are identified regarding discrepancies in terminology, source fragmentation and a redundancy and downplay of social media utilization, in turn constituting a future research agenda for this under-researched topic.     

Ciguatera: A public health perspective

Ciguatera fish poisoning is a seafood-borne illness caused by consumption of fish that have accumulated lipid-soluble ciguatoxins. In the United States, ciguatera is responsible for the highest reported incidence of food-borne illness outbreaks attributed to finfish, and it is reported to hold this distinction globally. Ciguatoxins traverse the marine food web from primary producers, Gambierdiscus spp., to commonly consumed fish in tropical and subtropical regions of the world. Ciguatoxins comprise 12 known congeners among Caribbean and tropical Atlantic fish and 29 reported congeners among Pacific fish. Expanding trade in fisheries from ciguatera-endemic regions contributes to wider distribution and increasing frequency of disease among seafood consumers in non-endemic regions. Ciguatoxins produce a complex array of gastrointestinal, neurological and cardiological symptoms. Treatment options are very limited and supportive in nature. Information derived from the study of ciguatera outbreaks has improved clinical recognition, confirmation, and timely treatment. Such studies are equally important for the differentiation of ciguatoxin profiles in fish from one region to the next, the determination of toxicity thresholds in humans, and the formulation of safety limits. Analytical information from case and outbreak investigations was used to derive Pacific and Caribbean ciguatoxin threshold contamination rates for adverse effects in seafood consumers. To these threshold estimates 10-fold safety factors were applied to address individual human risk factors; uncertainty in the amount of fish consumed; and analytical accuracy. The studies may serve as the basis for industry and consumer advisory levels of 0.10 ppb C-CTX-1 equivalent toxicity in fish from the tropical Atlantic, Gulf of Mexico, Caribbean, and 0.01 ppb P-CTX-1 equivalent toxicity in fish from Pacific regions.     

Ciguatera incidence and fish toxicity in Okinawa, Japan

Okinawa being located in the subtropical region has the highest incidence of ciguatera in Japan. Officially, 33 outbreaks involving 103 patients have been reported between 1997 and 2006. The implicated species were Variola louti, Lutjanus bohar, Lutjanus monostigma, Epinephelus fuscoguttatus, unidentified Lutjanus sp., Plectropomus areolatus, Oplegnathus punctatus, Epinephelus polyphekadion, Caranx ignobilis and moray eel. Toxicities of the leftover meals, as determined by mouse bioassays, ranged from 0.025 to 0.8 MU/g or above (equivalent to 0.175-5.6 ng CTX1B/g). We collected 612 specimens of fish belonging to L. monostigma, L. bohar, Lutjanus argentimaculatus, Lutjanus russellii, V. louti, Variola albimarginata, and E. fuscoguttatus from the coasts around Okinawa and examined the toxicity of the flesh by the mouse bioassay. The rate of toxic fish was as follows: L. monostigma: 32.3%, L. bohar: 11.9%, V. louti: 14.3%, E. fuscoguttatus: 20.8%. Only one out of 36 samples of V. albimarginata and two of 74 samples of L. russellii were found toxic. None of the 35 samples of L. argentimaculatus was toxic. Nor the L. bohar samples weighing less than 4 kg were toxic. In all toxic samples, CTX1B was detected by LC/MS analysis but CTX3C and 51-hydroxyCTX3C were not.     

Ciguatera: Australian perspectives on a global problem.

Ciguatera is a global disease caused by the consumption of certain warm-water fish that have accumulated orally effective levels of sodium channel activator toxins (ciguatoxins) through the marine food chain. Symptoms of ciguatera arising from the consumption of ciguateric fish include a range of gastrointestinal, neurological and cardiovascular disturbances. This review examines progress in our understanding of ciguatera from an Australian perspective, especially the laboratory-based research into the problem that was initiated by the late "Bob" Endean at the University of Queensland.     

Ciguatera: a rapid procedure for extraction of ciguatoxin

A rapid procedure for extraction and partial purification of ciguatoxin has been achieved and compared to one of the routine methods. Fish from two species which provided extracts of differing purity by the routine method were used. From 8 g of raw flesh, 1.0 +/- 0.2 mg of a semi-purified extract of ciguatoxin of homogeneous quality was obtained within 1 hr, whatever the species or toxicity of the fish. The results were reproducible, making the procedure very promising.     

Large Outbreaks of Ciguatera after Consumption of Brown Marbled Grouper

Brown marbled grouper (Epinephelus fuscoguttatus) is an apex predator from coral reefs of the Indo-Pacific region. All five published case series of ciguatera after consumption of brown marbled grouper were reviewed to characterize the types, severity and chronicity of ciguatera symptoms associated with its consumption. Three of these case series were from large outbreaks affecting over 100–200 subjects who had eaten this reef fish served at banquets. Affected subjects generally developed a combination of gastrointestinal, neurological and, less commonly, cardiovascular symptoms. Gastrointestinal symptoms occurred early and generally subsided in 1–2 days. Some neurological symptoms (e.g., paresthesia of four limbs) could last for weeks or months. Sinus bradycardia and hypotension occurred early, but could be severe and prolonged, necessitating the timely use of intravenous fluids, atropine and dopamine. Other cardiovascular and neurological features included atrial ectopics, ventricular ectopics, dyspnea, chest tightness, PR interval >0.2 s, ST segment changes, polymyositis and coma. Concomitant alcohol consumption was associated with a much higher risk of developing bradycardia, hypotension and altered skin sensation. The public should realize that consumption of the high-risk fish (especially the ciguatoxin-rich parts and together with alcohol use) and repeated ciguatoxin exposures will result in more severe and chronic illness.     

Glyphosate Poisoning

Glyphosate is used extensively as a non-selective herbicide by both professional applicators and consumers and its use is likely to increase further as it is one of the first herbicides against which crops have been genetically modified to increase their tolerance. Commercial glyphosate-based formulations most commonly range from concentrates containing 41% or more glyphosate to 1% glyphosate formulations marketed for domestic use. They generally consist of an aqueous mixture of the isopropylamine (IPA) salt of glyphosate, a surfactant, and various minor components including anti-foaming and colour agents, biocides and inorganic ions to produce pH adjustment. The mechanisms of toxicity of glyphosate formulations are complicated. Not only is glyphosate used as five different salts but commercial formulations of it contain surfactants, which vary in nature and concentration. As a result, human poisoning with this herbicide is not with the active ingredient alone but with complex and variable mixtures. Therefore, It is difficult to separate the toxicity of glyphosate from that of the formulation as a whole or to determine the contribution of surfactants to overall toxicity. Experimental studies suggest that the toxicity of the surfactant, polyoxyethyleneamine (POEA), is greater than the toxicity of glyphosate alone and commercial formulations alone. There is insufficient evidence to conclude that glyphosate preparations containing POEA are more toxic than those containing alternative surfactants. Although surfactants probably contribute to the acute toxicity of glyphosate formulations, the weight of evidence is against surfactants potentiating the toxicity of glyphosate. Accidental ingestion of glyphosate formulations is generally associated with only mild, transient, gastrointestinal features. Most reported cases have followed the deliberate ingestion of the concentrated formulation of Roundup®¹ (41% glyphosate as the IPA salt and 15% POEA). There is a reasonable correlation between the amount ingested and the likelihood of serious systemic sequelae or death. Advancing age is also associated with a less favourable prognosis. Ingestion of >85mL of the concentrated formulation is likely to cause significant toxicity in adults. Gastrointestinal corrosive effects, with mouth, throat and epigastric pain and dysphagia are common. Renal and hepatic impairment are also frequent and usually reflect reduced organ perfusion. Respiratory distress, impaired consciousness, pulmonary oedema, infiltration on chest x-ray, shock, arrythmias, renal failure requiring haemodialysis, metabolic acidosis and hyperkalaemia may supervene in severe cases. Bradycardia and ventricular arrhythmias are often present pre-terminally. Dermal exposure to ready-to-use glyphosate formulations can cause irritation and photo-contact dermatitis has been reported occasionally; these effects are probably due to the preservative Proxel® (benzisothiazolin-3-one). Severe skin burns are very rare. Inhalation is a minor route of exposure but spray mist may cause oral or nasal discomfort, an unpleasant taste in the mouth, tingling and throat irritation. Eye exposure may lead to mild conjunctivitis, and superficial corneal injury is possible if irrigation is delayed or inadequate. Management is symptomatic and supportive, and skin decontamination with soap and water after removal of contaminated clothing should be undertaken in cases of dermal exposure.     

Pentachlorophenol Poisoning

Despite being banned in many countries and having its use severely restricted in others, pentachlorophenol (PCP) remains an important pesticide from a toxicological perspective. It is a stable and persistent compound. In humans it is readily absorbed by ingestion and inhalation but is less well absorbed dermally. Its distribution is limited, its metabolism extensive and it is eliminated only slowly. Assessment of the toxicity of PCP is confounded by the presence of contaminants known to cause effects identical to those attributed to PCP. However, severe exposure by any route may result in an acute and occasionally fatal illness that bears all the hallmarks of being mediated by uncoupling of oxidative phosphorylation. Tachycardia, tachypnoea, sweating, altered consciousness, hyperthermia, convulsions and early onset of marked rigor (if death occurs) are the most notable features. Pulmonary oedema, intravascular haemolysis, pancreatitis, jaundice and acute renal failure have been reported. There is no antidote and no adequate data to support the use of repeat-dose oral cholestyramine, forced diuresis or urine alkalinisation as effective methods of enhancing PCP elimination in poisoned humans. Supportive care and vigorous management of hyperthermia should produce a satisfactory outcome. Chronic occupational exposure to PCP may produce a syndrome similar to acute systemic poisoning, together with conjunctivitis and irritation of the upper respiratory and oral mucosae. Long-term exposure has also been reported to result in chronic fatigue or neuropsychiatric features in combination with skin infections (including chloracne), chronic respiratory symptoms, neuralgic pains in the legs, and impaired fertility and hypothyroidism secondary to endocrine disruption. PCP is a weak mutagen but the available data for humans are insufficient to classify it more strongly than as a probable carcinogen.     

Ricin Poisoning

Ricin is a naturally occurring toxin derived from the beans of the castor oil plant Ricinus communis. It is considered a potential chemical weapon. Ricin binds to cell surface carbohydrates, is internalised then causes cell death by inhibiting protein synthesis. Oral absorption is poor and absorption through intact skin most unlikely; the most hazardous routes of exposure being inhalation and injection. Features of toxicity mainly reflect damage to cells of the reticuloendothelial system, with fluid and protein loss, bleeding, oedema and impaired cellular defence against endogenous toxins. It has been estimated that in man, the lethal dose by inhalation (breathing in solid or liquid particles) and injection (into muscle or vein) is approximately 5–10 µg/kg, that is 350–700µg for a 70kg adult. Death has ensued within hours of deliberate subcutaneous injection. Management is supportive. Prophylactic immunisation against ricin toxicity is a developing research initiative, although presently not a realistic option in a civilian context.     

Paraquat Poisoning

This paper deals with the development of methods for the detection and determination of the weed-killer, paraquat, in body fluids (urine, blood, gastric aspirate, dialysates) and tissues. These have been obtained from 6 cases of paraquat poisoning (2 of which were fatal) admitted to hospital and from several other negative cases. A specific colour reaction is described for the detection and determination of paraquat. Thus when sodium hydrogen carbonate followed by sodium dithionite is added to the test solution, a blue colour is produced. The detection limit is about 1 microgram/ml. Following admission to hospital shortly after the ingestion of paraquat, the reaction can be applied directly to diluted urine and diluted (filtered) gastric aspirate. Paraquat can be detected in small quantities in urine for quite a long period after ingestion. It is necessary, however, to use a column of a cation exchange resin to achieve concentration and also to remove any interfering substances. Under these conditions, it is preferable to assess the absorbance of the blue colour on a recording spectrophotometer. The concentration of paraquat in the blood serum is extremely low and only detectable shortly after ingestion. It has been extremely difficult to detect any traces of paraquat in dialysates (haemo- and peritoneal). Depending on the interval of time between ingestion and death, paraquat may be detected in some tissues e. g. liver and kidney. Using the cation exchange resin technique, paraquat in quantities of 50 to 100 micrograms added to 100 ml of urine can be recovered with an accuracy of 86 to 91 %.     

Veratrum Poisoning

Several species of the Veratrum genus are associated with toxicity in humans and animals. The principal toxins are steroid alkaloids; some have a modified steroid template, whereas others differ in their esterified acid moieties. These alkaloids act by increasing the permeability of the sodium channels of nerve cells, causing them to fire continuously. Increased stimulation, associated with the vagal nerve results in a reflex that causes the triad of responses known as the Bezold-Jarisch reflex: hypotension, bradycardia and apnoea. Clinically, various Veratrum extracts were marketed for clinical use as antihypertensive drugs, but because of their narrow therapeutic index were withdrawn from the market. Following the ingestion of Veratrum alkaloids, expected signs and symptoms include vomiting and abdominal pain, followed by cardiovascular effects such as bradycardia, hypotension and cardiac conduction abnormalities and death. Similar symptoms arise in other mammalian species ingesting these alkaloids; teratogenic effects may occur to the fetuses of animals that have grazed on Veratrum californicum. Treatment consists of supportive care, with an emphasis on haemodynamic stability with fluid replacement, atropine and vasopressors. The onset of symptoms occurs between 30 minutes and 4 hours, and the duration of the illness can range from 1 to 10 days; however, with prompt supportive care, patients typically make a full recovery within 24 hours.