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Bothrops (Fer-de-lance) snakebites in the French departments of the Americas (Martinique and Guyana): Clinical and experimental studies and treatment by immunotherapy [1]

['Dabor Resiere', 'Cardiovascular Research Team', 'Université Des Antilles', 'Fort De France', 'Department Of Critical Care Medicine', 'Toxicology', 'Emergency', 'Chu Martinique', 'University Hospital Of Martinique', 'Fort-De-France']

Date: 2023-04

3.1. B. atrox envenomation in French Guiana

In South America, epidemiological studies suggest that the majority of snakebite cases are caused by different species of snakes of the genus Bothrops. A study carried out in the Amazonian state of Rondônia, Brazil, a region with a high incidence of snakebites, showed that most victims are adult men (20 to 50 years) living in rural areas of the Brazilian agricultural frontier, who are bitten during work activities [51]. A higher incidence of envenomations occurred during the rainy season and during the diurnal period of the day, while most venomous snakes have nocturnal habits [51,52]. Likewise, B. atrox is responsible for the majority of snakebites in French Guiana [2].

Clinical features of B. atrox envenomation in French Guiana resemble the classic syndrome associated with bites from viperids, including local effects at the bite site (pain, edema, blistering, bleeding, necrosis) and systemic effects (hypotension, coagulopathies, systemic hemorrhages) [2,8,53–55]. The venoms of snakes of the genus Bothrops are hemorrhagic, damaging the vascular endothelium and consuming coagulation factors, i.e., inducing venom-induced consumption coagulopathy, and eliciting inflammation [55–58]. Blister formation typically occurs following bites by B. atrox and has been related to inflammatory processes and poor local prognosis as they increase the risk of infection and necrosis [59]. Complications of B. atrox envenomation may also include compartment syndrome of the bitten muscle, wound infection, hemodynamic instability and shock, and acute kidney injury (AKI) [2].

Though the precise number of snakebites is unknown, an estimated annual incidence of envenomation in French Guiana exceeded 20 cases per 100,000 inhabitants, with a case fatality rate of 3% [1]. From 2007 to 2015, 283 patients with snakebite envenomations were admitted to Cayenne General Hospital. Among them, 43 (15.8%) were considered severe, and 4 ultimately led to death (1.4% case fatality rate in people suffering real envenomations) [60,61]. From 2016 to 2019, similar results were observed in a prospective observational study conducted on 133 patients admitted to the Intensive Care Unit (ICU) of Cayenne General Hospital for snakebite envenomation [2]. In this work, envenomation was considered severe in 26.2% of cases. Snake identification was performed in 51% of cases, and B. atrox was identified in 43.6% of cases. The main clinical manifestations were edema (98.5%), pain (97.7%), systemic hemorrhage (18%), blisters (14.3%), and local hemorrhage (14.3%). Circulatory shock (1.5%), AKI (15%), and systemic hemorrhage (18%) were the most frequent complications. The elapsed time from snakebite to the development of systemic hemorrhage was 4.5 h. Infections such as abscesses (65%), necrotizing fasciitis (18.6%), and cellulitis (27.9%) were recorded in this group of the patients. In this series, overall mortality was 1.5% [2].

AKI is the main systemic complication and a common cause of death in Bothrops envenomation [62]. Several epidemiological studies describe a great variation in AKI incidence ranging from 6% in B. atrox to 38.5% in B. asper [50]. Proposed mechanisms of Bothrops venom-induced AKI include the direct action of venom on the kidney, the hemodynamic alterations, myoglobinuria, hemoglobinuria, glomerular microthrombi deposit due to coagulation abnormalities, and immunologic mechanisms [62–64]. In experimental models using viperid snake species, kidney hemodynamic changes varied according to the snake species but typically presented renal vascular resistance and glomerular filtration rate decreases [65]. Overall, a multifactorial origin of AKI is proposed, which emphasizes the role of hemodynamic disorders with bleeding or fibrin deposits in tubular structures, inflammatory processes, formation of immune complexes, and nephrotoxic action of venom.

Administration of antivenom is the only specific treatment to counteract Bothrops snakebite envenomation [12,66]. Antivenom typically comprises concentrated immunoglobulins, which are refined to produce F(ab′) 2 fragments, although some antivenoms are made of whole IgG molecules. There are two main types of antivenom, namely monospecific (or monovalent) antivenom, which is generated against the venom of a single snake species, and polyspecific (or polyvalent) antivenom, which is made using the venom of multiple snake species as immunogens [66].

In French Guyana, Bothrops envenomations are treated with Antivipmyn-Tri, a polyvalent antivenom for Bothrops and other viperid species (Instituto Bioclon, Mexico) [53,67]. This antivenom neutralizes the lethal, hemorrhagic, and in vitro coagulant activities of venoms of B. atrox endemic of French Guiana [68]. In this study, the intravenous route of injection was used to assess lethality. Since 2014, Antivipmyn-Tri has been used in this country, and preliminary preclinical and clinical reports of its efficacy and safety in envenomings by various species have been presented [2,53,68–70]. Retrospective studies that evaluated the efficacy in severe Bothrops envenomations in French Guiana (Saint-Laurent-du-Maroni, Western Guiana Hospital, and Cayenne General Hospital) failed to demonstrate evidence of clinical benefit [53]. However, another study showed that the time from Bothrops snakebite to achieve normal dosages of coagulation parameters was shorter in patients who received antivenom than in those who did not [2]. These conflicting findings urge for more detailed evaluations and also for the need to consider the possibility of using of other antivenoms available in the region and to compare their efficacy and safety with Antivipmyn-Tri in French Guiana envenomed patients.

Immunological and functional in vitro assays and preclinical efficacy of a freeze-dried antivenom manufactured in Costa Rica (Polival-ICP) against the lethal, hemorrhagic, coagulant, and myotoxic effects have recently highlighted the therapeutic potential of this antivenom against B. atrox venom endemic of French Guiana [37]. Regarding neutralization by antivenoms, Polival-ICP antivenom was effective in neutralizing lethality of B. atrox venom, while in contrast, Antivipmyn-Tri antivenom did not neutralize lethal activity even at the highest antivenom level tested [37]. In this study, the intraperitoneal route of injection was used for assessing lethality. Compared with Antivipmyn-Tri, Polival-ICP showed significantly higher neutralizing activity against hemorrhagic and in vitro coagulant activities of the venom. Polival-ICP and Antivimpyn showed similar neutralizing profile against myotoxicity [37]. These results are in agreement with previous studies showing the efficacy of Polival-ICP against the venoms of B. atrox from Colombia, Peru, Brazil, and Ecuador [71,72]. Moreover, several polyvalent antivenoms manufactured in Brazil, Argentina, Colombia, Perú, Bolivia, and Costa Rica also neutralize toxic activities of the venom of B. atrox from various localities in South America [71]. Interestingly, strong cross-reactivity of Bothrofav antivenom against Bothrops venoms has been shown in the neutralization of the procoagulant activity B. atrox from French Guiana [18], and this antivenom was also shown to be effective in the neutralization of other toxic activities of B. atrox venom [42]. Overall, there is an urgent need to evaluate the efficacy and safety of some of these antivenoms in the treatment of snakebite envenomation in French Guiana and to develop standard treatment protocols to be applied in this region.

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[1] Url: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0011083

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