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Differential Permethrin Susceptibility of Head Lice
Sampled in the United States and Borneo

Richard J. Pollack, PhD; Anthony Kiszewski, DSc; Philip Armstrong, DSc; Christine Hahn, MD; Nathan Wolfe, DSc;Hasan Abdul Rahman, MD; Kayla Laserson, DSc; Sam R. Telford III, DSc; Andrew Spielman, ScD Background: Pediculiasis is treated aggressively in the
of the Sabahan children were so exposed.
United States, mainly with permethrin- and pyrethrin-containing pediculicides. Increasingly frequent anec- Main Outcome Measure: Survival of head lice ex-
dotal reports of treatment failure suggest the emergence of insecticidal resistance by these lice.
Results: Permethrin did not affect head lice sampled from
Objective: To confirm or refute the susceptibility of head
chronically infested US children who had previously been lice sampled in the United States to permethrin.
treated for pediculiasis. The slope of the dose-responseregression line for these lice did not differ significantly Design: Survey. Head lice were removed from children
from zero (P = .66). This pediculicide immobilized lice residing where pediculicides are readily available and sampled in Sabah. Mortality correlated closely with per- where such products are essentially unknown. Their sur- methrin concentration (P = .008).
vival was compared following exposure to residues ofgraded doses of permethrin in an in vitro bioassay.
Conclusions: Head lice in the United States are less sus-
ceptible to permethrin than are those in Sabah. The py-
Setting: School children from Massachusetts, Idaho, and
rethroid susceptibility of the general population of head lice in the United States, however, remains poorly de-fined. Accordingly, these relatively safe over-the- Subjects: In the United States, 75 children aged 5 to 8
counter preparations may remain the pediculicides of years. In Sabah, 59 boys aged 6 to 13 years. Virtually all choice for newly recognized louse infestations.
sampled US children had previously been treated withpediculicides containing pyrethrins or permethrin; none Arch Pediatr Adolesc Med. 1999;153:969-973 Editor’s Note: It looks like we’re very far from scratching lice
and the lay press began to suggest that head at about this time. Thus, lice taken from residents of Israel1 in 1994 survived longer choice against head lice (Pediculus capi- exposure to this pediculicide than did lice tis). Preferred treatments came to in- to 1995 and in the Czech Republic3 in 1992 similarly survived such exposure. Each of these studies, however, defined suscepti- bility in terms of mortality of lice con- tive absence of recognized mammalian tox- icity contributed to the acceptability of (Dr Hahn); and the SabahDepartment of Health, Kota these products for application to the heads so many anecdotal reports of treatment fail- crease with duration of survival of the test ARCH PEDIATR ADOLESC MED/ VOL 153, SEP 1999 1999 American Medical Association. All rights reserved.
SUBJECTS AND METHODS
no longer than 1 month. Lice were combed gently from theheads of children, and those that appeared undamaged were POPULATION SAMPLED
transferred by means of fine forceps to the treated paperswithin minutes of sampling. Lice were randomly distrib- Lice were sampled from the heads of US children by nurses uted onto filter disks, ensuring that some were always de- assigned to schools in Massachusetts (in Cambridge and posited onto nontreated disks. The preparations were then Brookline, located near Boston) and in Idaho (in Boise). These maintained in the dark at ambient temperature in a water- lice mainly came from children aged 5 to 8 years who were saturated atmosphere within sealed polyethylene bags. The referred to their school nurse because their teachers sus- activity of these lice was monitored after specified periods pected that lice might be present in their hair. Additional head of continuous contact with these residue-containing pa- lice were sampled from children residing near Boston whose pers. Lice that were mobile were considered to be alive, and parents reported to us directly. The study was approved by those not moving in response to a probe to be dead.
the human subjects committee of the Harvard School of Pub- In Massachusetts, school nurses were supplied with lic Health, Boston, and the appropriate institutional review our disk assay kits and instructed in their use. They were board of each cooperating school district.
asked to place lice in the assay plates and convey the kits In Sabah, head lice were sampled from children pre- to us by courier within 1 hour. In Idaho, lice were sampled screened by nurses employed by the regional department directly by one of us (C.H.) and evaluated after 18 hours.
of health who searched for lice in an elementary school and In Sabah, assays were conducted by several of us (A.S., S.R.T, a residential community located in Kota Kinabalu (the capi- H.A.R., N.W.) and insecticidal effect recorded after 6 hours.
tal of Sabah) and in 3 schools in Telupid. The human sub-jects committee of the Harvard School of Public Health and QUESTIONNAIRE
the appropriate authority in the Sabah Department of Healthapproved this study and authorized the nurses’ services.
After US children were examined for pediculiasis, a ques-tionnaire was sent home with each louse-infested student DISK ASSAY AGAINST PERMETHRIN RESIDUES
to be completed by his or her caregiver. The questionnairesolicited information concerning each student’s prior ex- Our “disk assay” test for evaluating the susceptibility of head perience with louse infestations, that of other members of lice to permethrin residues used a graded array of the household, and any pediculicidal treatments that may impregnated filter paper disks. To prepare these papers, 10 µL of serial semilogarithmic dilutions of permethrin([3-phenoxyphenyl] methyl [±] cis-trans-3-[2,2-di- STATISTICAL METHODS
chloroethenyl]-2,2 dimethyl-cyclopropanecarboxylate; cis-trans isomers ratio: min 35% [±] cis and max 65% [±] trans; We sought to test at least 5 lice to each concentration of Coulston International Corp, Easton, Pa) dissolved in ac- insecticide in each assay, and each test was replicated 3 times.
etone were evaporated onto 1.5-cm disks of filter paper To describe patterns of mortality of lice exposed to graded placed in the bottoms of wells of 24-well flat-bottom cell doses of pediculicide, linear regression coefficients were culture plates (Linbro; Flow Laboratories Inc, McLean, Va).
compared by means of probit analysis.4 Abbott’s formula The plates were then covered, the wells coded, and the plates was used to adjust data relevant to insecticide-associated stored in the dark at ambient temperature (24°C-26°C) for mortality with mortality due to all other factors.4 insect. The frequency of permethrin susceptibility could correlate more closely with pediculicide dose than would not, therefore, directly be described. Therapeutic rec- that of insusceptible lice. We also estimated the inten- ommendations based on either study would further be sity of exposure of head lice in each of these sites to py- burdened by their passive mode of sampling, a proce- dure that might bias them toward lice taken from childrenwho were repeatedly exposed to pediculicide. Although head lice infesting certain residents of Europe and theMiddle East have become insusceptible to permethrin dur- INTENSITY OF INFESTATION
ing the past decade, the therapeutic efficacy of this pe-diculicide in the United States remains uncertain.
Head louse infestations detected passively by school nurses It may be that lice infesting the heads of children in our US study sites were surprisingly infrequent. Al- residing in the United States are more frequently insus- though school nurses in the participating Brookline and ceptible to permethrin than are those sampled where simi- Cambridge school districts sampled lice from infested chil- lar pediculicides may be less readily applied. Thus, we dren, few reports were received throughout this 2-year determined whether lice sampled passively from the heads study, and many of these proved to be spurious. In all, of US residents of Massachusetts and Idaho were as sus- we discovered only 11 louse infestations in Massachu- ceptible to permethrin as lice infesting residents of Sabah setts, comprising a total of 48 lice, and only 64 in Idaho, (Malaysian Borneo). We sampled head lice from chil- comprising 215 lice. An average of 3.5 discernible dren residing in each of these sites and recorded sur- trophic-stage lice were present in each confirmed infes- vival of these lice following exposure to graded doses of tation. Parents of these infested children who re- permethrin residues. We anticipated that the resulting sponded to a questionnaire (56% of sample) all re- mortality pattern of permethrin-susceptible lice would ported that they were aware of and had treated these ARCH PEDIATR ADOLESC MED/ VOL 153, SEP 1999 1999 American Medical Association. All rights reserved.
Figure 1. Effect of increasing permethrin concentration on mortality of head lice taken from the heads of children residing in Sabah, Malaysian Borneo, and the
United States. Left, Data not corrected for nonspecific mortality. Right, Data corrected for nonspecific mortality by means of Abbott’s formula.4
infestations within the previous month, generally with We inquired into the use of pediculicides in Sabah.
a pediculicide containing pyrethrins or permethrin. Pas- Each of the 3 pharmacies that we visited displayed sham- sive sampling detected remarkably few cases, and these poos containing either lindane or malathion, and none infestations were apparent to caregivers.
marketed louse treatments containing pyrethrins or per- Louse-infested children were readily identified in methrin. Two traditional herbalists that we visited said Sabah. The Sabah Department of Health routinely moni- that they marketed no products designed for lice and sug- tored pediculiasis in schoolchildren, and we chose to gested that their customers would perceive no need for sample children from particular schools in Kota Kinabalu such a product. Indeed, we noted no burden associated and Telupid because health records indicated that chil- with head louse infestations in our subjects. Although dren in these schools were particularly subject to this con- no signs of inflammation were apparent, nor were cases dition. We detected nymphal or adult lice in the hair of of louse-borne rickettsiosis or relapsing fever reported 59 (61%) of 97 children who had been selected because to public health officials, these authorities placed suffi- louse eggs were apparent in their hair. An average of 5.1 cient priority on this condition that they monitored preva- such trophic-stage lice were found on each of these 59 lence of head lice in each school in Sabah. Pyrethroids children. Head louse infestations seem relatively com- seem to be rarely applied as remedies against head lice monplace in Sabah and are apparent to school health SUSCEPTIBILITY OF HEAD LICE
HISTORY OF EXPOSURE TO PEDICULICIDES
TO PERMETHRIN RESIDUES
To describe the perceived history of pediculiasis in louse- The susceptibility of head lice removed from children in infested US children, we administered a questionnaire to the United States and Sabah was evaluated by disk as- those who were infested. Of 75 questionnaires that were say. The 215 lice sampled from Idaho were exposed to distributed, 42 (56%) were completed and returned to permethrin in groups of 28 to 55 per treatment and the us. The respondents informed us that these 42 children 48 from Massachusetts in groups of 5 to 11 per treat- had experienced a mean of 2 prior infestations during ment. An exposure interval of 18 hours seemed to be sat- their lifetimes and had missed an average of 3.8 days (SD, isfactory for recording mortality because virtually all non- 6.4 days) of school owing to louse infestations during the treated lice survived in our disk assay devices this long.
preceding year. Of these 42 infested children, the care- By then, about half of the permethrin-exposed lice had givers of 39 stated that at least 1 other family member become immobile, regardless of insecticide concentra- was infested at the time of the survey, and all but 2 in- tion (Figure 1). The slope of the dose-response regres-
dicated that pediculicide had been applied during the sion line for these lice did not differ significantly from 0 course of the current infestation. Nix was the most fre- (P = .66); no differences were apparent between lice quently used pediculicide, comprising more than a third sampled from Massachusetts and Idaho. Although vir- of all treatments, with the pyrethrin-based alternatives tually all nontreated head lice removed from Sabahan chil- RID, A-200 (Hogil Pharmaceutical Corp, Purchase, NY), dren survived for 8 hours thereafter, about half became and Pronto (Del Laboratories, Farmingdale, NY) com- immobile after 10 hours (Figure 2). We chose, there-
prising 17%, 4%, and 4% of treatments, respectively. Home fore, to record insecticide-induced mortality in Sabah af- remedies included vinegar, rubbing alcohol, margarine, ter 8 hours of exposure. A total of 239 lice in cohorts of and laundry detergent. Pediculiasis is perceived as a heavy 12 to 41 were tested. About half of the lice become im- social burden by parents of louse-infested US children mobile after exposure to the 0.03% concentration of per- and is treated aggressively, mainly with the use of pyre- methrin, and virtually all become immobile after expo- sure to the 0.3% residue. Mortality of Sabah-derived head ARCH PEDIATR ADOLESC MED/ VOL 153, SEP 1999 1999 American Medical Association. All rights reserved.
diculicidal interventions. The louse-tolerant attitude of certain traditional societies is exemplified by the Bedouin proverb5 equating a “deserted head [with] an ungener-ous mind.” A societal abhorrence of ectoparasites, on the other hand, drives the intensive and extensive use of pe- diculicides in the United States as well as the various “nonits” policies that prevail in many local schools. Saba- han school children seem similar to some Bedouin in theiracceptance of these ectoparasites, and no pyrethroid- containing pediculicides seem to be marketed in Sabah.
These considerations persuade us that pyrethroid selec-tion pressure on head lice infesting children residing in Massachusetts and in Idaho greatly exceeds that in Sabah, and they are consistent with our finding that head licein the United States are less susceptible to permethrin Figure 2. Survival of head lice harvested in Sabah, Malaysian Borneo, and in
than those infesting children in Sabah. Indeed, head lice Massachusetts confined in disk assay devices containing no pediculicide.
from relatively poor Argentinian children, who were notlikely to have been treated, were more susceptible to pe- lice correlated closely with permethrin concentration diculicides than those sampled from families with greater (P = .008). Whereas permethrin seemed not to affect US head lice in our disk assay, mortality of those from Sabah Insect populations exposed to a pyrethroid insecti- correlated closely with the dose of this pediculicide.
cide tend to lose susceptibility to that general class ofchemicals. This insusceptibility is generally attributed to an amino acid substitution in a protein that induces“knockdown resistance,” thereby desensitizing cholin- Our system of exposing head lice to graded concentra- ergic nerves to the activity of these toxins as well as to tions of permethrin deposited on paper disks provided a that of DDT.7 Such toxins bind to paratype sodium chan- useful measure of insecticide susceptibility. Mortality nel membrane proteins, thereby blocking nervous con- among fully susceptible lice from Sabah following expo- duction or inducing tetanus by delaying signal inactiva- sure to these papers correlates closely with permethrin tion.8 Somewhat narrower spectra of cross-resistance content. A classic linear relationship links the loga- accompany more specific enzymatic detoxification such rithm of the dose with the probit of percent mortality.
as that due to DDT dehydrochlorinase or malathion car- Interpretation of this assay system is somewhat limited boxylesterase. Broader spectra characterize less specific in that tested lice remain in continuous contact with the detoxifying or sequestering enzymes such as hydrolases insecticidal residues throughout the holding period. Al- or cytochrome-dependent P450 oxidase.9 Lindane, the though this practice effectively delivers the greatest in- main organochlorine pediculicidal alternative to the py- secticidal dose to those lice that survive longest, the ef- rethroids, is detoxified in resistant houseflies by conju- fect does not seem to have modified the linearity of the gation to a glutathione transferase.10 Interestingly, the same response of Sabah-derived lice. This practice was dic- enzyme specifically degrades methyl parathion. Lin- tated by our requirement for simplicity, reflecting our need dane resistance has been documented in head lice.11 Syn- for a system of testing that can be executed by generalist ergists generally, but not always, fail to restore pyre- personnel working in remote locations. Assays performed throid effectiveness.12 Although the specificity of in Israel,1 in comparison, relied on just 1 insecticide- permethrin insusceptibility in head lice remains unex- treated surface and recorded mortality in terms of dura- plored, permethrin insusceptibility probably extends to tion of survival. Our disk assay system seems to be valid.
related pyrethroid compounds, even when synergized, Our practice of holding lice sampled in the United States for a longer exposure period than for lice sampled Our demonstration of permethrin insusceptibility in Sabah requires comment. The duration of this pe- in US head lice must be interpreted cautiously, because riod, in both cases, was dictated by the condition ob- our system of passive sampling may have biased our ob- served in lice not exposed to pediculicide. Lice sampled servations toward insusceptible lice. Many of the in- in the United States survive host deprivation longer (18 fested residents sampled were infested repeatedly or hours) than do those in Sabah (8 hours), and those in chronically, and virtually all had previously been treated the United Kingdom2 survive even longer (24 hours). Al- for pediculiasis. Few susceptible lice would remain in the though differing ambient temperatures may account for “problem infestations” that comprise such a sample. This these differences, the effect may also reflect some inher- sampling limitation similarly burdens other recent at- ent biological difference between these populations of lice.
tempts to measure susceptibility of head lice, including In either event, our use of longer postexposure holding those performed in Israel1 and the United Kingdom.2 Al- periods in the United States than in Sabah seems justified.
though the degree of pyrethroid susceptibility of the US The apparently greater prevalence of head louse in- head louse population was not recorded before these pe- festations in Sabah than in the United States may mirror diculicides became available there, the frequency of py- a sharply differing set of attitudes toward this condition rethroid resistance seems to have increased. It is evident in these societies and probably reflects the effect of pe- that lice infesting pediculicide-exposed US children are ARCH PEDIATR ADOLESC MED/ VOL 153, SEP 1999 1999 American Medical Association. All rights reserved.
far less susceptible to permethrin than are lice infesting Accepted for publication February 8, 1999. This study was supported in part by grants from the The pyrethroid susceptibility of the general popula- Evelyn Lilly Lutz Foundation, Beverly, Mass; the Warner- tion of head lice in the United States, however, remains Lambert Co, Morris Plains, NJ; and a gift (to Drs Arm- poorly defined. These relatively safe over-the-counter strong and Laserson) from the National Pediculosis Asso- preparations may remain the pediculicides of choice for newly diagnosed louse infestations on the heads of US resi- Reprints: Richard J. Pollack, PhD, Laboratory of Pub- dents. Repeated applications or the use of more concen- lic Health Entomology, Harvard School of Public Health, trated pyrethroid formulations, however, are ill advised 665 Huntington Ave, Boston, MA 02115 (e-mail: because those US head lice that are insusceptible to per- methrin seem solidly resistant, regardless of dose. The cur-rent susceptibility of these insects to the organochlorineinsecticide lindane and the organophosphate insecticide malathion has not yet been analyzed in the United States.
Prescription preparations containing these insecticides 1. Mumcuoglu KY, Hemingway J, Miller J, et al. Permethrin resistance in the head should be considered as alternative pediculicides if live lice louse Pediculus capitis from Israel. Med Vet Entomol. 1995;9:427-432.
persist after treatments with pyrethroid-based pediculi- 2. Burgess IF, Brown CM, Peock S, Kaufman J. Head lice resistant to pyrethroid insecticides in Britain. BMJ. 1995;311:752-753.
cides. Such potentially toxic materials must be applied con- 3. Rupes V, Moravec J, Chmela J, Ledvinka J, Zelenkova J. A resistance of head servatively, particularly when the diagnosis rests solely on lice (Pediculus capitis) to permethrin in Czech Republic. Centr Eur J Public Health.
the discovery of nits by nonspecialized personnel. We note 4. Finney DJ. Probit Analysis. 3rd ed. Cambridge, England: Cambridge University that desperate parents or caregivers whose children have been excluded from school and generally ostracized ow- 5. Lawrence TF. The Seven Pillars of Wisdom. New York, NY: Country Life Press; ing to perceived pediculiasis may apply inappropriate and 6. Picollo MI, Vassena CV, Casadio AA, Massimo J, Zerba EN. Laboratory studies potentially damaging remedies. Court orders may com- of susceptibility and resistance to insecticides in Pediculus capitis (Anoplura; Pe- pel action, and the problem may become pernicious if di- diculidae). J Med Entomol. 1998;35:814-817.
7. Park Y, Taylor MFJ. A novel mutation L1029H in sodium channel gene hscp as- agnosis rests on the discovery of spurious objects. In- sociated with pyrethroid resistance for Heliothus virescens (Lepidoptera: Noc- deed, of 56 diagnostic samples from children with tuidae). Insect Biochem Molec Biol. 1997;27:9-13.
presumed pediculiasis submitted to us for verification from 8. Pauron D, Barhanin J, Amichot M, Pravalorio M, Berge JB, Ladzunski M. Pyre- throid receptor in the insect Na+ channel: alteration of its properties in pyrethroid- residents scattered across the United States between April resistant flies. Biochemistry. 1989;28:1673-1677.
and August of 1998, 37 (66%) proved to be spurious. Even 9. Oppenoorth, FJ. Biochemistry and genetics of insecticide resistance. In: Kerhut GA, Gilbert LD, eds. Comprehensive Insect Physiology, Biochemistry and Phar- when correctly diagnosed, hatched or dead eggs may re- macology. New York, NY: Pergamon Press; 1985:731-773.
main in the hair long after living lice have been elimi- 10. Syvanen M, Zhou Z, Wharton J, Goldsbury C, Clark A. Heterogeneity of the glu- nated; such findings do not justify pediculicidal treat- tathione transferase genes encoding enzymes responsible for insecticide deg-radation in the housefly. J Molec Evol. 1996;43:236-240.
ment nor exclusion of a child from school. In addition to 11. Kucirka SA, Parish LC, Witkowski JA. The story of lindane resistance and head pediculicidal treatment, the hair of chronically infested chil- lice. Int J Dermatol. 1983;22:551-555.
dren should be groomed manually, perhaps with the aid 12. Mazzari MB, Georghiou GP. Characterization of resistance to organophosphate, carbamate, and pyrethroid insecticides in field populations of Aedes aegypti from Venezuela. J Am Mosq Control Assoc. 1995;11:315-322.
ARCH PEDIATR ADOLESC MED/ VOL 153, SEP 1999 1999 American Medical Association. All rights reserved.

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