A new insight into the cellular mechanisms of envenomation: Elucidating the role of extracellular vesicles in Loxoscelism.

Envenomation by the Loxosceles genus spiders is a recurring health issue worldwide and specially in the Americas. The physiopathology of the envenomation is tightly associated to the venom's rich toxin composition, able to produce a local dermonecrotic lesion that can evolve systemically and if worsened, might result in multiple organ failure and lethality. The cellular and molecular mechanisms involved with the physiopathology of Loxoscelism are not completely understood, however, the venom's Phospholipases D (PLDs) are known to trigger membrane injury in various cell types. Here, we report for the first time the Loxosceles venom's ability to stimulate the production of extracellular vesicles (EVs) in various human cell lineages. Components of the Loxosceles venom were also detectable in the cargo of these vesicles, suggesting that they may be implicated in the process of extracellular venom release. EVs from venom treated cells exhibited phospholipase D activity and were able to induce in vitro hemolysis in human red blood cells and alter the HEK cell membranes' permeability. Nonetheless, the PLD activity was inhibited when an anti-venom PLDs monoclonal antibody was co-administered with the whole venom. In summary, our findings shed new light on the mechanisms underlying cellular events in the context of loxoscelism and suggest a crucial role of EVs in the process of envenomation.

Brown recluse (L. rufescens) can bite in Northern Italy, too: first case report and review of the literature.

The brown recluse, or fiddleback (violin) spider, is a poisonous spider of the Loxosceles genus that resides in warmer regions and old structures making the warm Mediterranean climate a natural habitat for the European species, L. rufescens Even in infested households, however, bites are rare, as they are nocturnal and unaggressive. In 2015, the first supposed death by L. rufescens occurred in Italy, but before and even after such bite, the literature on these spiders has been under-represented. This case report documents a confirmed bite by a violin spider on a medical student in Pavia, Italy. The presentation in this case was initially with general systemic, flu-like symptoms, then as cellulitis with lymphangitis that persisted for nearly 2 weeks until resolving without prolonged or complicated pathology. We present the first documented case of a L. rufescens bite in Northern Italy, to the best of our knowledge.

Latrodectismo en una paciente pediátrica / Latrodectism in a pediatric patient

Introducción: el conjunto de síntomas y signos provocados por la mordedura de la araña Latrodectus mactans, llamada viuda negra, se conoce como latrodectismo. En Cuba son escasos los estudios realizados y publicados al respecto. Solo se han reportado cuatro casos en adultos en un artículo del año 1998 y uno en un adolescente en el año 2006, todos de la provincia Ciego de Ávila.Objetivo: presentar el caso de una paciente pediátrica envenenada por la mordedura de una araña viuda negra, de interés por ser infrecuente.Presentación del caso: paciente femenina, de ocho años de edad, color de la piel blanco, residente en una zona suburbana del poblado Gaspar, municipio Baraguá, provincia Ciego de Ávila. Fue mordida por una araña pequeña, de color negro. Presentó mareos, dolor en el abdomen y el muslo izquierdo, y marcada palidez. Fue hospitalizada y posteriormente manifestó dolores en ambos miembros inferiores, entumecimiento, sudoración en pies y manos, e insomnio. Este cuadro clínico se mantuvo varios días. Los exámenes complementarios resultaron normales. En el electrocardiograma se detectó taquicardia sinusal. El tratamiento consistió en gluconato cálcico al 10 por ciento en perfusión endovenosa, sedación y alivio del dolor.Conclusiones: los médicos de las áreas rurales o suburbanas deben estar prevenidos ante la eventualidad de recibir pacientes con latrodectismo, debido al cuadro clínico inespecífico, que dificulta el diagnóstico. Sería conveniente la realización en Cuba de estudios toxicológicos acerca de Latrodectus mactans, por el problema de salud que entrañan su toxicidad y el no contar con el antídoto específico(AU)

Introduction: the set of symptoms and signs caused by the bite of the spider Latrodectus mactans, called black widow, is known as latrodectism. In Cuba there are few studies carried out and published in this regard. Only four cases have been reported in adults in an article of the year 1998 and one in a teenager in 2006, all of the province of Ciego de Ávila.Objective: to present the case of a pediatric patient poisoned by the bite of a black widow spider, of interest because it is infrequent.Case presentation: female patient, eight years old, white skin, resident in a suburban area of Gaspar village, Baraguá municipality, Ciego de Ávila province. She was bitten by a small, black spider. He presented dizziness, pain in the abdomen and left thigh, and marked pallor. She was hospitalized and later manifested pain in both lower limbs, numbness, sweating in hands and feet, and insomnia. This clinical picture remained several days. Complementary tests were normal. Electrocardiogram detected sinus tachycardia. The treatment consisted of 10 percent calcium gluconate in intravenous perfusion, sedation and pain relief.Conclusions: physicians in rural or suburban areas should be aware of the possibility of receiving patients with latrodectism, due to the nonspecific clinical picture, which makes diagnosis difficult. It would be convenient to carry out toxicological studies in Cuba about Latrodectus mactans, due to the health problem that implies its toxicity and not having the specific antidote(AU)

First report of clinical presentation of a bite by a running spider, Philodromus sp. (Araneae: Philodromidae), with recommendations for spider bite management.

This article describes the clinical progression of symptoms over a period of 5 days of a bite inflicted by a Philodromus sp. spider. Commonly known as 'running spiders', these are not considered to be harmful to humans. This report, however, is the first description of an actual bite by a member of this group of spiders showing cytotoxic envenomation. Management of the bites should be as recommended for other cytotoxic spider bites.

Clinical Serum Therapy: Benefits, Cautions, and Potential Applications.

Blood serum from immunized humans or animals (e.g., horses) contains relevant antibodies and has been used as serum therapy to treat many diseases or envenomation events. The effectiveness of blood serum was initially discovered in 1890 when Kitasato and von Behring observed the effectiveness of this type of therapy against diphtheria and tetanus. Serum therapies played an important role in the advancement of modern medicine prior to the development of penicillin and steroids. At present, several types of serum therapy remain in clinical use. However, some physicians have a limited understanding of the nature and the benefits of serum therapy and the factors that require particular attention. In this review, we set out to clarify the benefits, cautions, and potential applications of serum therapy in the context of conditions such as gas gangrene, diphtheria, botulism, and tetanus and bites from three snake species (mamushi, habu, and yamakagashi) and the redback spider. It is hoped that this review will help clinicians to learn about clinical serum therapies and become familiar with their applications.

Defining the complex phenotype of severe systemic loxoscelism using a large electronic health record cohort.

OBJECTIVE: Systemic loxoscelism is a rare illness resulting from the bite of the recluse spider and, in its most severe form, can lead to widespread hemolysis, coagulopathy, and death. We aim to describe the clinical features and outcomes of the largest known cohort of individuals with moderate to severe loxoscelism. METHODS: We performed a retrospective, cross sectional study from January 1, 1995, to December 31, 2015, at a tertiary-care academic medical center, to determine individuals with clinical records consistent with moderate to severe loxoscelism. Age-, sex-, and race-matched controls were compared. Demographics, clinical characteristics, laboratory measures, and outcomes of individuals with loxoscelism are described. Case and control groups were compared with descriptive statistics and phenome-wide association study (PheWAS). RESULTS: During the time period, 57 individuals were identified as having moderate to severe loxoscelism. Of these, only 33% had an antecedent spider bite documented. Median age of individuals diagnosed with moderate to severe loxoscelism was 14 years old (IQR 9.0-24.0 years). PheWAS confirmed associations of systemic loxoscelism with 29 other phenotypes, e.g., rash, hemolytic anemia, and sepsis. Hemoglobin level dropped an average of 3.1 g/dL over an average of 2.0 days (IQR 2.0-6.0). Lactate dehydrogenase and total bilirubin levels were on average over two times their upper limit of normal values. Eighteen individuals of 32 tested had a positive direct antiglobulin (Coombs') test. Mortality was 3.5% (2/57 individuals). CONCLUSION: Systemic loxoscelism is a rare but devastating process with only a minority of patients recalling the toxic exposure; hemolysis reaches a peak at 2 days after admission, with some cases taking more than a week before recovery. In endemic areas, suspicion for systemic loxoscelism should be high in individuals, especially children and younger adults, presenting with a cutaneous ulcer and hemolysis or coagulopathy, even in the absence of a bite exposure history.

Microcirculation abnormalities provoked by Loxosceles spiders' envenomation.

Loxoscelism is caused by envenomation by spiders from Loxosceles genus. Clinical symptoms only appear a few hours after envenomation and can evolve in local reactions, such as dermonecrosis, and systemic reactions, including intravascular haemolysis, intravascular coagulation and renal failure. Considering that alterations in the microcirculatory network are involved in the pathogenesis of different diseases, including the inflammatory process, the aim of this study was to investigate the action of venoms of males and females of Loxosceles intermedia and Loxosceles laeta on the microcirculatory network and examine the systemic production of inflammatory mediators in a murine model of loxoscelism. We observed that during systemic envenomation, the alterations in the microcirculation include increase in the number of rolling cells, which was more intense in animals injected with female Loxosceles spider venoms. This positively correlated with increase in TNF-α and NO serum levels, induction of which was higher by female venoms when compared with male venoms. The increase of leukocytes rolling was not accompanied by increase of cell adhesion. The absence of leukocyte extravasation may explain why in mice, in contrast to humans, no cutaneous loxoscelism occurs. Thus, targeting the neutrophil adhesion and extravasation in Loxosceles envenomed patients may prevent cutaneous pathology.

[Neurotoxic manifestations of black widow spider envenomation in paediatric patients]. / Manifestaciones de neurotoxicidad en el envenenamiento por mordedura de araña «viuda negra¼ en edades pediátricas.

INTRODUCTION: Envenomation by black widow spiders manifests clinically with signs of neurotoxicity in paediatric patients. OBJECTIVE: Identify typical neurological signs and symptoms in paediatric patients of different ages, and describe treatment and outcomes in a paediatric hospital in northwest Mexico. MATERIAL AND METHODS: We reviewed 70 clinical records of patients hospitalised due to black widow spider bite between 1978 and 2014. We divided the total into 2 groups: Group 1, infants and preschool children; and Group 2, school-age children and adolescents. The demographic variables were age, sex, birthplace, place where envenomation occurred, body part(s) affected, degree of envenomation according to signs and symptoms, treatment, clinical outcome, and statistical differences. RESULTS: Boys accounted for 61.4% of all cases, and infants younger than one year old made up 14.2%. Most patients (70%) were bitten by the spider at home; the anatomical areas most frequently affected were the legs, neck, thorax, and abdomen. The neurological signs and symptoms displayed by Group 1 were irritability, constant crying, sialorrhoea, nausea, tachycardia, arrhythmias, fatigue when walking, agitation, muscle spasms paraesthesia, tetany, seizures, and nystagmus. Signs in Group 2 included localized pain, headache, sialorrhoea, paraesthesia, profuse sweating, anxiety, muscle weakness, muscle spasms, and fine tremor. The predominant autonomic sign in Group 1 was sialorrhoea (P<.0001) and in Group 2, paraesthesia (P<.0001). Patients who received Fab antivenom treatment displayed better outcomes and shorter hospital stays than those who did not. No deaths were reported. CONCLUSIONS: The neurological signs and symptoms caused by black widow spider bite are predominantly autonomic, and identifying them permits early diagnosis and more effective treatment.

Acidente loxoscélico / Loxoscelic accident

Os acidentes com aranhas do gênero Loxosceles podem apresentar variadas evoluções clínicas, dificultando a realização do diagnóstico e a escolha correta de uma medida terapêutica. Este artigo de revisão tem como objetivo abordar os mais importantes mecanismos de evolução, principais desfechos e os tratamentos de escolha para o acidente loxoscélico (AU)

Accidents with Loxosceles genus spiders may have different clinical outcomes, hindering the diagnosis and the correct choice of a therapeutic measure. This review article aims to address the main mechanisms of evolution, main outcomes and treatments of choice for loxoscelic accident (AU)

The black widow spider bite: differential diagnosis, clinical manifestations, and treatment options.

Unrecognized and untreated black widow spider bites cause significant pain, impairment, and rarely death. The widow venom, a powerful neurotoxin known as a-latrotoxin, causes muscle pain, diaphoresis, tachycardia, flushing, and hypertension. Treatment is usually symptomatic with a combination of opioid analgesics and muscle relaxants. If symptom resolution fails, an equine IgG antiserum is available, but a high index of clinical suspicion coupled with a knowledgeable patient history often allows successful treatment, especially when the treating physician possesses awareness of this type of bite and its usual course and possible complications.

Not as docile as it looks? Loxosceles venom variation and loxoscelism in the Mediterranean Basin and the Canary Islands.

The medical importance of Loxosceles spiders has promoted extensive research on different aspects of their venoms. Most of the reported cases of loxoscelism have occurred in the Americas, and thus, much work has focused on North and South American Loxosceles species. Interestingly, loxoscelism cases are rare in the Mediterranean Basin although Loxosceles rufescens, endemic to the Mediterranean, is an abundant spider even in human-altered areas. Thus, it has been suggested that the venom of L. rufescens could be of less medical relevance than that of its congeners. In this study, we challenge this hypothesis by using multiple approaches to study venom variation in selected species and lineages from the Mediterranean Basin and the Canary Islands. We found that SMase D activity, the key bioactive component of Loxosceles venom, is comparable to American species that are confirmed to have medically relevant bites. The venom protein composition using SDS-PAGE presents some differences among regional Loxosceles taxa in banding pattern and intensity, mostly between the Canarian and L. rufescens lineages. Differences between these species also exist in the expression of different paralogs of the SicTox gene family, with the Canarian species being less diverse. In conclusion, our results do not support the challenged hypothesis, and suggest that venom of these species may indeed be as potent as other Loxosceles species. Pending confirmation of loxoscelism with direct evidence of Loxosceles bites with species identification by professionals, Loxosceles in the Mediterranean region should conservatively be considered medically relevant taxa.

Latrodectus envenomation in Greece.

During the summer period 2011-2012, seven widow spider bites in Greece were reported to the Hellenic Center for Disease Control and Prevention. Widow spiders (in the genus Latrodectus) are found all over the world, including Europe, Asia, Africa, Australia, and the US. Alpha-latrotoxin (main mammalian toxin) causes the toxic effects observed in humans. Victims should receive timely medical care to avoid suffering. Latrodectus bites are very rarely fatal. All the patients reported having an insect bite 30 minutes to 2 hours before they arrived at the Emergency Department of the local hospital. Severe muscle cramps, weakness, tremor, abdominal pain, and increased levels of creatinine phosphokinase were present in all patients. The Emergency Operation Center of the Hellenic Center for Disease Control and Prevention was informed immediately in all cases. Antivenin was administered to four patients upon the request of their physicians. All patients recovered fully. It is essential that health care workers recognize early the symptoms and signs of Latrodectus bites to provide the necessary care. The management of mild to moderate Latrodectus envenomations is primarily supportive. Hospitalization and possibly antivenin should be reserved for patients exhibiting serious systemic symptoms or inadequate pain control. The most important thing for all of these patients is early pain relief.

Swiss prospective study on spider bites.

Knowledge of spider bites in Central Europe derives mainly from anecdotal case presentations; therefore we aimed to collect cases systematically. From June 2011 to November 2012 we prospectively collected 17 cases of alleged spider bites, and together with two spontaneous notifications later on, our database totaled 19 cases. Among them, eight cases could be verified. The causative species were: Cheiracanthium punctorium (3), Zoropsis spinimana (2), Amaurobius ferox, Tegenaria atrica and Malthonica ferruginea (1 each). Clinical presentation was generally mild, with the exception of Cheiracanthium punctorium, and patients recovered fully without sequelae. In Switzerland, spider bites generally have a benign clinical course, which is characterised by minor effects, with rapid and complete recovery. Since only verified spider bites can be regarded as spider bites, in the case of clinically important arachnidism, the spider should be sent to an expert for identification. Our study may help to diminish spider fear and reassure people who have experienced a bite.

Envenomation by spiders of the genus Hololena (Araneae: Agelenidae).

Three verified bites from Hololena spiders (Family Agelenidae) are presented here. Two male victims, each over 100 kg weight (bitten by female spiders), experienced headaches and 4-h episodes of vomiting. A female bite victim (bitten by a male spider) experienced minor reaction. None sought medical attention; symptoms resolved in a few days. Although these incidents were not serious, reactions in the male victims were more dynamic than usual generic spider bites (minor edema, minor erythema).

Úlcera provocada por picadura de araña. A propósito de un caso / Ulcer caused by bites of spider. Purpous of a case

Se presenta un caso de úlcera de larga evolución (más de un año), que pasa por diferentes fases y tratamientos, Su origen fue provocado por una picadura de araña(AU)

A case of ulcer of long evolution (more than one year), what happens is presented by different phases and treatment, its origin was caused by a spider bite (AU)

Sponge implant in Swiss mice as a model for studying loxoscelism.

Envenomation by Loxosceles spider bite leads to a set of signs and symptoms, called loxoscelism, which in most cases manifests through the dermonecrotic frame. The development of a smaller size animal model, of easy handling and maintenance, and lower cost is needed to study the loxoscelism pathogenesis. The inflammatory effects of the Loxosceles similis crude venom was evaluated considering neutrophil and macrophage activation, vasodilatation, hyperhaemia, edema and hemorrhage and TNF-α and VEGF production using the murine sponge implant model. Thirty two male Swiss mice (6-8 weeks old) were implanted subcutaneously with polyether-polyurethane sponge discs. Fourteen days post implantation, animals were separated into two groups: (1) control group--16 mice received 30 µL of saline intra-implant; (2) treated group-sixteen mice injected with 0.5 µg/30 µL of L. similis crude venom intra-implant. The animals were euthanized with xylazine/ketamine after 1 and 4 h post- injection. Microscopically, implants of the treated groups presented an acute inflammation characterized by: neutrophilic infiltrate, edema, vasodilatation hyperhaemia, and severe hemorrhage. Some vessels presented ruptured walls. Under morphometric analysis, vessel area was bigger in the treated groups compared with the control ones. The biochemical parameters, hemoglobin content, inflammatory enzyme activities (myeloperoxidase and n-acethyl-ß-D glucosaminidase) and levels of the cytokines, TNF-α and VEGF, were also significantly higher in the venom-treated groups. The effects of Loxosceles venom in the granulation tissue of the implant in mice were similar to those observed in cutaneous loxoscelism in other species (human and rabbits). Consequently, the murine sponge implant model provides a new method to investigate cellular/molecular mechanisms associated with cutaneous loxoscelism.

Loxoscelismo cutáneo. A propósito de un caso clínico / Skin loxoscelism. A clinical case report

Loxosceles laeta es una araña de distribución mundial y la necrosis cutánea caracteriza a su mordedura. Las formas sistémicas son de baja frecuencia pero alta mortalidad. El diagnóstico es de sospecha ante una lesión intensamente dolorosa o por la identificación del arácnido. La recomendación para la utilización de suero antiloxosceles no es uniforme. En este artículo reportamos un caso de loxoscelismo a forma cutáneo necrótica que requirió cirugía de debridamiento temprano y con buena evolución. El objetivo es concientizar a los pediatras de la existencia de esta entidad que sólo será diagnosticada tempranamente si pensamos en ella, lo que permitirá el oportuno y adecuado abordaje del paciente.