Hyaluronidase

Abstract

Envenomation from the brown recluse (Loxosceles recluse) spider commonly proceed on one of three clinical pathways. The majority of bites (90%) result in nothing more than a local reaction. They are essentially self-limiting, require little if any attention, and resolve spontaneously. A great majority of the remaining bites will produce necrotic ulcerations of various sizes and dimensions, with systemic sequela ranging from fever to hemolysis and kidney failure. Finally, and in the most rare cases, the patient will succumb a fatal systemic reaction. Current therapeutic options for these wounds remain controversial and include the following: local care, corticosteroids, dapsone, and hyperbaric oxygen (HBO) therapy. This article will review the application of HBO therapy for patients who are envenomated by brown recluse spiders. Information for this manuscript was derived from multiple MEDLINE searches as well as searches of the National Baromedical Service's hyperbaric specialty literature collection.

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Thirteen species of spider genera Loxosceles have been identified within the United States. Bites from only 5 of the Loxosceles species have been associated with toxic dermatologic manifestations, or necrotic arachnidism (Figure 1). (1) These spiders can be identified by a dark violin-shaped patch on its cephalothorax. Adults have a body measuring up to a 1 cm, with a leg span ranging up to 5 cm. Further, this species has 6 eyes arranged as 3 pairs, instead of the 8 eyes common in other spider species.

L. reclusa are distributed throughout the Southeastern and Midwestern parts of the United States. This timid spider is nocturnally active and inhabits dry dark areas such as rock overhangs, embankments, and cliffs. With the encroachment of human society upon its habitat, L. reclusa has expanded its range to include wood piles, rafters in sheds, eaves of houses, closets, attics, and basements. The spiders hibernate during the winter so most bites occur between April and October when humans unknowingly happen upon their lair. (2) Both sexes of Loxosceles are venomous. They can survive up to 6 months without food, and have a lifespan ranging between 550 and 625 days. (3) Loxosceles will only bite when threatened or crushed against the skin.

About 90% of bites are associated with nothing more than a local inflammatory response. The remaining 10% result in a necrotic ulcerative reaction or even a fatal systemic reaction in rare cases. (4) For the most part, outcomes can be determined within the first 72 hours. The majority of systemic reactions occur within the first 48 hours and most bites that necrose proceed into the initial phases of break-down by the second or third day. (4)

The bite will start as an erythematous macule surrounding a central papule. Should it advance to the necrotic phase the lesion will mature into a central blister with a surrounding dusky macule and ring of blanched skin that has a circumscribed, asymmetrical erythematous border. This somewhat pathognomonic presentation is called the "red, white, and blue sign" or "halo effect." During this period of evolution the bite usually becomes painful. (4,5)

There are 2 classification systems for L. reclusa bites. The Wilson-King system examines the circumstances surrounding the bite (Table 1). (4) Applying the criterion outlined in this classification system, the physician can guide their suspicion as to whether or not the patient was indeed bitten by a L. reclusa. There are many spiders that appear similar to the brown recluse; therefore, unless an identifiable specimen is brought in by the patient, there is always a risk of misdiagnosis. Further, since the initial bite is usually painless many patients are unsure of the exact circumstances surrounding the bite. Auer and Hershey (7) developed an alternative classification, one that examines the clinical sequela of the bite (Table 2). (7) This classification system grades bites as 1 to 4 depending on the severity of the patient's subsequent clinical course. Primarily, the local reaction determines the class, and the accompanying systemic sequela identifies the sub-class that the patient will be placed in. Any patient that has a resultant necrotic ulcer from a L. reclusa bite will be considered as at least a class 3.

[FIGURE 1 OMITTED]

Analysis of brown recluse venom shows that there are at least 9 distinct fractions. Their enzymatic functions include: hyaluronidase, esterase, alkaline phosphatase, 5'-ribonucleotide phosphohydrolase, and sphingomyelinase D. (8) Rekow et al (9) note that not all active fractions of the L. reclusa venom are produced in the venom apparatus and can be found in isolates from the cephalothorax and abdomen.

To date the treatment of L. reclusa bites remain controversial. Symptomatic treatment with analgesics, ice, compression, elevation, and rest are successful in decreasing the local edema, erythema, and any pain associated with the bite. Thus, since the initial differential diagnosis of an early spider bite includes a minor puncture wound with a possible dirty object, it has been suggested that patients should receive tetanus prophylaxis if their immunization is not up to date. (10) Further, corticosteroids are useful in patients who experience resulting hemolysis. (11) Antibiotics prophylaxis has been found to reduce the risk of secondary infection accompanying the bite. Dapsone has been used with some success in the treatment of resulting necrotic ulcerations. This drug is believed helpful because of its anti-neutrophil effects. (4,8,11,13) Another therapy that has been explored is hyperbaric oxygen (HBO) therapy. Both human and animal studies have been published on this intervention and will be reviewed in the next section.

Literature Review: Basic Science and Animal Data

At present, the necrotic brown L. reclusa bite offers diagnostic and therapeutic challenges with optimum management approaches yet to be standardized. Therapeutic recommendations range from symptomatic treatment with analgesics and local care to using dapsone for necrotic lesions and corticosteroids in patients who develop hemolysis. HBO therapy is theorized to work by oxygenating the wound environment and subsequently aiding in the healing process. Further, it is hypothesized that HBO therapy has some direct neutralizing effect on L. reclusa venom.

This later hypothesis was explored in a study by Merchant et al (14) who studied the effects of prolonged HBO therapy on Sphingomyelinase D activity of brown recluse venom. The parameters he used far exceeded the lethal dosing level of HBO therapy in all animal models. This was performed by subjecting venom samples to a 12-hour, 10.0 atmospheres absolute (ATA), 100% oxygen session. Subsequently, these samples were tested against untreated control samples using egg yolk sphingomyelin mixed micelles. Subjecting both the controls and treated venom micelle mixtures to [.sup.31]P nuclear magnetic resonance spectroscopy showed identical sphingomyelin breakdown peaks. This experiment demonstrated that sphingomyelinase activity of venom is unaltered by HBO therapy. (14)

Maynor et al (15) presented a 41 rabbit randomized trial in which the effects of both HBO therapy and delay to HBO therapy were examined. Animals were placed into 1 of 5 groups: group I was envenomated and given no HBO therapy; group II was envenomated and received one HBO therapy treatment immediately after venom; group III was envenomated and given 10 treatments of HBO therapy starting immediately; group IV was envenomated and received 10 treatments of HBO therapy starting 2 days after the venom was given; group V was envenomated and exposed to 8.4% [O.sub.2] at pressure, which served as a normoxic pressure control. All the HBO treatments were given at 2.5 ATA and 100% [O.sub.2] for durations of 90 minutes twice daily unless otherwise specified. The researchers looked at both largest lesion diameter and wound blood flow to evaluate the therapeutic options. Using laser Doppler probes, they determined that HBO therapy resulted in no significant change in wound blood flow within a 2-cm radius from the center of the wounds. However, exposure to 2.5 ATA. [O.sub.2] was shown to significantly decrease largest diameter wound measurements by day 10 (p < .0001). (15)

In 1995, an animal study by Hobbs et al (16) compared HBO therapy and dapsone in the treatment of L. reclusa envenomination of piglets. Thirty-two piglets were randomly divided amongst 4 groups with the following study paths: group I received no HBO therapy; group II received HBO therapy at 2.0 ATA for 120 minutes on days 1 to 3; group III received oral dapsone 50 mg on days 1 to 3; and group IV received oral dapsone 50 mg in addition to HBO therapy using the aforementioned criterion for days 1 to 3. To examine the efficacy that the 2 therapies had on necrosis reduction in 21 days, both wound necrosis and indurated area were measured for the first 7 days and then weekly until the day 21 conclusion point of the study. No significant difference between these groups was evident at any time during the study between any of the therapeutic avenues and controls. (16)

The final non-human study compared the efficacy of once or twice daily HBO therapy on spider bite wounds in rabbits. (17) Strain et al (17) randomly separated 24 rabbits into 3 groups: once per day HBO therapy, twice daily HBO therapy, and a control. All treatments were started 3 days after envenomation as the researchers believed this to be the expected delay in seeking medical attention. Each treatment was given at 2.0 ATA [O.sub.2] for 60 minutes X 7 days. Wounds treated with either once or twice daily HBO therapy showed no significant difference in wound healing percentage when compared to control populations. However, histological examination of the wounds revealed that 7 of the 8 rabbits in the twice daily HBO therapy group showed more advanced healing, demonstrated as almost complete re-epithelization, lack of inflammatory cells, absence of both deep necrosis, and scar development. Statistical analysis of these findings was not performed and thus the significance of this work was not established. (17)

Literature Review: Human Data

Maynor et al (18) described the evaluation and management of 14 consecutive patients seen between September 1987 and October 1991, with Auer class 3 or 4 brown recluse bites. The average patient received 7 HBO treatments at 2.0 to 2.5 ATA [O.sub.2] given once or twice daily. Therapy was started an average of 2.6 days after envenomation. The average presenting lesion size was 5.4 cm in greatest diameter. Eight of the patients received a course of antibiotic therapy in addition to their HBO therapy. All of the patients reported complete healing and no loss of function. Surgical repair of the affected area was required in only one of the cases. (18)

Svendsen (19) presented a 6-patient case series, in which all patients received twice daily HBO therapy at 2.0 ATA for 90 minutes for 1 to 3 days. All patents had Auer class 3 or 4 bites and presented 2 to 6 days after the incident. Two patients refused to complete all of the prescribed treatments. Both of these patients experienced second degree skin slough but subsequent healing without incident. One of the patients had a resultant flat brown scar at the bite area. The 4 patients who completed the prescribed course of HBO therapy experienced similar positive outcomes. Two of the patients experienced second degree skin slough and minimal scar formation. One of the remaining 2 patients healed completely without any slough or scar while the other experienced skin slough and healed with an erythematous papule at the bite area. (19)

The largest case series presented to date Kendall et al (20) examined 48 L. reclusa bites treated with HBO therapy. All patients received HBO therapy at 2.0 ATA once or twice daily for an average of 5.6 treatments. During the follow-up only one patient required surgical intervention to achieve complete healing. (20)

Conclusion

No uniform therapeutic approach to the necrotic wound resulting from a brown recluse bite has been established. While a necrotic ulcer is not a common outcome from a bite, when it does occur it requires medical attention and treatment. Physicians are left with animal studies and case series and reports to guide their decision-making when considering HBO therapy. Evidence from such studies has shown HBO therapy fares no better or worse to such treatments as dapsone and controls, thus providing no additional therapeutic benefits. Therefore, before HBO therapy can become more than an experimental therapy for necrotic L. reclusa envenominations more supportive data must be generated. To address this, it would be beneficial to create a central registry of outcomes, thus optimizing data collection. This would offer future researchers a database to further explore the efficacies of various therapies for a L. reclusa bite.

References

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12. Sams HH, Dunnick CA, Smith ML, King LE Jr. Necrotic arachnidism. J Am Acad Dermatol. 2001;44:561-573.

13. Cole HP 3rd, Wesley RE, King LE Jr. Brown recluse spider envenomation of the eyelid: an animal model. Ophthal Plast Reconstr Surg. 1995;11:1531-64.

14. Merchant ML, Hinton JF, Geren CR. Effect of hyperbaric oxygen on sphingomyelinase D activity of brown recluse spider (Loxosceles reclusa) venom as studied by 31P nuclear magnetic resonance spectroscopy. Am J Trop Med Hyg. 1997;56:335-338.

15. Maynor ML, Moon RE, Klitzman B, Fracica PJ, Canada A. Brown recluse spider envenomation: a prospective trial of hyperbaric oxygen therapy. Acad Emerg Med. 1997;4:184-192.

16. Hobbs GD, Anderson AR, Greene TJ, Yealy DM. Comparison of hyperbaric oxygen and dapsone therapy for loxosceles envenomation. Acad Emerg Med. 1996;3:758-761.

17. Strain GM, Snider TG, Tedford BL, Cohn GH. Hyperbaric oxygen effects on brown recluse spider (Loxosceles reclusa) envenomation in rabbits. Toxicon. 1991;29:989-996.

18. Maynor ML, Abt JL, Osborne PD. Brown recluse spider bites: beneficial effects of hyperbaric oxygen. J Hyperbaric Med. 1992:7;89-102.

19. Svendsen FJ. Treatment of clinically diagnosed brown recluse spider bites with hyperbaric oxygen: a clinical observation. J Ark Med Soc. 1986;83:199-204.

20. Kendall TE, Caniglia RJ. Hyperbaric oxygen with treatment of clinically diagnosed brown recluse spider bites: a review of 48 cases. Undersea Biomed Res Suppl. 1989:vol 16. (Abstract)

William D. Tutrone MD, (a) Kimberly M. Green MS, (b) Tom Norris MD, (b) Jeffrey M. Weinberg MD, (a) Dick Clarke (b)

a. Department of Dermatology, St. Luke's-Roosevelt Hospital Center and Beth Israel Medical Center, New York, NY

b. Palmetto Health Richland Hospital in Columbia, SC

Address for Correspondence

Jeffrey M. Weinberg MD

Department of Dermatology

St. Luke's-Roosevelt Hospital Center

1090 Amsterdam Avenue

Suite 11D

New York, NY 10025

Phone: 212-523-5898

Fax: 212-523-5027

e-mail: jmw27@columbia.edu

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