Clinical consequences of spider bites: recent advances in our understanding

Toxicon 43 (2004) 477–492 www.elsevier.com/locate/toxicon

Review

Clinical consequences of spider bites: recent advances in our understanding Geoffrey K. Isbistera,*, Julian Whiteb a

Emergency Department, Newcastle Mater Misericordiae Hospital and the University of Newcastle, Newcastle, NSW 2298, Australia b Faculty of Health Sciences, University of Adelaide, Women’s and Children’s Hospital, North Adelaide, SA, Australia

Abstract Spider bite continues to be a controversial subject worldwide and attribution of clinical effects to different spiders is problematic because of poor case definition and paucity of clinical evidence. The effects of medically important spiders are sometimes underestimated and simultaneously there is misattribution of effects to harmless spider groups. The majority of suspected spider bites present as skin lesions or necrotic ulcers where the history of a spider bite must be confirmed. To be a definite spider bite, the patient must immediately observe the spider and there be evidence of the bite, such as pain. Important groups of spiders worldwide include the widow spiders (latrodectism), recluse spiders (loxoscelism) and some mygalomorph spiders including the Australian Funnel web spider. Most spiders only cause minor effects, including a large number of groups that have been implicated in necrotic arachnidism. q 2004 Elsevier Ltd. All rights reserved. Keywords: Spider bite; Arachnidism; Latrodectism; Loxoscelism; Necrotic ulcer

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Spider bite: definition, clinical features and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. An approach to the diagnosis of suspected or probable spider bite . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Latrodectism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Steatodism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Loxoscelism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Australian Funnel web spiders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Spiders that have been implicated in necrotic arachnidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Common or recognisable spiders that cause minimal clinical effects . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Spider injuries other than bites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Spiders have been feared since ancient times and are associated with a variety of myths in different parts of * Corresponding author. Tel.: þ61-2-49-21-1293; fax: þ 61-249-60-2088. E-mail address: [email protected] (G.K. Isbister). 0041-0101/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.toxicon.2004.02.002

477 478 479 480 483 484 484 485 486 488 488 488

the world (Vetter, 2000; Isbister, 2001b). Little research has been focussed on defining the clinical effects of bites of spiders in most parts of the world and most recent research has been focussed on isolation and characterisation of spider toxins to be developed as therapeutic drugs, pharmacological tools and insecticides. Information on the clinical effects of spider bite continues to be unreliable and has been based mainly on case reports and small case series, and in many of

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these the spider is not caught or identified by an expert (Karcioglu et al., 2001; Wasserman, 1990; Sadler et al., 2001; Spring, 1987). This has lead to misinformation and propagation of myths about different spiders based on the effects of suspected spider bites, particularly in relation to necrotic arachnidism (Isbister, 2001b; Vetter and Bush, 2002b). There are few published series of spider bites that include only definite bites which are far better for defining the spectrum of the clinical effects seen with different spiders (White et al., 1989; Isbister and Gray, 2002; Isbister et al., 2001; Ribeiro et al., 1990). The majority of spider bites cause only minor effects (Isbister and Gray, 2002), but a few important groups cause more significant effects (Nicholson and Graudins, 2002; Isbister and Gray, 2003b) and in a minority of cases specific therapy such as antivenom is required (Isbister et al., 2003a; Heard et al., 1999). Worldwide only a few groups of spiders are medically significant including the widow spiders (Latrodectus spp.) and the recluse spiders (Loxosceles spp.) (White et al., 1995; Wong et al., 1987). At least two other spiders with much smaller geographical distributions cause more severe envenoming, including the Australian Funnel web spider (FWS; Atrax and Hadronyche spp.) (Torda et al., 1980) and the armed or banana spider (Phoneutria spp.) from Brazil (Bucaretchi et al., 1999; White et al., 1995). The majority of spider bites involve only a few families of spiders, and often only a few species within these, compared to the vast spider biodiversity. In Australia 82% of bites were caused by six major families of spiders (Isbister and Gray, 2002) and five of these have worldwide distribution and have been responsible for bites outside Australia (Russell, 1986; Ribeiro et al., 1990; Clark et al., 1992; Muller, 1993; Huntley, 1997; Gorham and Rheney, 1968; Stallybrass, 1969). The popular fear of spiders and the recent attention paid to necrotic arachnidism has meant that in Australia at least, spider bite is the second most common call to the largest poison information centre (PIC) in the country, with between 4000 and 5000 calls each year (Duggin et al., 2002). Many of these calls are generated by concern about the effects of bites, but in the majority of cases only minor effects occur (Isbister and Gray, 2002). In the United States enquiries regarding spider bite are less common with only 3.8% of calls to a PIC being in regard to a bite or sting (Litovitz et al., 2002) although other sources estimate larger numbers of black widow and brown recluse spider bites (Schuman and Caldwell, 1991). It is thus important to provide reliable and evidence based information to persons being bitten by spiders so that they can be reassured and not over-use health care resources inappropriately. In this review, we will cover the major groups of widely distributed medically significant spiders: the widow spiders (Latrodectus spp.), including some recent information on related genera; the recluse spiders (Loxosceles spp.) and the problems with over-diagnosis of necrotic arachnidism; and finally some notorious groups of spiders that cause either

significant effects or have been erroneously attributed with significant effects and do not cause medical problems, based on evidence from definite bites.

2. Spider bite: definition, clinical features and epidemiology A discussion of spider bite requires an understanding of what constitutes good evidence in clinical toxinology and the conditions that must be met for definite spider bite cases (Isbister, 2002b; White, 1987). For a spider bite to be regarded as a definite bite by a particular species, all of the following must be satisfied: (1) Evidence of a bite, including clinical effects at the time or soon after the bite, including discomfort or pain, which is an almost universal characteristic of spider bites (Isbister and Gray, 2002), the apparent major exception being bites by Loxosceles spiders, which are considered painless at the time of the bite, a characteristic that adds greatly to the confusion in the literature over which cases are actually loxoscelism (White et al., 1995); (2) Collection of the spider at the time or immediately after the bite; (3) Identification of the spider by an expert arachnologist so that clinical effects can be correctly attributed to different species (Isbister, 2002b). Both the general public and health professionals often incorrectly identify spiders. For example, in 12 suspected white-tail spider bites (where the spider was collected at the time), only nine were confirmed to be Lampona spp., and the medical officer was wrong in two of the three misidentified cases (Isbister and Gray, 2000). The majority of studies of spider bite have been retrospective and suffer from incomplete clinical details and rarely follow up of cases recruited from either hospital attendance or calls to a PIC. Prospective studies of definite bites, with follow up of patients, allows the collection of much more complete information about bites by different species, in particular the duration of effects such as pain and local inflammation (Isbister and Gray, 2002). Pain or discomfort is a universal finding in spider bite and the prolonged absence of pain following a suspected spider bite is strong evidence against it. The characteristics of the pain are often helpful in distinguishing effects by different spiders, including duration of pain, initial increase in pain or radiating pain. Other important local effects include: (1) fang marks or bleeding which are indicative of the size of fangs and thus the size of the spider; (2) redness or red mark which is variable in size, but appears to be a constant finding in 60 – 80% spider bites; (3) itchiness (immediate or delayed); (4) presence of spines (Isbister and Hirst, 2002); but (5) swelling is an uncommon finding. Table 1 provides the frequency of local and systemic effects for all spiders and then a breakdown of this for major spider groups (Isbister and Gray, 2002).

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479

Table 1 Clinical effects of bites by important spider groups (genus or family) in Australia Clinical effects (%)

All spiders Latrodectus Steatoda Sparassidae Redback Cupboard Huntsman spiders spiders spiders

Lycosidae Lamponidae Wolf White-tail spiders spiders

Mygalomorphae Australian FWS, Mouse spiders, Trapdoor spiders

Number of cases

750

68

23

168

46

130

45

Local effects Severe pain (%) Duration of paina Radiating pain (%) Fang marks (%) Initial bleeding (%) Redness/red mark (%) Swelling (%) Local diaphoresis (%) Itchiness (%)

27 10 min 7 28 13 69 13 3 21

62 36 h 38 6 1 74 7 34 38

26 6h 13 17 4 96 9 0 48

27 5 min 4 40 35 57 16 0 14

24 10 min 7 30 13 65 20 0 13

27 5 min 2 17 4 83 8 0 44

49 60 min 18 58 27 36 13 0 0

Systemic effectsb (%)

13

35

30

4

7

9

36

56 37 12 Putting on shoe (28%)

78 30 26 Dressing (48%)

56 48 26 37 17 17 Interfering with – spider (76%)

95 64 5 Trapped b/w material and skin (63%)

36 16 16 Garden related (42%)

46

52

82

25

91

Circumstances Indoors (%) 61 Night (%, 6 p.m.–6 a.m.) 34 Winter (%, May–Aug) 11 Typical activity – Bite region Distal limb bite (%)

49

72

The majority of the information is taken from previous studies (Isbister and Gray, 2002, 2003b,c,d; Isbister and Framenau, 2003; Isbister and Hirst, 2003) although some has been derived directly from the same database, but has not been previously published. a Median duration of pain. b Systemic effects were mainly nausea, vomiting, headache and malaise.

In addition to obtaining clear information about the clinical effects of spider bites, information about the circumstances of the bites has been shown to be useful in distinguishing bites by different spider groups. Information about the circumstances of bites, including season, geography, location and activity at the time of the bite have been shown to be predictive of the type of spider (Isbister and Gray, 2002, 2003b) and may be a valuable tool in determining the spider type in cases of probable and suspected bites where no spider is collected.

3. An approach to the diagnosis of suspected or probable spider bite It is not uncommon for patients to present to health care facilities with signs and symptoms that they attribute to a spider bite. In the majority, the presentation is with skin lesions or necrotic ulcers, and there is usually no history of spider bite at all. It is essential in these cases that the history of a spider bite is confirmed or excluded. If there is no history of bite the diagnosis

and investigation must focus on important causes of necrotic ulcers including infectious, inflammatory, vascular and neoplastic aetiologies (Isbister, 2001b; Vetter, 2000; Vetter and Bush, 2002b). An approach to this is outlined in detail elsewhere (Isbister and Whyte, 2004) and is pertinent to most parts of the world because the misattribution of effects to spider bite is not confined to any one country. In cases where there is a history of a definite bite, particularly if the spider is collected at the time, then effects can be attributed to the spider bite and management can proceed appropriately. The management of definite spider bite requires good information on effects of spiders in the region where the spider occurs. Currently, information of this type is not available in many parts of the world making it hard to treat many types of spider bite, even if the creature is identified. In Australia, definite spider bites can be divided into bites by three clinically relevant groups: big black spiders, Redback spiders (Latrodectus) and all other spiders. Big black spiders include Funnel web spiders, Mouse spiders and other mygalomorphs that should be treated

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as FWS bites in eastern Australia. Latrodectism, resulting from the bite of Latrodectus spp., is not a rapidly developing condition or likely to be, life-threatening, but recent evidence suggests that it can cause significant pain and unpleasantness for the patient. The remaining spiders responsible for bites in Australia cause minor effects only, so if the person has not been bitten, by either a big black spider or a Redback spider they can be reassured that there will be no major effects. Probable bites by medically important spiders should be managed based on clinical effects. Information on the circumstances of the bite and geographical distribution of spiders can help to confirm the diagnosis.

4. Latrodectism Over 40 species of widow spiders (Theridiidae: Latrodectus spp.) occur worldwide, including L. hasselti (Redback spider), L. mactans and L. hesperus (Black widow spiders), L. tredecimguttatus (European widow spider), L. indistinctus and L. geometricus (Brown widow spider). Bites by these spiders cause latrodectism which is responsible for significant morbidity in many countries (Isbister and Gray, 2003b; Maretic, 1983; Clark et al., 1992), but deaths are rarely reported (Pneumatikos et al., 2003; Parrish, 1959, 1963; Schuman and Caldwell, 1991; Sutherland and Tibballs, 2001; Bogen, 1932). The epidemiology and impact of these spiders worldwide is poorly understood, particularly in many parts of Asia and northern and central Africa (White et al., 1995). It is estimated that there are at least 5000 Redback spider bites in Australia each year although this figure is a gross approximation based on prospective studies, hospital admissions, antivenom use, PIC calls and personal experience of the authors. In addition, the incidence of bites has significant geographical variation with far more bites in the temperate regions of Australia, and far fewer in the colder south or tropical north (Isbister et al., 2001; Woo and Smart, 1999; Isbister and Gray, 2002). The venom of Latrodectus spp. has been studied extensively, initially with work on L. tredecimguttatus (Grishin, 1998; Grasso, 1976) and more recently with work on a number of Latrodectus spp. and the cross-reactivity of antivenom (Graudins et al., 2001; Daly et al., 2001). The isolation and characterisation of alpha-latrotoxin and other components of widow spider venoms has been reviewed previously (Nicholson and Graudins, 2002; Rash and Hodgson, 2002). Despite the commonness of bites by widow spiders there are few studies that clearly define the clinical effects of these spiders and the majority of these are from Australia (Trethewy et al., 2003; Mollison et al., 1994; Sutherland and Trinca, 1978; Jelinek et al., 1989; Wiener, 1961; Isbister and Gray, 2003b; Mead and Jelinek, 1993), the United States (Clark et al., 1992; Alsop and Albertson, 2001;

Mossm and Binder, 1987), South America (Artaza et al., 1982; Lira-da-Silva et al., 1995), South Africa (Muller, 1993) and Europe (Muller, 1993; Diez et al., 1996). There are many reviews on the subject which continue to base information regarding the spectrum and severity of clinical effects on case reports and small retrospective series. A recent prospective study of Redback spider bites in Australia provides a better picture of the clinical effects, at least for L. hasselti (Isbister and Gray, 2003b). Based on the similarities in Latrodectus venoms the differences in latrodectism in different parts of the world may be more a function of the quality of clinical research to date, and this recent study may provide some insight into the severity of latrodectism. Table 2 includes the incidences of clinical effects for different Latrodectus species based on the largest and most accurate studies available. Although there appear to be distinct differences, after taking into consideration the study designs (mainly retrospective without follow up), patient groups included (PIC calls, hospital admission or Redback spider antivenom reports submitted to Commonwealth Serum Laboratories in Australia), widely differing definition of clinical effects and reporting biases, there are similarities across the different widow spiders included in the table. Until data exist to compare properly the clinical effects of different widow spiders, the wide spectrum of known effects with any particular species, the similarities in Latrodectus venoms (Graudins et al., 2001; Daly et al., 2001) and the information in Table 2, latrodectism appears to present a similar clinical syndrome worldwide. A recent study of 68 L. hasselti bites has showed that the majority of bites cause significant effects with severe and persistent pain occurring in two-thirds, sufficiently severe to prevent the patient sleeping in almost a third of all cases (Isbister and Gray, 2003b). The pattern of the pain is characteristic, increasing over the first hour in 54% of cases, confirming previous reports that the bite may only cause an initial irritation or discomfort (White et al., 1995). Because they are small, widow spiders rarely leave puncture marks or cause bleeding at the bite site and swelling is also uncommon (Isbister and Gray, 2003b). The frequency of some features such as hypertension, hyperthermia, neuromuscular effects and other objective signs are more difficult to establish because this study of Redback spider bites did not include patients seen only in hospital, and the majority were not examined. The number of paediatric cases was insufficient to define properly the effects in children. This remains an unresolved issue in Australia with one recent study showing that systemic and severe effects occurring in 85% of children, 65% having all three signs of diaphoresis, hypertension and irritability (Trethewy et al., 2003), in contrast to only 22% in an earlier study (Mead and Jelinek, 1993). However, both studies were retrospective and only included patients admitted to hospital, with widely varying rates of antivenom use. A series of 12 paediatric black widow spider bites demonstrated that hypertension was almost universal

Table 2 Incidence of major clinical effects in widow spider bites from different regions of the world (Artaza et al., 1982; Isbister and Gray, 2003b; Sutherland and Trinca, 1978; Diez et al., 1996; Lira-da-Silva et al., 1995; Muller, 1993; Clark et al., 1992) Features of bites

L. hasselti

Number of bites and relevant study criteria

15 (positive 89 68 (Prospective; 2144 (Retrospective; 163 (Retrospective 77 (Retrospective 30 (Retrospective; 12 (Retrospective; follow-up AV reports) ED; 72% with reports; ID in 75% positive ID three positive ID, six ID in 10 cases) (Retrospective) seen by the patient) PIC calls) positive ID) of cases) in six cases); all received AV

Other local/ regional (%) Diaphoresis (%) Redness/ red area (%) Swelling (%) Puncture marks (%) Itchiness (%) Systemic effects (%) Nausea (%) Vomiting (%) Headache (%) Malaise (%) Lethargy (%) Generalised diaphoresise (%) Abdominal rigidity (%)

L. mactans

L. curaca-viensis

L. indistinctis

L. tredecim-guttatus

100 62 66 54

76

38

56

67

38

39

18

41

57

9

17

17

67

6

4

10

30

0

10

47 80

7 13

56 3 34

15

74 7

33 24

6 38

4

35 24 4 10 10 10 4

22

13 (28)c 21 17

67

L. geometricus

93

7 83

27

(41)d 67

L. mactans

83

53

91b 70

80

88

5

20 20 4 10

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Pain Local paina (%) Severe pain (%) Pain .24 h (%) Increasing pain (first h, %) Radiating pain to limb (%) Abdominal pain (%) Chest pain/ constriction (%) Back pain (%) Generalised Myalgia (%)

L. hasselti

5

11 11 9

5 8

17 17 21

25 25 33

0 0 0

10 (28)

(70)

7

(70)

70

7

45 481

(continued on next page)

482

Table 2 (continued) Features of bites

1

L. hasselti 3 8

10

L. mactans 29

1

Bite site Distal extremity (%) Proximal limb (%) Trunk (%) Head/neck (%)

46 26 21 7

48 28 18 5

Circumstances of bite Putting on shoe (%) Dressing (%)

28 10

(15)h (15)

L. curaca-viensis

L. indistinctis

4 12 14

(60)f 17 50 47 13 13

21 29

(67)g (67) 23 10

L. tredecim-guttatus

33

L. geometricus 0 13 13 13 0 0 (60) (60) 27 13

L. mactans 17 44 0 12

83 83 2 7

Due to different study designs, definitions of clinical effects and data collection techniques, much data is missing and many listed clinical effects may not be defined in similar ways. In the majority of studies local pain appears to refer to persistent or severe pain only, rather than any discomfort of the bite (initial or persistent), which differs to the prospective study in Australia. b Includes radiating and local pain. c Unclear regarding regional diaphoresis. d Includes hypertension and sialorrhoea. e Many studies did not distinguish regional and generalised diaphoresis and these are included in brackets. f Included hypertension or tachycardia. g Distal and proximal limbs not distinguished. h 15% for both dressing or putting on shoes. PIC—Poison information centre; AV—antivenom. a

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Hypertension (%) Raised temperature (%) Agitation/irritation (%) Weakness/ataxia (%) Paraesthesia (%) Fasciculations/tremor (%)

L. hasselti

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(11 cases), other features including generalised pain (100%), abdominal rigidity (50%), agitation/irritability (75%) and diaphoresis (25%), which is more consistent with the more recent study of Redback spider bites in Australia. This study, again, only included hospitalised patients (Woestman et al., 1996). The treatment of latrodectism varies considerably in different parts of the world based on local availability of antivenom, perceived effectiveness of antivenom and other treatments that are believed to be effective, based on anecdotal evidence. There is currently no good evidence of the effectiveness of different antivenoms in humans or of the most appropriate route of administration (Isbister et al., 2003a). There is an ongoing reluctance to use widow spider antivenoms in some regions, notably North America, because of a perceived high risk of allergic reactions. There is unlikely to be a high rate of early allergic reactions with most widow spider antivenoms, but the rate of delayed reactions may be higher than previously recognised (Sutherland and Trinca, 1978; Clark, 2001). However, many widow spider bites cause significantly severe effects (Trethewy et al., 2003; Isbister and Gray, 2003b; Woestman et al., 1996) such that the use of antivenom is justified in up to two-thirds of cases. A further problem is with the route of administration of antivenom, and this pertains mainly to Australia. There is increasing evidence that intramuscular antivenom is far less effective than previously believed (Isbister, 2002c; Isbister and Gray, 2003b). There are currently two randomised controlled trials being undertaken in Australia to clarify the route of administration. However, personal experience of one of the authors (JW) suggests that intramuscular antivenom is effective in some, but not all cases. Latrodectus spiders have been introduced to many countries of the world as a result of human travel and container shipments which has most recently occurred in Japan (White J, personal communication). With increasing international travel, it is likely that widow spiders will be introduced to many places. Latrodectism is one of the most important clinical syndromes resulting from spider bite worldwide and it will be important that well designed studies are carried out in different regions of the world to characterise the spectrum and severity of clinical effects.

5. Steatodism Although the term steatodism has been used for over 30 years (Maretic et al., 1964), human bites by Steatoda spp. have been poorly reported and not recognised in most parts of the world (Isbister and Gray, 2003d). Steatoda spiders belong to the family Theridiidae (comb-footed spiders) which includes widow spiders. Until recently there were few reports of bites by Steatoda spiders (South et al., 1998; Graudins et al., 2002b; Warrell et al., 1991; Winkel

483

et al., 2000), and the majority were from Australia (Isbister and Gray, 2003d). Steatoda spp. occur in many regions of the world, including Australia, South Africa, the Americas and Europe (Maretic, 1978; Levi, 1962, 1957; Warrell et al., 1991). Some spiders in the genus such as S. grossa and S. capensis may be mistaken for widow spiders, being of comparable size, hence the common name ‘false widow spider’. All bites reported in Australia are from these two introduced species, S. capensis and S. grossa (Isbister and Gray, 2003d), which are common and widely distributed, especially in urban areas. S. grossa is a cosmopolitan species that originated in Europe and has spread to many other continents, including America, while S. capensis is a South African spider (Levi, 1962). A recent prospective study of 23 bites by Steatoda spp. demonstrates that steatodism is similar to, but less severe than, latrodectism and may cause prolonged and radiating pain (median duration 6 h) and systemic effects (nausea, headache, malaise and lethargy) (Isbister and Gray, 2003d; Table 1). In the most severe cases, the effects are almost indistinguishable from Latrodectus bite, except for the absence of local and regional diaphoresis (Isbister and Gray, 2003d). Overall the effects were less severe than Latrodectus bites based on bites in the same study (Isbister and Gray, 2003b). It is possible that some bites that are consistent with latrodectism, but where no spider has been collected, may in fact be severe cases of steatodism. Significant effects have also been reported in a definite bite by S. nobilis in Europe (Warrell et al., 1991) and there are reports of bites in the United States (Vetter, personal communication, 2003). A clinical study (Isbister and Gray, 2003d) and previous reports support animal work demonstrating that the venom of Steatoda causes similar, but less potent effects than Latrodectus spp. (Cavalieri et al., 1987; Mironov et al., 1986; Maretic et al., 1964; Graudins et al., 2002b). Male Steatoda spiders are only slightly smaller than their female counterparts, unlike tiny Latrodectus males. They are thus as capable of biting humans as the female spiders, but are less common with only two reported cases (Isbister and Gray, 2003d). These two bites by male Steatoda spiders (one each of S. capensis and S. grossa) (Isbister and Gray, 2003d) caused significant pain lasting 1 – 2 h in each case (Isbister, unpublished data). Juvenile Steatoda spiders caused similar effects to adult spiders (Isbister and Gray, 2003d). The treatment of steatodism is symptomatic in the majority of cases with simple analgesia. In more severe cases intravenous Redback spider antivenom (or other widow spider antivenoms (Isbister et al., 2003a)) may be considered based on case reports of its use in Steatoda bites (Isbister and Gray, 2003d; Graudins et al., 2002b; South et al., 1998). This is consistent with in vitro work (Graudins et al., 2002b), but further clinical trials are required before this can be uniformly recommended.

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Achaearanea spiders, also from the family Theridiidae, have also been reported to cause similar effects to Latrodectus and Steatoda in five definite bites from Australia, but no systemic effects occurred (Isbister and Gray, 2003d). Bites have been reported by both A. tepidariorum, a widely distributed cosmopolitan species, and A. veruculata, a native species that has been introduced to Europe and New Zealand (Isbister and Gray, 2003d; White et al., 1989). This suggests that the syndrome of persistent pain and generalised systemic effects occurs in envenoming from at least three genera of theridiid spiders (Isbister and Gray, 2003d).

6. Loxoscelism Loxosceles spp. are the only group of spiders where there is substantial evidence (human case series and research on the venom) to support a causal relationship between bites and necrotic arachnidism (White et al., 1995). Loxosceles spiders occur in many parts of the world. In South American, they are the most medically important spider causing bites across the continent (White et al., 1995). They have a far more limited distribution in the United States and the most important, L. reclusa, occurs in the central Midwest from Nebraska south to Texas and eastward to southernmost Ohio and north-central Georgia (Vetter, 2000). However, there continues to be an over-diagnosis of the condition in the United States, particularly in areas where Loxosceles spp. are rarely found and not endemic (Vetter and Bush, 2002a,b). Occasional bites are reported from Europe (L. rufescens) and also southern Africa (White et al., 1995; Newlands and Atkinson, 1990). Although Loxosceles spp. occur across parts of Asia there is limited information on bites. An introduced Loxosceles sp. has been reported in Australia, but has remained confined to Adelaide, a southern city (Southcott, 1976b). Because many cases of local tissue injury are blamed on loxoscelism, particularly in the United States, it is hard to define the true epidemiology of loxoscelism because strict criteria for inclusion (i.e. spider sighted and identified) are rarely used. Recent work by Vetter in the United States has highlighted the likely misdiagnosis of loxoscelism in many cases by comparing spider distribution and density with reported cases of suspected loxoscelism (Vetter and Barger, 2002; Vetter et al., 2003a; Vetter and Bush, 2002a). Vetter demonstrates that in the western states of the United States there are large numbers of suspected cases of necrotic arachnidism reported, but there are no endemic spider populations in these states where human populations are located (Vetter et al., 2003a). In addition, Vetter reports that in Kansas, an area where L. reclusa is endemic, a home-owner collected 2055 brown recluse spiders (over 400 large enough to bite), but no one in the house was bitten in the 6 month period of collection or during the 6

year occupancy of the house (Vetter and Barger, 2002). It is not uncommon in these endemic areas for dozens of spiders to be present in a house, but no bites or necrotic lesions are reported (Vetter and Barger, 2002). A survey of houses in Chile found a similar thing where occupants of heavily infested houses (average of 163 spiders per house in the five most infested) had never shown evidence of bites (Schenone et al., 1970). This suggests that, even with exposure to high densities of Loxosceles, bites are unlikely, and so in nonendemic areas bites should be non-existent. Loxoscelism presents in two forms; cutaneous and viscerocutaneous, the latter much less common than the former in South America and rare elsewhere (White et al., 1995; Sezerino et al., 1998). Both share similar clinical features in the bitten area. The bite is minor and may be painless, frequently occurring at night when the patient moves in bed, squashing the spider. Within the first 12 – 24 h, the bite site becomes erythematous, mildly oedematous, painful and may develop mottled haemorrhagic areas or blisters, which correspond to the area of impending necrosis (White et al., 1995). The necrosis may take up to a week to develop, often with a necrotic eschar overlying. The resultant ulcer is generally painful and slow to heal, with cycles of partial healing followed by breakdown, sometimes extending over months. In cutaneous loxoscelism, the patient frequently develops a non-specific systemic illness in the first 48 h, with fever and malaise. In viscerocutaneous loxoscelism, a severe, sometimes lifethreatening systemic illness develops, with haemolysis, coagulopathy, shock, renal failure and multiple organ damage (White et al., 1995). Because of considerable morbidity and mortality from bites by Loxosceles spiders in South America there has been the development of antivenoms (White et al., 1995; Isbister et al., 2003a). Although there is widespread use of antivenom in Brazil, there is little evidence to support its effectiveness. Animal studies have demonstrated that antivenom given within 4 h attenuates dermonecrotic lesions (Gomez et al., 1999). The majority of clinical cases present later than 4 h and therefore antivenom may not be effective after this time, explaining the disappointing results with antivenom in Brazil (White et al., 1995; Sezerino et al., 1998). The reason for delayed presentation, and also the likely reason for the very low rate of collected spiders in studies of loxoscelism, is that most bites are relatively painless, and substantial effects take 24 h or longer to evolve (White et al., 1995).

7. Australian Funnel web spiders Australian FWS (Hexathelidae: Atracinae: Atrax and Hadronyche spp.) are the most venomous spiders in the world based on clinical experience in Australia and animal lethal dose studies (Gray and Sutherland, 1978;

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Wiener, 1957; Bettini and Maroli, 1978). They occur in eastern Australia from Tasmania in the south to the far north of Queensland, but severe envenoming and deaths have only been reported in a smaller region from southern New South Wales to southern Queensland (Musgrave, 1949; Miller et al., 2000; Musgrave, 1927; Beazley, 1930; Irwin, 1952). Considerable research has been conducted on the venoms of Australian FWS which has identified a number of neurotoxins responsible for envenoming (Nicholson and Graudins, 2002; Nicholson et al., 1994, 1998; Graudins et al., 2002a). The most clinically relevant are the d-atracotoxins which have been shown to slow tetrodotoxin (TTX)-sensitive voltage-gated Naþ current inactivation and reduce peak TTX sensitive current (Nicholson et al., 1994, 1998). The structure –function relationships of d-atracotoxins are the subject of a separate article in this issue. FWS bites are uncommon and severe envenoming even less common. Only eight of the 750 spider bites (1.1%) in a recent Australian study were due to FWS, and in only one patient was there severe envenoming requiring antivenom (Isbister and Gray, 2002). It is likely that there are only 5 – 10 severe envenomings each year in Australia requiring antivenom (White et al., 1995), but because of the rapid onset of life-threatening effects and the availability of effective treatment, FWS envenoming is an important clinical condition. The reason for the high rate of ‘dry’ bites is not completely clear. In the past there was often the impression that FWS envenoming was an all-or-none phenomena. This is unlikely to be the case and of the eight cases in the prospective study there was one patient with severe envenoming, two with generalised systemic effects (headache, nausea, lethargy and malaise) and three with paraesthesia (local and regional; Isbister, unpublished data). In another recent study of Hadronyche bites from Queensland, there was a similar proportion of less severe cases (Harrington et al., 1999). Local effects included puncture marks at the bite site and local bleeding which is more common than any other spider types. In addition local pain is often severe and may last for 30 – 60 min (Table 1). The impression of an all-or-none phenomena is more likely a reflection of publication bias of severe envenoming only. Severe FWS envenoming is characterised by (1) neuromuscular excitation, including paraesthesia (local, distal and peri-oral) and fasciculations (local, regional and tongue); (2) massive autonomic stimulation/excitation (both sympathetic and parasympathetic) with generalised diaphoresis, hypersalivation, hyperlacrimation, hypertension, bradycardia or tachycardia and miosis or mydriasis; (3) pulmonary oedema; and (4) generalised systemic effects. Prior to the introduction of antivenom, further effects included neuromuscular paralysis, coma, intractable hypotension, secondary coagulopathy and multi-organ failure (Torda et al., 1980). Antivenom is the main treatment in severe envenoming although atropine may be used for control of excessive secretions. FWS antivenom is a rabbit-derived IgG antivenom produced against the venom of the Sydney

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FWS (A. robustus) that appears to reverse envenoming effectively following Atrax (Fisher et al., 1981) and Hadronyche spp. bites (Miller et al., 2000; Dieckmann et al., 1989; Hartman and Sutherland, 1984). Recent work has demonstrated that the in vitro effects of 10 different Hadronyche and Atrax species can be reversed by FWS antivenom (Graudins et al., 2002a), supporting the clinical accounts. All patients should be admitted to an intensive care unit and observed because delayed effects can occur, and a number of cases of delayed non-cardiogenic pulmonary oedema have been reported. The management of suspected FWS envenoming, or bites by an unidentified big black spider are more problematic. Initially, all bites by a large, black spider in Eastern Australia should be treated as a suspected FWS envenoming and the patient should have a pressure immobilisation bandage put on and be transported rapidly to hospital. The patient should then be observed closely in an emergency department for 2– 4 h. The pressure immobilisation bandage can be removed after 1 h if there is no evidence of envenoming and FWS antivenom is available. If there is no evidence of severe envenoming after 2 h, it is unlikely to occur, but it is prudent to observe the patient for 4 h. Australian Mouse spiders or Missulena spp. have been implicated in one case of severe envenoming in Australia (Rendle Short, 1985) and recent work on the venom of the Eastern Mouse spider M. bradleyi demonstrated that the venom caused similar effects to FWS venoms and these effects were reversed by FWS antivenom (Rash et al., 2000a). This has not been confirmed in almost 20 bites, which caused only minor to moderate effects (Isbister et al., 2001; Musgrave, 1949; Isbister and Gray, 2002; Faulder, 1993; Lake, 1990), 12 of these in the prospective study of Australian spider bites (Isbister and Gray, 2002). However, because of the similarity of these spiders, like many other Trapdoor spiders, to FWS, it would be advisable that all suspected Mouse spider bites should be treated as suspected FWS bites and be observed for at least 4 h.

8. Spiders that have been implicated in necrotic arachnidism A large number of spiders have been implicated in necrotic arachnidism from all over the world, and include the white-tail spider (Lampona spp.) in Australia and New Zealand (Sutherland, 1983; Spring, 1987; St George and Forster, 1991; Pincus et al., 1999), wolf spiders (Lycosidae) (Sams et al., 2001), Cheiracanthium spp. (running or sac spiders) (Newlands et al., 1980; Gorham and Rheney, 1968), Hobo spider (Tegenaria agrestis) (Vest, 1987b), black house spiders (Badumna spp.) (Pincus et al., 1999; Young and Pincus, 2001) and garden or orb weaving spiders (Argiope aurantia) (Gorham and Rheney, 1968).

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White-tail spiders (L. cylindrata and L. murina) have been implicated in necrotic arachnidism in Australia for about 20 years which has lead to an unreasonable fear of these spiders—often promoted by the medical community. There have been increasing numbers of cases that appear to be misattributed to bites by white-tail spiders, where a spider is usually not even seen (Pincus et al., 1999; St George and Forster, 1991; Spring, 1987; Isbister, 2001a). However, recent clinical studies (Isbister and Gray, 2002, 2003c; Isbister and Whyte, 2003d) and venom research (Young and Pincus, 2001; Rash and Hodgson, 2002; Rash et al., 2000b) do not support the role of Lampona spp. in necrotic arachnidism and suggest that Lampona spp. do not cause necrotic lesions. In a prospective study of 130 white-tail spider bites, there were no cases of necrotic ulcers (Isbister and Gray, 2003c) which supports previous reports based on definite bites (White et al., 1989; Musgrave, 1949). There were three patterns of clinical effects following definite bites by Lampona spiders: pain only, pain and a red mark lasting less than 24 h, and a third moderately severe group with a persistent red mark and associated itchiness, pain or lump (Isbister and Gray, 2003c). The spectrum of local, and systemic effects of white-tail spider bite is included in Table 1. A related study of only suspected white-tail spider bites demonstrated that in all cases another diagnosis could be found after appropriate investigation and in the majority of cases a spider was never seen (Isbister and Whyte, 2003d). Studies of the venom of Lampona spp. have demonstrated that it does not contain important components, such as sphingomyelinases (Young and Pincus, 2001), which have been implicated in the mechanism of cytotoxicity in Loxosceles bites (Tambourgi et al., 1998). Despite a number of authors suggesting that collagenases in midgut extractions may be responsible for necrosis (Young and Pincus, 2001; Atkinson and Wright, 1992), this has been shown to be unlikely based on the fact that other spiders not implicated in necrotic arachnidism contain collagenases (Isbister, 2001a) and that collagenases injected into rabbits did not cause necrosis (Foradori et al., 2001). The hobo spider or Tegenaria agrestis is a European agelenid spider introduced to the United States last century that has established itself in western North America. Despite Tegeneria spp. being regarded as innocuous in Europe and there being no previous reports of necrosis from Europe (Binford, 2001), medical professionals in the northwestern United States started attributing cases of apparent necrotic arachnidism to its bite (Vest, 1987a,b; Fisher et al., 1994). Previously, bites in this region of the United States had been attributed to Loxosceles spp. (Wand, 1972; Lee et al., 1969), but Loxosceles does not occur in the region (Gertsch and Ennik, 1983; Vetter et al., 2003b). Vest published a series of 22 probable cases of necrotic arachnidism from 75 cases of suspected spider bites and suggested that T. agrestis was the responsible agent (Vest, 1987b). However, in only four cases did the patient witness a spider on them (all reported no immediate pain) and in no

cases was the spider submitted for expert identification (Vest, 1987b). No definite cases have since been published although cases of suspected necrotic arachnidism continue to be attributed to this spider (Fisher et al., 1994; Sadler et al., 2001). This is supported by work on the venom of T. agrestis comparing populations collected from Europe and the United States. Examination of the venoms with liquid chromatography and insect bioassays revealed no difference between the two population groups (Binford, 2001). Thus, current evidence suggests that T. agrestis is not responsible for necrotic lesions and cases in the north western parts of North America should be investigated for other causes. The running or sac spiders belonging to the genus Cheiracanthium have also been implicated in necrotic lesions in many parts of the world, including the United States (Krinsky, 1987), Europe (Stingeni et al., 1998) and South Africa (Newlands et al., 1980). Again this is based on limited clinical cases. Nine bites have been reported in Australia in which there were no cases of necrosis, but moderate local effects occurred in a number of cases (Isbister and Gray, 2002). The main effects were local pain that persisted for hours to days in some cases, associated with erythema in most cases (Isbister, unpublished data). Black house spiders (Badumna spp.) have been implicated in necrotic arachnidism in Australia (Pincus et al., 1999). Again this has not been supported by recent clinical studies (Isbister, unpublished data) or venom research (Young and Pincus, 2001; Isbister, 2001a). In 25 definite bites by Badumna spp., transient pain occurred (median duration of 5 min) and erythema in two-thirds of cases. Four cases had mild systemic effects and none had necrosis (Isbister and Gray, 2003a). Similar to Lampona spp., no sphingomyelinases were identified in the venom of B. insignis (Young and Pincus, 2001). Wolf spiders have been implicated in necrotic arachnidism in the Americas (Sams et al., 2001), but large studies from Brazil suggest they do not cause necrosis (Ribeiro et al., 1990). This has recently been confirmed in Australia, where 45 bites by lycosid spiders caused only minor effects with no cases of necrosis (Isbister and Gray, 2002).

9. Common or recognisable spiders that cause minimal clinical effects There are a number of families of spiders that are well recognised and commonly encountered worldwide that cause minor effects. Spiders of the Family Sparassidae occur throughout tropical and temperate regions of the world and are variously referred to as Banana spiders (Heteropoda venatoria), crab spiders or huntsman spiders. They are large modern spiders or araneomorphs that are often feared by people because of their size and ability to

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climb walls and ceilings. There are few reports of definite sparassid bites and previous case reports have suggested that particular genera (Neosparassus) can cause severe effects (Musgrave, 1949; Sutherland and Tibballs, 2001; Raven and Gallon, 1987). However, a recent prospective study of 168 bites has shown them to cause only minor effects which can be accounted for by mechanical effects of their large fangs (Table 1; Isbister and Hirst, 2003). Three quarters of bites occurred because the spider was interfered with (e.g. picked up or caught). Eighty-two percentage of bites occurred on distal limbs, which was also consistent with handling or treading on the spider. The clinical effects were characterised by immediate and transient pain with a median time of 5 min. Puncture marks or bleeding occurred in more than half of the bites and distinguished bites by these spiders from other types (but not from other large spiders such as mygalomorphs). Systemic effects were rare (,4%) and were minor. Features consistent with local infection occurred in 2.3% of cases, and this was more common than with any other group of spiders (Isbister and Gray, 2002). There were no major differences between genera, including the widely distributed tropical huntsmen Heteropoda spp., and Neosparassus spp. which did not cause major effects. Spiders from the family Lycosidae (wolf spiders) are common in many parts of the world. These are hunting spiders that range from very small spiders of only a few millimetres to large spiders that have fangs of a size sufficient to cause a painful bite. A large study from Brazil of Lycosa bites showed that the predominant effect of bites was local pain (Ribeiro et al., 1990). The identification and taxonomic placement of this species, currently Lycosa erythrognatha Lucas, 1836, remains obscure, because this species has not been treated taxonomically since the early 1960s). A more recent study of bites by Australian Wolf spiders has shown that bites cause minor effects (Isbister and Framenau, 2003). The clinical effects are listed in Table 1. Most bites were by spiders from four generic groupings, Tasmanicosa (including Lycosa), Venatrix, Venator and Hogna. Tasmanicosa spider bites caused significantly more itchiness and redness, and larger Wolf spiders more often caused severe pain and left fang marks (Isbister and Framenau, 2003). The effects are likely to be due to mechanical injury although minor local envenomation appeared to occur with Tasmanicosa (Lycosa) bites (Isbister and Framenau, 2003) consistent with histamine being the principal pharmacological component of L. godeffroyi venom (Rash et al., 1998). There are also reports of lycosid bites from the United States (Campbell et al., 1987) and Europe (Maretic, 1979). Campbell reported two bites from North America and reviewed three previously reported bites (four Lycosa spp. and one Arctosa sp.). All these bites caused only minor effects, suggesting that North American Lycosidae do not cause necrosis (Campbell et al., 1987). As in Australia, the taxonomy of North American Lycosidae, is poorly resolved (Dondale and Redner,

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1990). Currently, all species reported by Campbell et al. as Lycosa are classified as Hogna spp., although some authorities suggest they belong in a separate genus. Maretic discusses L. tarantula, a true member of the genus Lycosa, and the reported effects of bites in Europe (Maretic, 1979). In the only case reported, the spider was not caught and although the patient developed a necrotic lesion, it is uncertain whether this was caused by a lycosid spider (Maretic, 1979). The family Araneidae contains members that have been responsible for bites in many parts of the world (Gorham and Rheney, 1968; Haddad, 2002; Southcott, 1976a), including Australia where they are responsible for 21% of all spider bites, second only to sparassid spiders (Isbister and Gray, 2002). In Australia most araneid bites are by spiders of the genus Eriophora or garden orb weaving spiders. Bites by these spiders characteristically occur when clothes are put on which have been on the washing line, typically left overnight. This nocturnal spider will climb into washing during the day to shelter. Bites only cause minor effects with transient and not severe pain, associated with redness at the bite site (Isbister and Gray, 2002; White et al., 1989). Bites from other genera, including Argiope (banded orb weavers) and Nephila (golden orb weavers) are uncommon in Australia, but appear to cause only minor effects (Isbister and Gray, 2002). Although the venom of Nephila spp. has been investigated and the spider occurs in other parts of the world, there are no reports of bites (Joo et al., 2002). Argiope spp. have been reported to cause minor effects in the United States (Gorham and Rheney, 1968). Spiders of the family Theraphosidae, better known as tarantulas, are familiar to both the general public and toxin researchers, and are now being increasingly kept as pets. Theraphosid spiders are the largest of the mygalomorph spiders and occur in all parts of the world. Bites from theraphosid spiders, although potentially lethal to some domestic animals (Isbister et al., 2003b), appear to cause little effect in humans based on series of bites from Australia and Brazil (Lucas et al., 1994; Isbister et al., 2003b). In the Australian series local pain was the commonest effect, usually associated with puncture marks and bleeding. In one case the spider had bitten through the patient’s fingernail. Mild systemic effects occurred in only one case. Bites in canines were far more severe with death occurring in all seven reported cases (Isbister et al., 2003b). Other families of spiders are responsible for a significant number of bites. Jumping spiders (Salticidae) making up 5% of bites in Australia did not cause major effects, although the family includes a diverse group of spiders (Isbister and Gray, 2002). The families Corinnidae (Darting spiders) and Zodariidae (Spotted or ant spiders) each caused 2% of bites in Australia (Isbister and Gray, 2002). Bites from spiders of both families caused a higher proportion of systemic effects than other families, and Zodariidae caused pain lasting a median duration of 45 min (Isbister and Gray, 2002).

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10. Spider injuries other than bites Although the majority of clinical effects following spider injuries are a result of bites, a number of other effects have been reported that range from minor effects such as injuries from external spider spines (i.e. setae; Isbister and Hirst, 2002) to more serious allergic reactions and eye injuries resulting from contact with spiders (Isbister, 2002a; Cooke et al., 1973; Castro et al., 1995; Blaikie et al., 1997; Cobcroft, 1984; Fuller, 1984; Isbister, 2003; Isbister and Balit, 2001). Injuries from the spines on the front legs of spiders have been reported recently. These injuries are characterised by pain at the time of contact with the spider, often mistaken for a bite, but distinguished from bites by the presence of ‘splinters’ at the bite site (Isbister and Hirst, 2002). In rare cases this can lead to local inflammation that may persist for a number of days. It has been recognised for some time that the hairs (setae) of South American spiders of the family Theraphosidae can cause urticarial skin reactions (Castro et al., 1995; Cooke et al., 1973) and more importantly ocular injuries (Blaikie et al., 1997; Bernardino and Rapuano, 2000). The urticating hairs of these spiders are likely to pose far more risk to the owner than bites from the spiders (Isbister et al., 2003b). There is one unusual report of pharyngeal irritation following ingestion of a theraphosid spider as exotic cuisine because the abdominal hairs were not appropriately removed (Traub et al., 2001). There has been one report of an acute allergic reaction following contact with an araneomorph spider (probable sparassid), which resulted in systemic effects including bradycardia and hypotension (Isbister, 2002a). The mechanism of the reaction in this case is not clear because the implicated spider has only very fine body hairs. There have been five cases reported of conjunctival inflammation following the contents of squashed spiders entering the eye (Cobcroft, 1984; Fuller, 1984; Isbister and Balit, 2001; Isbister, 2003). This has resulted from either small spiders, such as daddy long legs (Pholcidae) being rubbed in the eyes (Isbister and Balit, 2001), or large spiders being hit with objects and the contents of the spider being projected into the eye (Isbister, 2003; Cobcroft, 1984). This results in transient, but severe conjunctival inflammation characterised by redness, oedema and significant pain. Treatment is by irrigation of the eye and analgesia and the effects resolve within 24 h (Isbister, 2003).

11. Conclusion Spider bite is common, but most species cause minimal or no effects. Significant morbidity is restricted to a few, well-characterised groups, mostly with distinct clinical patterns of local and systemic effects. Only three groups of spiders—widow spiders, Phoneutria spp. and Australian

FWS—cause envenoming clearly responsive to antivenom and only in the latter group is antivenom crucial in management and survival. Spider bite, particularly ‘necrotic arachnidism’, is often over-diagnosed and should not become a convenient ‘explanation’ for cases of initially unexplained local tissue injury. Far more prospective data are required to fully delineate the clinical effects and optimal treatment for most types of spider bite.

Acknowledgements We thank Rick Vetter for providing in depth information about many groups of spiders in the Americas and in particular his work on suspected necrotic arachnidism and the distribution of Loxosceles and Tegeneria in western North America.

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