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Schistosomiasis prophylaxis in vivo using N,N-Diethyl-m-toluamide (DEET)
TRANSACTIONSOF THE ROYALSOCIETYOF TROPICALMEDICINEAND HYGIENE(2003) 97, 449-450
Schistosomiasis prophylaxis in vivo using N,N-Diethyl-m-toluamide (DEET) F. Jackson, J. F. D o h e r t y and R. H. B e h r e n s WC I E 6A U, UK
Hospital for Tropical Diseases, Mortimer Market Centre, London
Abstract Topical N,N-Diethyl-m-toluamide (DEET) was studied as a schistosomiasis prophylactic in vivo for the use of individuals with limited exposure. Fifteen subjects, on a 3-week expedition to Lake Malawi in September 2001, applied 50% D E E T to their skin after exposure to lake water. No subjects developed evidence of a new infection at 3-month follow-up. Keywords: schistosomiasis, Schisrosoma haematobium, prophylaxis, cercaricide, DEET, travel, Lake Malawi Introduction The life cycle of the trematode Schistosoma haematobium involves humans as the definitive host of adult worms, and freshwater snails as the intermediate host. H u m a n infection is acquired by direct penetration of intact skin by cercariae released from infected freshwater snails. Adult flukes mature around 3 months after infection and produce ova that migrate from the venous plexus to the lumen of the bladder and rectum, and thence to the environment. Infection may cause morbidity both locally, in the urinary tract and rectum, and distally, from ova embolizing to the central nervous system, liver, or lungs. Schistosomiasis is one of the most prevalent parasitic infections in the world. Disease control has significant consequences for endemic countries and disease morbidity has great impact on indigenous populations in infected areas (Chitsulo et al., 2000). Many methods of disease control have been tried over the last century; the use of molluscicides, cercarial predators, drug chemoprophylaxis and, also, personal methods such as protective clothing, sometimes impregnated with chemicals, ointments, repellents, cercaricides, barrier creams and plant extracts (Pellegrino, 1967). We studied the use of topical N,N-Diethyl-m-toluamide (DEET) in vivo as a preventative measure postexposure. The technique is aimed at travellers and those with limited water exposure. In vitro studies using animal models describe the cercariae remaining in the skin for up to 72 h after penetration (Miller & Wilson, 1978). Also, topical DEET, present in most commercial insect repellent preparations, was found to be 99% effective in preventing cercarial entry through mouse tail skin (Salafsky et al., 1998). Therefore, if topical D E E T is applied within 72 h of exposure infection may be prevented. Methods A group of 15 subjects on an expedition visiting Cape Maclear and travelling to Likoma Island, along the eastern shore of Lake Malawi, provided an opportunity to study the prophylactic effect of D E E T by agreeing to participate in this study. The 3-week expedition in September 2001 set out to record various fauna of the lake including Bulinus nyassanus and B. globosus, the intermediate snail hosts for the schistosome. The participants collected specimens by either wading, kayaking along the shore, or Scuba diving in full-length wetsuits off a dive boat. Samples were frequently collected from marsh areas, a typical habitat for the Bulinus snail. Subjects recorded their daily exposure to lake water in a diary revealing an average water contact time of 47 h. They also recorded their D E E T application for a record of compliance (Figure). The participants applied a 50% D E E T (Nomad Travellers Store, London, UK) preparation over the Address for correspondence: Dr Ron Behrens, Hospital for Tropical Diseases, Mortimer Market Centre, London WC1E 6AU, UK; phone +44 (0)20 7388 8989, fax +44 (0)20 7383 4817, e-mail [email protected]
whole body, excluding scalp and genitalia, at about 17:00 after their evening wash and just before dusk. To be effective, sufficient D E E T needed to diffuse across the skin to produce a cercaricidal effect. A 50% D E E T solution in ethyl-alcohol was used, which has been shown to reach adequate dermal concentrations (Stinecipher & Shah, 1997). At the same time, subjects were required to follow the standard antimalarial personal protection advice given by the Hospital for Tropical Diseases Travel Clinic, London, UK. This entailed applying a second preparation, Ultrathon ® (Travel Medicine Inc., Northampton, M_A, USA), to all skin exposed to biting mosquitoes (usually just the hands, face, and ankles). Uhrathon ® is " an extended duration, ' microencapsulated preparation containing 31.58% DEET, 1.75% other isomers, and 66.67% inert ingredients (lotion).
Results and D i s c u s s i o n There is historical evidence of a significant risk of schistosomal infection following exposure in the resort areas on the western shore of Lake Malawi, particularly at Cape Maclear (Cetron et aL, 1996; Whitty et al., 2000) where our subjects spent 2 d. A study of 21 schoolchildren who swam in the same area of Cape Maclear during a 4-week expedition in July 2001 revealed a 90% attack rate of schistosomiasis (N. J. Beeching, personal communication). Host snails were identified at 10 of the 20 sites sampled along the 260 km of coast visited by the expedition. Specimens from 3 of these sites were found to be infected with cercariae. It is probable that the group had a significant risk of exposure to schistosomal infection during their aquatic exposure detailed in the Figure. Fourteen of the 15 subjects were followed-up 3 months after return to the U K and examined for evidence of parasitic infections and schistosomiasis. One was lost to followup (no. 13). Concentrated urine microscopy, eosinophilia, and schistosomal egg antigen measured by the enzyme-linked immunosorbent assay (ELISA), a very sensitive and specific serological assay, revealed evidence of an infection in 2 subjects (no. 14 and no. 15). In both individuals blood samples collected before departure were positive by ELISA at the same titres as found at the 3-month examination. They reported a previous exposure during a diving expedition to Cape Maclear. Two subjects reported a history of swimmer's itch during the expedition (no. 2 and no. 9), a symptom of cercarial invasion with fork-tailed/fucocercous schistosome cercariae, the symptoms typically developing within 48 h of exposure. According to the subjects' diaries, D E E T was regularly applied (average of 87% of all evenings required) and no major side effects or problems were reported. D E E T is a safe and effective mosquito repellent widely used for the prevention of insect bites and malaria. However, it has an unappealing odour and poor cosmetic properties, which may influence compliance when in wider general use. Newer topical formulations such as Ultrathon ® are likely to improve compliance in the future.
F. JACKSON ETAL.
450
o .~ e~
8 8
1
95%
2
90%
3
90%
4
83%
5
95%
6
71%
7
48%
8
95%
9
86%
10
90%
11
95%
)
3 B
12 100% 13
86%
14
90%
15
90%
Ave 87% 0
10
20
30 Water contact time (h) • Diving
[] Swim
40
50
60
[] Kayak
Figure. Water contact by different activities and the percentage compliance to daily DEET application for each study participant during a 3-week expedition to Cape Maclear, Lake Malawi, September 2001. W e believe all o u r subjects were likely to have b e e n exposed to schistosomiasis. T h e historical evidence of the h i g h t r a n s m i s s i o n t h a t occurs in Lake M a l a w i has b e e n r e p o r t e d in the literature ( C e t r o n et al., 1996; W h i t t y et al., 2000). H o s t snails, some of w h i c h carried infective cercariae, were identified at the sites w h e r e subjects h a d w a t e r exposure a n d 2 subjects m a n i f e s t e d s w i m m e r ' s itch. W e f o u n d n o n e w infections in the g r o u p following t h e study period. T h e w i d e s p r e a d d e r m a l application of D E E T 8 - 1 2 h following exposure to infection m a y p r e v e n t schistosomiasis in travellers a n d individuals with limited exposure. A l t h o u g h D E E T is inexpensive (approx. £7/L of 5 0 % in bulk) the logistics of daily application of D E E T w o u l d p r o b a b l y p r o h i b i t its use for p o p u l a t i o n s in e n d e m i c regions. A f u r t h e r s t u d y is p l a n n e d to c o n f i r m the effect.
Acknowledgements We would like to thank The Hospital for Tropical Diseases Travel Clinic, London, U K for donating the Ultrathon * and Nomad Travellers Store, London, U K for donating the 50% DEET. We also thank the Scientific Exploration Society and the expedition members for their assistance and participation in this study. References Cetron, M., Chitsulo, L., Sullivan, J., Pilcher, J., Wilson, M.,
Noh, J., Tsang, V., Hightower, A. & Addiss, D. (1996). Schistosomiasis in Lake Malawi. Lancet, 348, 1274-1278. Chitsulo, L., Engels, D., Montresor, A. & Savioli, L. (2000). The global status of schistosomiasis and its control. Acta Tropica, 77, 41-51. Miller, P. & Wilson, R. A. (1978). Migration ofLhe schistosomula of Schistosoma mansoni from skin to lungs. Parasitology, 77, 281-302. Pellegrino, J. (1967). Protection against human schistosome cercariae. ExperimentalParasitology, 21, 112-131. Salafsky, B., Ramaswamy, K., He, Y.-X., Anderson, G. L., Nowicki, D. K. & Shibuya, T. (1998). Evaluation of N,Ndiethyl-m-toluamide (DEET) as a topical agent for preventing skin penetration by cercariae of Schistosoma mansoni. American Journal of Tropical Medicine and Hygiene, 58, 828-834. Stinecipher, J. & Shah, J. (1997). Percutaneous permeation of N,N-diethyl-m-toluamide (DEET) from commercial mosquito repellents and the effect of solvent. Journal of Toxicology and EnvironmentalHealth, 52, 119-135. Whitty, C. J. M., Mabey, D. C. W., Armstrong, M., Wright, S. G. & Chiodini., P. L. (2000). Presentation and outcome of 1107 cases of schistosomiasis from Africa diagnosed in a non-endemic country. Transactions of the Royal Society of TropicalMedicine and Hygiene, 94, 531-534.
Received 18 November 2002; revised 20 January 2003; acceptedfor publication 31 January 2003
Schistosomiasis prophylaxis in vivo using N,N-Diethyl-m-toluamide (DEET) F. Jackson, J. F. D o h e r t y and R. H. B e h r e n s WC I E 6A U, UK
Hospital for Tropical Diseases, Mortimer Market Centre, London
Abstract Topical N,N-Diethyl-m-toluamide (DEET) was studied as a schistosomiasis prophylactic in vivo for the use of individuals with limited exposure. Fifteen subjects, on a 3-week expedition to Lake Malawi in September 2001, applied 50% D E E T to their skin after exposure to lake water. No subjects developed evidence of a new infection at 3-month follow-up. Keywords: schistosomiasis, Schisrosoma haematobium, prophylaxis, cercaricide, DEET, travel, Lake Malawi Introduction The life cycle of the trematode Schistosoma haematobium involves humans as the definitive host of adult worms, and freshwater snails as the intermediate host. H u m a n infection is acquired by direct penetration of intact skin by cercariae released from infected freshwater snails. Adult flukes mature around 3 months after infection and produce ova that migrate from the venous plexus to the lumen of the bladder and rectum, and thence to the environment. Infection may cause morbidity both locally, in the urinary tract and rectum, and distally, from ova embolizing to the central nervous system, liver, or lungs. Schistosomiasis is one of the most prevalent parasitic infections in the world. Disease control has significant consequences for endemic countries and disease morbidity has great impact on indigenous populations in infected areas (Chitsulo et al., 2000). Many methods of disease control have been tried over the last century; the use of molluscicides, cercarial predators, drug chemoprophylaxis and, also, personal methods such as protective clothing, sometimes impregnated with chemicals, ointments, repellents, cercaricides, barrier creams and plant extracts (Pellegrino, 1967). We studied the use of topical N,N-Diethyl-m-toluamide (DEET) in vivo as a preventative measure postexposure. The technique is aimed at travellers and those with limited water exposure. In vitro studies using animal models describe the cercariae remaining in the skin for up to 72 h after penetration (Miller & Wilson, 1978). Also, topical DEET, present in most commercial insect repellent preparations, was found to be 99% effective in preventing cercarial entry through mouse tail skin (Salafsky et al., 1998). Therefore, if topical D E E T is applied within 72 h of exposure infection may be prevented. Methods A group of 15 subjects on an expedition visiting Cape Maclear and travelling to Likoma Island, along the eastern shore of Lake Malawi, provided an opportunity to study the prophylactic effect of D E E T by agreeing to participate in this study. The 3-week expedition in September 2001 set out to record various fauna of the lake including Bulinus nyassanus and B. globosus, the intermediate snail hosts for the schistosome. The participants collected specimens by either wading, kayaking along the shore, or Scuba diving in full-length wetsuits off a dive boat. Samples were frequently collected from marsh areas, a typical habitat for the Bulinus snail. Subjects recorded their daily exposure to lake water in a diary revealing an average water contact time of 47 h. They also recorded their D E E T application for a record of compliance (Figure). The participants applied a 50% D E E T (Nomad Travellers Store, London, UK) preparation over the Address for correspondence: Dr Ron Behrens, Hospital for Tropical Diseases, Mortimer Market Centre, London WC1E 6AU, UK; phone +44 (0)20 7388 8989, fax +44 (0)20 7383 4817, e-mail [email protected]
whole body, excluding scalp and genitalia, at about 17:00 after their evening wash and just before dusk. To be effective, sufficient D E E T needed to diffuse across the skin to produce a cercaricidal effect. A 50% D E E T solution in ethyl-alcohol was used, which has been shown to reach adequate dermal concentrations (Stinecipher & Shah, 1997). At the same time, subjects were required to follow the standard antimalarial personal protection advice given by the Hospital for Tropical Diseases Travel Clinic, London, UK. This entailed applying a second preparation, Ultrathon ® (Travel Medicine Inc., Northampton, M_A, USA), to all skin exposed to biting mosquitoes (usually just the hands, face, and ankles). Uhrathon ® is " an extended duration, ' microencapsulated preparation containing 31.58% DEET, 1.75% other isomers, and 66.67% inert ingredients (lotion).
Results and D i s c u s s i o n There is historical evidence of a significant risk of schistosomal infection following exposure in the resort areas on the western shore of Lake Malawi, particularly at Cape Maclear (Cetron et aL, 1996; Whitty et al., 2000) where our subjects spent 2 d. A study of 21 schoolchildren who swam in the same area of Cape Maclear during a 4-week expedition in July 2001 revealed a 90% attack rate of schistosomiasis (N. J. Beeching, personal communication). Host snails were identified at 10 of the 20 sites sampled along the 260 km of coast visited by the expedition. Specimens from 3 of these sites were found to be infected with cercariae. It is probable that the group had a significant risk of exposure to schistosomal infection during their aquatic exposure detailed in the Figure. Fourteen of the 15 subjects were followed-up 3 months after return to the U K and examined for evidence of parasitic infections and schistosomiasis. One was lost to followup (no. 13). Concentrated urine microscopy, eosinophilia, and schistosomal egg antigen measured by the enzyme-linked immunosorbent assay (ELISA), a very sensitive and specific serological assay, revealed evidence of an infection in 2 subjects (no. 14 and no. 15). In both individuals blood samples collected before departure were positive by ELISA at the same titres as found at the 3-month examination. They reported a previous exposure during a diving expedition to Cape Maclear. Two subjects reported a history of swimmer's itch during the expedition (no. 2 and no. 9), a symptom of cercarial invasion with fork-tailed/fucocercous schistosome cercariae, the symptoms typically developing within 48 h of exposure. According to the subjects' diaries, D E E T was regularly applied (average of 87% of all evenings required) and no major side effects or problems were reported. D E E T is a safe and effective mosquito repellent widely used for the prevention of insect bites and malaria. However, it has an unappealing odour and poor cosmetic properties, which may influence compliance when in wider general use. Newer topical formulations such as Ultrathon ® are likely to improve compliance in the future.
F. JACKSON ETAL.
450
o .~ e~
8 8
1
95%
2
90%
3
90%
4
83%
5
95%
6
71%
7
48%
8
95%
9
86%
10
90%
11
95%
)
3 B
12 100% 13
86%
14
90%
15
90%
Ave 87% 0
10
20
30 Water contact time (h) • Diving
[] Swim
40
50
60
[] Kayak
Figure. Water contact by different activities and the percentage compliance to daily DEET application for each study participant during a 3-week expedition to Cape Maclear, Lake Malawi, September 2001. W e believe all o u r subjects were likely to have b e e n exposed to schistosomiasis. T h e historical evidence of the h i g h t r a n s m i s s i o n t h a t occurs in Lake M a l a w i has b e e n r e p o r t e d in the literature ( C e t r o n et al., 1996; W h i t t y et al., 2000). H o s t snails, some of w h i c h carried infective cercariae, were identified at the sites w h e r e subjects h a d w a t e r exposure a n d 2 subjects m a n i f e s t e d s w i m m e r ' s itch. W e f o u n d n o n e w infections in the g r o u p following t h e study period. T h e w i d e s p r e a d d e r m a l application of D E E T 8 - 1 2 h following exposure to infection m a y p r e v e n t schistosomiasis in travellers a n d individuals with limited exposure. A l t h o u g h D E E T is inexpensive (approx. £7/L of 5 0 % in bulk) the logistics of daily application of D E E T w o u l d p r o b a b l y p r o h i b i t its use for p o p u l a t i o n s in e n d e m i c regions. A f u r t h e r s t u d y is p l a n n e d to c o n f i r m the effect.
Acknowledgements We would like to thank The Hospital for Tropical Diseases Travel Clinic, London, U K for donating the Ultrathon * and Nomad Travellers Store, London, U K for donating the 50% DEET. We also thank the Scientific Exploration Society and the expedition members for their assistance and participation in this study. References Cetron, M., Chitsulo, L., Sullivan, J., Pilcher, J., Wilson, M.,
Noh, J., Tsang, V., Hightower, A. & Addiss, D. (1996). Schistosomiasis in Lake Malawi. Lancet, 348, 1274-1278. Chitsulo, L., Engels, D., Montresor, A. & Savioli, L. (2000). The global status of schistosomiasis and its control. Acta Tropica, 77, 41-51. Miller, P. & Wilson, R. A. (1978). Migration ofLhe schistosomula of Schistosoma mansoni from skin to lungs. Parasitology, 77, 281-302. Pellegrino, J. (1967). Protection against human schistosome cercariae. ExperimentalParasitology, 21, 112-131. Salafsky, B., Ramaswamy, K., He, Y.-X., Anderson, G. L., Nowicki, D. K. & Shibuya, T. (1998). Evaluation of N,Ndiethyl-m-toluamide (DEET) as a topical agent for preventing skin penetration by cercariae of Schistosoma mansoni. American Journal of Tropical Medicine and Hygiene, 58, 828-834. Stinecipher, J. & Shah, J. (1997). Percutaneous permeation of N,N-diethyl-m-toluamide (DEET) from commercial mosquito repellents and the effect of solvent. Journal of Toxicology and EnvironmentalHealth, 52, 119-135. Whitty, C. J. M., Mabey, D. C. W., Armstrong, M., Wright, S. G. & Chiodini., P. L. (2000). Presentation and outcome of 1107 cases of schistosomiasis from Africa diagnosed in a non-endemic country. Transactions of the Royal Society of TropicalMedicine and Hygiene, 94, 531-534.
Received 18 November 2002; revised 20 January 2003; acceptedfor publication 31 January 2003