Walton 2

Scabies: New Future for a Neglected Disease
Shelley F. Walton1,*, Deborah C. Holt2, Bart J. Currie1,3 and

David J. Kemp2
1
Menzies School of Health Research, Australia and Charles Darwin
University, Darwin, NT 0811, Australia
2
The Queensland Institute of Medical Research, Australia and Australian
Centre for International and Tropical Health and Nutrition, The University
of Queensland, Brisbane, QLD 4029, Australia
3
Northern Territory Clinical School, Flinders University, Royal Darwin
Hospital, Darwin, NT 0810, Australia
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
2. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
3. Biology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
3.1. Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
3.2. Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
3.3. Lifecycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
3.4. Transfer of Mites . . . . . . . . . . . . . . . . . . . . . . . . . . 315
3.5. Survival and Infestivity . . . . . . . . . . . . . . . . . . . . . . . 316
4. Animal Scabies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
4.1. Zoonoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
5. Taxonomy and Population Structure. . . . . . . . . . . . . . . . . . . 320
5.1. Determination of a Single Species . . . . . . . . . . . . . . . . 320
5.2. Population Genetics of Host Specificity . . . . . . . . . . . . . 321
5.3. Population Genetics of S. scabiei . . . . . . . . . . . . . . . . . 322
6. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
6.1. Cyclical Pattern of Infection . . . . . . . . . . . . . . . . . . . . 325
6.2. Sex and Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
6.3. Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
*Author for correspondence. E-mail: Shelley.Walton@menzies.edu.au
ADVANCES IN PARASITOLOGY VOL 57 Copyright ß 2004 Elsevier Inc.

ISSN: 0065-308X All rights of reproduction in any form reserved
DOI: 10.1016/S0065-308X(04)57005-7
310 S.F. WALTON ET AL.
6.4. Poverty, Overcrowding and Poor Hygiene . . . . . . . . . . . . 328

6.5. Significance in Indigenous Communities . . . . . . . . . . . . 329
7. Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
7.1. Immunodiagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . 332
7.2. Reinfestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
7.3. Secondary Infection . . . . . . . . . . . . . . . . . . . . . . . . . 334
7.4. Crusted (Norwegian) Scabies . . . . . . . . . . . . . . . . . . . 334
7.5. Genetic Composition of S. scabiei Populations in
Sequential Crusted Scabies . . . . . . . . . . . . . . . . . . . . 336
8. Host Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . 338
8.1. Scabies Specific Immune Response . . . . . . . . . . . . . . . 339
8.2. Similarities Between Scabies Mite Infections and Allergy
to House Dust Mite Antigens . . . . . . . . . . . . . . . . . . . 341
9. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
10. Chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
10.1. Drug Resistance in Scabies Mites . . . . . . . . . . . . . . . . 345
10.2. Permethrin Resistance . . . . . . . . . . . . . . . . . . . . . . . 346
10.3. Ivermectin Resistance . . . . . . . . . . . . . . . . . . . . . . . 348
10.4. Consequences of Drug Resistance . . . . . . . . . . . . . . . 349
11. Novel Acaricides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
12. Recombinant DNA Technology Applications in Scabies
Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
12.1. Identification of Clones by Screening Expression
Libraries With Antibodies . . . . . . . . . . . . . . . . . . . . . 351
12.2. S. scabiei Gene Discovery . . . . . . . . . . . . . . . . . . . . 354
12.3. The Scabies Mite Inactivated Protease Paralogues
(SMIPPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
13. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
ABSTRACT
Scabies is a disease of global proportions in both human and animal

populations, resulting from infestation of the skin with the ‘‘itch’’
mite Sarcoptes scabiei. Despite the availability of effective chemo-
therapy the intensely itching lesions engender significant morbidity
primarily due to secondary sepsis and post-infective complications.
Some patients experience an extreme form of the disease, crusted
scabies, in which many hundreds of mites may infest the skin causing
severe crusting and hyperkeratosis. Overcrowded living conditions
SCABIES: NEW FUTURE FOR A NEGLECTED DISEASE 311
and poverty have been identified as significant confounding factors

in transmission of the mite in humans. Control is hindered by diffi-
culties with diagnosis, the cost of treatment, evidence for emerging
resistance and lack of effective vaccines. Historically research on
scabies has been extremely limited because of the difficulty in
obtaining sufficient quantities of the organism. Recent molecular
approaches have enabled considerable advances in the study of
population genetics and transmission dynamics of S. scabiei.
However, the most exciting and promising development is the
potential exploitation of newly available data from S. scabiei cDNA
libraries and EST projects. Ultimately this knowledge may aid early
identification of disease, novel forms of chemotherapy, vaccine
development and new treatment possibilities for this important but
neglected parasite.
1. INTRODUCTION
The burrowing ectoparasitic mite Sarcoptes scabiei is regarded as

an important public health problem world-wide, especially for
indigenous populations and immunocompromised individuals. It is
also a significant veterinary disease. The disease scabies manifests as
an allergic type skin reaction resulting in visible hypersensitive lesions
and pruritus, although symptoms vary considerably in intensity and
resultant morbidity (Burgess, 1994). Despite the availability of
effective treatments estimations indicate that worldwide up to 300
million people are affected at any one time (Taplin et al., 1990).
Infants, the elderly, patients with HIV/AIDS and other immuno-
compromised conditions are predisposed to infestations (Chosidow,
2000) that can be more severe (Commens, 1994). In many developing
countries it is a major problem, with transmission commonly
associated with overcrowding and poverty (Green, 1989). In remote
Aboriginal communities in northern and central Australia scabies is
endemic in both human and dog populations, and it is believed that
repeated infestations and recurrent secondary skin sepsis may
contribute to the extreme levels of renal disease and rheumatic heart

disease observed in these communities (Currie et al., 1994; Hoy,
1996). A wide range of host species are affected and S. scabiei is
considered a ubiquitous parasite among some economically impor-
tant livestock and companion animals with, for example, approxi-
mately 50 to 95% of pig herds worldwide infested with S. scabiei
mites (Cargill et al., 1997). Additionally Sarcoptes is responsible for
epizootic disease worldwide in wild populations of canids, cats,
ungulates, boars, wombats, koalas, great apes and bovids (reviewed
in Pence and Ueckermann, 2002). Although scabies has been known
to mankind since ancient times and history has recorded numerous
epidemics and local outbreaks, the population dynamics and
immunobiology of this parasite are still not well understood.
Only now, long after recombinant DNA technology brought much
of biology into the molecular era in the 1970s, has molecular research
on scabies become possible. Severe technical limitations with regard
to availability of sufficient numbers of scabies mites, which preven-
ted molecular studies on scabies, have been overcome by several
approaches. Libraries of cDNA clones are now available upon
request. A public sequence database is currently emerging and this
will expand dramatically over the next few years. This review will
briefly outline current knowledge on the biology and host–parasite
interactions of the scabies mite, summarise existing chemotherapies
and emerging resistance, and finally discuss the more recent
molecular advances that have enabled scabies mite gene discovery
programs. These have significantly facilitated the genetic characteri-
sation of S. scabiei and we assess the enormous potential for mining
this information to provide meaningful insights into the prevention,
diagnosis, treatment and control of scabies.
2. HISTORY
Scabies is believed to be the first disease of man with a known cause

when the mite was described and illustrated by the Italians Bonomo
and Cestoni in 1689 as the causal agent of scabies (Montesu and
Cottoni, 1991). This represented the first mention of the parasitic

theory of infectious diseases and the beginning of a new era in
medicine. However scabies was first observed in the ancient world
by Aristotle and Cicero, having been described as ‘‘lice in the flesh’’,
and it has been a recognised disease for at least 3000 years with
reference to scabies found in the Old Testament of the Bible and the
work of Shakespeare (Alexander, 1984).
3. BIOLOGY
3.1. Classification
Sarcoptes scabiei is a member of the class Arachnida, subclass

Acari ( ¼ Acarina), order Astigmata and family Sarcoptidae. The
Astigmata are slow moving mites with thinly sclerotised integument
and no detectable spiracles or tracheal system. The sarcoptid mites
are obligate parasites burrowing into the skin of mammals
(Sarcoptidae), birds (Knemidokoptidae) or bats (Teinocoptidae).
The family Sarcoptidae includes S. scabiei, Notoedres cati (cat mite),
and Trixacarus caviae (guinea pig mite) (Kettle, 1984).
3.2. Morphology
Sarcoptes scabiei is a creamy white colour with brown sclerotised legs

and mouthparts (Figure 1). The idiosoma is oval, dorsally convex
and ventrally flattened. The adult female measures 300–500 mm long
by 230–340 mm wide and the male 213–285 mm long by 160–210 mm
wide. The integument has transversely ridged striations that are
broken on the dorsal surface by a central patch of triangular scales
which are of taxonomic significance (Fain, 1978). Also on the dorsal
surface are six or seven pairs of spine like projections arranged
symmetrically on both sides of the posterior midline and three pairs
of lateral spines about midway along the body.
Figure 1 Ventral view of Sarcoptes scabiei var. hominis. Male adult.

Original magnification 200.
The male and female mites both exhibit stalked pulvilli (sometimes
referred to as suckers) on the pretarsi of legs I and II enabling the
mite to grip the substrate (Figure 2). The tarsus of legs III and IV in
the female end in long setae, whereas the male has stalked pulvilli on
leg IV. Additionally the tarsi of both sexes bear two spur like claws,
however in the male there is only one spur like claw on leg IV.
The larvae differ from the nymphs and adults in only having six
legs. The nymphs are similar to the female but smaller and lack an
oviporus.
3.3. Lifecycle
The lifecycle of S. scabiei includes three active developmental

instars. The larvae emerge 50–53 h after the eggs are laid. After three
Figure 2 Scanning electron micrograph (JEOLJSM-T330) of upper leg

of S. scabiei var. hominis. Plate supplied by Ms. Ellie Haywood, Charles
Darwin University, Darwin, Australia.
to four days the larvae moult into protonymphs which develop

over two to three days. The protonymphs moult into tritonymphs
from which an adult male or female emerges after a total of
10–13 days. Mellanby (1944) stated however that the earliest new
adult female of the second generation was observed 21 days after
experimental infection with the majority appearing after a month.
This suggests that many of the developmental instars do not reach
maturity.
3.4. Transfer of Mites
Mellanby (1944) believed the stage responsible for transmission was

the young, newly fertilised adult female which wandered around on
the skin surface before burrowing. This is in contrast to Elgart (1990)
who maintained the young female is fertilised inside the burrow, and
continues to burrow after fertilisation is completed, rarely returning
to the skin surface. During active infestation immature mites

considerably outnumber the parent and these are observed to wander
frequently across the surface of the skin. They would therefore
have greater opportunity of establishing themselves on a new host.
Mellanby (1944) was unable to demonstrate an infestation using
immature mites only. His studies on transmission however
determined that scabies cases with a high parasite rate of over 100
adult female mites are more likely to spread the disease than those
with a few parasites. As the number of mites in developmental instars
well outnumbers the total adult female population this suggests that
the immature life cycle stage may be capable of transmitting the
disease. According to Alexander (1984) other researchers have
managed to demonstrate that transmission is possible with immature
mites.
3.5. Survival and Infestivity
Detailed studies by Arlian et al. (1984a) have demonstrated that

human and canine scabies mites are capable of surviving for 24–36 h
at room conditions (21 C and 40–80% relative humidity) and still
remain infestive and capable of penetration. Female mites survive
longer than males in comparable conditions. Low temperatures (10–
15 C) and high relative humidity favoured survival, with var. canis
mites surviving up to 19 days at 10 C and 97% relative humidity.
However, the time required for complete penetration of the epidermis
increased as a function of time off the host, attesting to the mites’
weakened condition. It should be noted that at temperatures below
20 C S. scabiei are virtually immobile whereas at 35 C activity is
greatly increased.
According to Arlian and Vyszenski-Moher (1988) all life stages
of var. canis mites frequently leave their burrow, move across the
skin surface and may be dislodged. Live mites have been recovered
from the homes of scabietic patients (Arlian et al., 1988a). Host-
seeking experiments indicate that canine mites dislodged from a host
respond to host odour and thermal stimuli by actively seeking their
source (Arlian et al., 1984c, 1988b). These factors coupled with the
survival and penetrative abilities of S. scabiei suggest that fomites
could be a potential source of infection, Mellanby (1944) however
found fomites to be a poor source of transmission. From 272
attempts to infect volunteers, who climbed into warm beds just
vacated by heavily infected patients, only four new cases resulted.
Nevertheless, in a region of high mite density, such as a patient or dog
with severe (crusted) scabies, coupled with high humidity and warm
ambient temperature (e.g. 30 C) fomites should be considered a
significant source of transmission. At 30 C and 75% relative
humidity the LT100 for female mites was 55–67 h.
4. ANIMAL SCABIES
Worldwide S. scabiei causes mange in many companion and livestock

animals and is responsible for epizootic disease in wild populations of
canids, cats, ungulates, boars, wombats, koalas, great apes and
bovids (reviewed in Pence and Ueckermann, 2002). Sarcoptic mange
is considered a major cause of mortality amongst natural red foxes
(Vulpes vulpes) (Morner, 1992; Bates, 2003), coyote populations
(Pence et al., 1983) and the common wombat (Vombatus ursinus)
(Seddon and Albiston, 1968; Martin et al., 1998). In addition
sarcoptic mange has been recorded in the Australian dingo (Canis
familiaris dingo), the koala (Phascolarctos cinereus) and the agile
wallaby (Macropus agilis) (Skerratt et al., 1998 and Walton, S.F.,
unpublished observations).
The scabies mite is considered a ubiquitous parasite among
some economically important livestock with reports documented
from numerous countries including Australia, Belgium, Denmark,
Germany, Greece, Netherlands, Jordan and the United States
of America (Davies et al., 1996; Al-Rawashdeh et al., 2000;
Fthenakis et al., 2001; Smits and Merks, 2001; Jensen et al., 2002;
Mercier et al., 2002; Rehbein et al., 2003). Current estimates indicate
that between 50 and 95% of pig herds worldwide are infested
with S. scabiei (Cargill et al., 1997). Veterinary concerns include

difficulties in diagnosis and control and the economic effect
of mange on feed conversion efficiency. In production herds the
intense pruritus associated with the disease interferes with milk
production, weight gain and leather quality and can inflict serious
economic losses on primary industries (Davis and Moon, 1990;
Elbers et al., 2000; Rehbein et al., 2003). Furthermore significant
costs are associated with the continuous use of acaricides in
infested herds.
The clinical signs for animals are slightly raised red papules seen on
the sparsely haired regions of the body. Intense pruritus is evident
with consequential scratching, excoriation, and skin inflammation.
If left untreated loss of hair, scaling, and crusting of the skin with
dried exudate of serum is observed. Secondary pyoderma may occur.
Distribution of lesions varies with species but common sites are
muzzle, ears, and face (cats, dogs, sheep, goats, pigs), legs (dogs),
inner thighs (cattle), neck (horses, cattle), trunk (pigs), tail (dogs,
cattle) (Stevenson and Hughes, 1988). Transmission of mites among
a group of animals is most likely through direct contact or via
contaminated bedding.
Chronically and severely affected dogs may become anorexic,
depressed and develop weight loss and secondary bacterial pyoderma
(Scott and Horn, 1987). According to Scott and Horn (1987)
canine scabies has no apparent age, breed, or sex predilections.
However in Aboriginal communities in northern Australia puppies
and old or debilitated dogs appear more at risk (Walton, S.F.,
unpublished observation). Orkin (1975) also cites canine infestations
occurring more frequently in puppies, especially those under-
nourished and heavily infested with other parasites. The disease is
very contagious for other dogs and often several members of a litter
are infested. Often multiple skin scrapings and microscopic
examination are necessary to identify mites, and frequently no
mites can be demonstrated. Prevalence of scabies in domestic animals
in first world communities has declined in recent years probably as a
result of the routine application of insecticides for tick and flea
control.
4.1. Zoonoses
Many animal scabies mite infestations have been recorded as

zoonotic but differ clinically in the lack of burrows, shorter incu-
bation period, distinct distribution pattern and temporary nature.
Natural transmission of animal scabies between host species has been
reported and described as responsible for outbreaks in human
populations (MacDonald, 1922; Beck, 1965; Norins, 1969; Elgart and
Higdon, 1972; Charlesworth and Johnson, 1974; Chakrabarti et al.,
1981; Estes et al., 1983; Schwartzman, 1983).
It has been reported that after 24 h of exposure to an affected dog,
household members may develop pruritic papular or vesicular
erythemic lesions, primarily on the trunk, forearms and thighs
(Tannenbaum, 1965) but not the interdigital finger spaces which is
commonly seen with human scabies. The described difference in the
temporal sequence of the usual human and such canine scabies
reactions can most simply be understood if the particular human
hosts were already sensitised. It may be that the infestations with dog
scabies were actually reinfestation, and that the patients had a
previous, unrecognised, primary infestation with the human-derived
mite. Alternatively, cross reactions with either atypical host antigens
or antigens derived from some other species of parasite may be
causing the sensitisation. A similar observation has been described
with dog and cat hookworm infestations in people compared
with human hookworm infestations. The former causes a marked
sensitisation whereas the latter often goes unnoticed (Loukas and
Prociv, 2001 and Currie, B.J., unpublished observations).
The possibility of cross infestations acting as a reservoir for
transmission back to the primary host needs to be considered. Self-
limiting infestations on some atypical hosts can last up to 13 weeks.
Hosts exhibited hyperkeratosis similar to that seen with normal
scabies before the disease spontaneously recovered (Arlian et al.,
1984b). This could explain treatment failures in some domestic
animals with reinfestation occurring from atypical hosts. However,
as the mites are morphologically very similar it is difficult to deter-
mine how often, if at all, this happens. Ruiz-Maldonado et al. (1977)
report a case of a 14-year-old girl with Turners syndrome and crusted

scabies due to S. scabiei var. canis. Evidence for this was the patient
lived with three severely infested dogs and several members of her
family developed self-limiting rashes after sleeping with her.
Additionally a normal dog was successfully infested with mites
from the patient but the investigators were unable to initiate an
infestation on rabbits or nude mice.
5. TAXONOMY AND POPULATION STRUCTURE
5.1. Determination of a Single Species
Fain (1978) made a comparative study of the morphology of various

strains of S. scabiei in an attempt to define species or subspecies from
various hosts. At that point up to 30 species and 15 varieties had been
described in the genus Sarcoptes. He proposed that some morpho-
logical characters were stable and others variable, and that variability
was more evident in the adult female. The morphological charac-
teristics that were most unstable included: (a) the extent and size of
the dorsal and ventro-lateral scales, (b) the size and shape of the
anterodorsal shield, (c) the size of the body and (d) the length of the
dorsal hairs. For example specimens from humans have no ventro-
lateral scales, and most have a bare area of variable size in the centre
of the dorsal scales. In contrast in specimens from carnivores (dogs,
foxes), the ventro-lateral scales are nearly always present and the
dorsal scales are usually complete with no bare area. The female
specimens from carnivore hosts are smaller (320–390 mm 250–300
mm) compared to human specimens (390–500 mm 290–420 mm).
However, variability in these unstable characteristics was observed:
(a) between populations from two different host species, (b) within a
single population infesting an individual and (c) between populations
from the same host species but in geographically distinct regions.
Fain concluded that there is only one valid but variable species and
proposed this to be a result of continuous interbreeding between
populations infesting humans and domestic animals (Fain, 1978).
Studies published subsequently indicate physiological differences

among scabies mites from different hosts. Arlian et al. (1984b)
describe unsuccessful experimental attempts to transfer scabies mites
from dogs to mice, guinea pigs, pigs, cattle, cats, goats and sheep.
However, scabies mites from dogs established a long-term infestation
on New Zealand white rabbits. These studies infer that strains of
S. scabiei are host specific by the demonstration of limited cross
infectivity between different host species.
Reasons for the host specificity of different ‘‘strains’’ of mites are
not yet understood but would relate to the interaction between both
parasite and host factors. Arlian (1989) suggests limiting factors
may include: physiological differences in dietary and environmental
requirements of different mite strains; differences in the physiological
properties of host skin epidermis; ability of the host to mount an
immune response; antigenicity factors of the parasite; and the ability
of the parasite to resist the hosts immune response.
5.2. Population Genetics of Host Specificity
Nucleic acid methodologies are becoming an increasingly important

tool in population systematics and DNA methods have several
advantages over morphology or protein methodologies for popula-
tion studies. These include the analysis of the genotype instead of
the phenotype, the selection of more than one sequence on the
basis of evolutionary rate or mode of inheritance, and the require-
ment for only small amounts of material to prepare DNA which can
then be stored indefinitely. Furthermore, markers can be chosen
that are not under direct selection pressure from the host organism,
as well as those that exhibit characteristics of high variability and
ease of detection. Methods include: (1) DNA–DNA hybridisation;
(2) polymerase chain reaction (PCR) amplification of mitochondrial
DNA (mtDNA), ribosomal RNA genes, single copy nuclear genes,
microsatellite DNA, and random amplification of polymorphic
DNA (RAPD); and (3) the analysis of fragments and restriction sites.
Data obtained from these studies are used to estimate parameters
such as genetic variability, gene flow, hybridisation, recognition of

species boundaries and phylogenetic relationships in both evolu-
tionary and ecological studies.
For analysis of population subdivision and estimating species
boundaries it is recommended to use more than one marker system
(Hillis et al., 1996). Closely related species (diverged <5 million
years ago) are best studied by relatively fast evolving regions of
the genome, including nuclear spacer regions, introns, or mtDNA.
Phylogenetic studies are also enhanced by studying several systems
that evolve at different rates, to resolve different parts of the
phylogeny.
MtDNA sequence polymorphisms have been used in a number
of studies on population structure in parasites and free-living
organisms (Lymbery et al., 1990; Gillepsie et al., 1994; Navajas et al.,
1994; Anderson et al., 1995; Richard et al., 1996). The non-nuclear
DNA, inherited exclusively through the maternal lineage, contains
both slowly evolving ‘‘highly conserved’’ regions as well as regions
of rapid evolution and ‘‘high variability’’. Other useful characteristics
include its small size and lack of recombination (reviewed in Simon,
1991). These divergent rates can therefore be applied to different
phylogenetic studies: rapidly evolving DNA is useful for recently
diverged taxa and more conserved regions are useful for more distantly
related taxa. The use of highly conserved ‘universal’ primers also
allow the amplification of DNA fragments in species where no
sequence information is available. They have been used to charac-
terise mtDNA haplotypes and delineate population substructure or
host clustering of parasites by estimating phylogenetic relationships.
Consequently mtDNA analysis has been used in a number of studies
to estimate both intra- and inter-species diversity (Kocher et al., 1989;
Croom et al., 1991; Salomone et al., 1996).
5.3. Population Genetics of S. scabiei
A number of studies investigating genetic variation in host-associated

populations of scabies mites infecting multiple hosts in Australia
and Europe have now been published. These studies have used a
variety of genetic markers and measured patterns of host-specific
differentiation and genetic distance, including investigating geogra-
phical variation. Walton et al. (1997) developed a genotyping system
based on three hypervariable microsatellite loci and subsequently
analysed population diversity in over 700 mites derived from people
and dogs in Australia and the Americas. Multi-locus analysis using a
distance algorithm based on the proportion of shared alleles revealed
that mites were segregating into two completely separate host-
associated populations (dog and human), although there were no loci
or alleles that were fixed for either population in the analysis
(Figure 3). This study suggested that S. scabiei from humans and
dogs were genetically distinct despite living in the same place and
Figure 3 Multi-locus clustering analysis of S. scabiei populations using

a similarity matrix based on the proportion of shared alleles (Walton et al.,
1999a). The study is based on 470 human-derived mites, 217 dog-derived
mites and 25 wombat derived mites. Mites were partitioned into 27 sub-
populations derived from individual hosts and time of collection. Analysis
assumes all single alleles are homozygous.
that interbreeding or cross-infection appeared to be extremely rare

(Walton et al., 1999a). However, although this data seems to imply
that these sub-species deserve biological species status, other studies
suggest monospecificity of the genus Sarcoptes, presumably a result
of interbreeding. Zahler et al. (1999) using a 450 bp nuclear ribosomal
marker ITS-2, studied 21 mites derived from populations of dog,
pig, cattle, fox, lynx, wombat, dromedary, and chamois, but were
unable to see any association between mite haplotype and host
species. Berrilli et al. (2002) also used the ITS-2 marker, as well as
407 bp of the mitochondrial 16S rRNA gene, in a study looking at
genetic variation in 28 mites derived from chamois and fox popu-
lations in northern Europe. They were able to distinguish structural
divisions in mite populations as a result of geographic isolation but
could see no host association of mites using both mitochondrial and
nuclear markers. Another study on 23 mites derived from wombats,
dogs, and human host populations in Australia, using a 326 bp
fragment of the mitochondrial 12S rRNA, could not differentiate any
genetic variation between host populations (Skerratt et al., 2002). The
polyphyletic associations between host strains of these latter studies
were based on limited samples and what appear to be short
uninformative fragments of mitochondrial or ribosomal spacer
regions. If a gene tree is to be used to infer histories of closely related
taxa, sampling and sequence data must be sufficiently resolved and
robust so phylogenetic patterns can be confidently documented
(Funk, 1999). More recently preliminary data using an extended
nuclear microsatellite fingerprinting system and additional mitochon-
drial markers again identified significant genetic dissimilarity between
mite populations obtained from northern Australian dog and human
hosts (Walton et al., in press). Molecular studies therefore continue to
support the proposition that dogs are not contributing to the
endemicity of scabies in people in northern Australia. Although no
fixed genotypic markers have been determined there is still convincing
molecular evidence in endemic communities that scabies control
programs should be directed against human to human transmission
and safely ignore the risk of zoonotic infection. This has now been
substantiated in community control programmes in which only
people were treated, and prevalence rates were reduced to around 5%

(Carapetis et al., 1997; Wong et al., 2001, 2002).
As discussed by Avise (1994), organismal mobility and environ-
mental fragmentation can exert significant influences on patterns of
phylogeographic structure. Similar molecular studies of populations
of Ascaris, Giardia, and Echinoccocus from different hosts have been
successful in defining genetic structure and epidemiology (Anderson
et al., 1993; Thompson and Lymbery, 1996; Hopkins et al., 1997).
Changes in host utilisation by parasites may give rise quickly to new
species reproductively isolated from their sympatric progenitors
(Bush, 1975).
There are a number of possible explanations for inter-host
divergence of S. scabiei populations within endemic communities in
northern Australia. Firstly, physical separation may restrict cross-
infection. This seems unlikely as people and dogs within a household
live and sleep in similar areas. Alternatively, pre- or post-mating
barriers may prevent gene flow between the two host derived
populations. Arlian et al. (1984b) has demonstrated the limited ability
of S. scabiei to maintain long term infestations on non-normal hosts.
Anecdotal evidence suggests dog scabies mites have a restricted life
span on humans. Such reports indicate host defence factors may
provide a host mediated barrier to gene flow or, alternatively,
hybridisation events may occur but result in reduced fitness of F1
hybrids and their progeny. The population dynamics and ecological
interactions of S. scabiei are still largely unknown and, despite the
limitations and difficulties encountered in scabies mite collection,
recent molecular genotyping studies are the first major advance in
understanding their fine-scale transmission dynamics.
6. EPIDEMIOLOGY
6.1. Cyclical Pattern of Infection
Early accounts of the epidemiology of human scabies described large

epidemics or pandemics that occurred in 30-year cycles (Mellanby,
1944; Shrank and Alexander, 1967). The principal peaks coincided

with major wars. However, this may be an oversimplification of
the facts and the supposed cyclical pattern may not be real. The
pandemics, although difficult to demarcate, seem to have occurred
between 1919–1925, 1936–1949 and 1964–1979 (Green, 1989).
Scabies is not a reportable disease and data is often based on
variable recording methods, the percentage incidence among skin
disease patients attending hospital clinics, as well as from countries
with widely varying social and physical environments. Peak inci-
dence of disease did not occur simultaneously in all countries
(Orkin, 1971).
Shrank and Alexander (1967) suggested herd immunity to account
for the supposed cyclical nature of the disease. However, this
explanation does not account for scabies that is endemic in many
tropical and sub tropical communities, for example, India (Sachdev
et al., 1982), South Africa (Henderson and Nykia, 1992), Panama
(Taplin et al., 1991) and northern Australia (Currie and Carapetis,
2000) without any apparent fluctuations in overall incidence. It is still
unclear exactly how infestation may be limited by an immune
population although Mellanby (1944) and Arlian et al. (1996b) have
demonstrated that subsequent reinfestations in both humans and
animals have a reduced parasitic burden and some previously infec-
ted individuals can eliminate a second infestation before clinical
manifestations develop. Furthermore, clearance of primary infesta-
tion itself is in part related to development of immunity (Mellanby,
1944).
Changing social circumstances in addition to immunity may play
a role in periodic epidemics, either voluntarily as observed in the
social revolution in the United States of America in the late 1960s
and early 1970s, or coercive as in wars (Funaki and Elpern, 1987).
Fain (1978) mentions that the increase in scabies runs parallel to an
increase in other external arthropod parasites such as the lice
Pediculus humanus and Phthirus pubis and that this is indicative of
changes in the social environment instead of elements such as herd
immunity to the parasite.
6.2. Sex and Age
Alexander (1984) concluded that scabies is generally commonest in

the very young, remains frequent in older children and young
adults and declines thereafter. It is assumed this represents a
combination of increased exposure and cross-infection between
children and absence of immunity. Yet as Andrews (1991) discusses,
these assumptions are based on clinical records and do not include
persons who were infested, but may have become tolerant to the
mite and therefore asymptomatic. It should be noted that it is yet
to be definitely established whether a history of infection with
S. scabiei will cause long term immunity. An increase in the incidence
of scabies is observed in the elderly in nursing homes. This is likely
to be multifactorial, including increased exposure, especially when
related to index cases of crusted (severe) scabies, possible immuno-
deficiency in the elderly and decreased ability to kill mites by scra-
tching in debilitated patients such as with dementia and following
strokes.
Scabies affects both sexes similarly, although there is some
variability between studies and mothers of young children appear
more commonly infected than other adults in some studies (Taplin
et al., 1991).
6.3. Ethnicity
A number of studies suggest some racial groups may be more

susceptible to scabies infection. In a population consisting of
48% black people, Alexander (1984) observed 36 of 37 patients in his
Maryland clinic with scabies were white people. In contrast to this,
a higher incidence of scabies was found in South African Blacks
than in any other race (Hersch, 1967). In a health survey of
New Zealand adolescent school children, Lines (1977) found the
highest incidence of scabies in Polynesian immigrants (16.1%),
followed by Maoris (11.4%). Funaki and Elpern (1987) in their
epidemiological study of scabies in Hawaii observed much higher

prevalence in Hawaiians and Whites than the Filipinos or Japanese.
They suggest that social customs and lifestyle play a significant factor
in disease expression. Racial differences in scabies susceptibility
or resistance therefore seem more related to differences in habits,
housing, socioeconomic factors and overcrowding rather than ethnic
origin.
6.4. Poverty, Overcrowding and Poor Hygiene
The relationship between scabies and relative levels of poverty,

crowding and hygiene within a household and a community is
complex and individual susceptibility and levels of exposure must
also be considered. Orkin (1971) suggests that poverty together
with crowded living conditions and inadequate hygiene, tends to
promote the occurrence of scabies. However evidence indicates that
scabies itself is not directly influenced by hygiene practices or the
availability of water and this can be observed in institutional
outbreaks where high standards of hygiene are observed and water
facilities and washing are excellent. Furthermore other studies
document a very high prevalence of scabies in overcrowded
populations in which careful daily personal hygiene are traditional
(Taplin et al., 1983) and among children living in overcrowded
conditions in the Solomon Islands where the children spend much of
their time in the sea (Eason and Tasman-Jones, 1985 and Lawrence,
G.W., personal communication). Thus, the stigma frequently
associated with this and other ectoparasites such as head lice as a
marker of poor hygiene is misplaced.
Scabies has been observed to affect people from all socioeconomic
levels. Poverty and overcrowding however are often concomitant,
and overcrowding is clearly associated with the spread of scabies.
Poverty also leads to other associated problems such as poor
nutritional status, which in turn can contribute to the immune status
of the individual and levels of disease within the community.
Several of the crusted scabies cases in Papua New Guinea were
observed to coincide with evidence of poor nutrition and beri beri

(Backhouse, 1929). Cases of crusted scabies in northern Australia
sometimes demonstrate folate deficiency, but this is common in some
remote communities, making attribution uncertain.
Intra-familial incidence of scabies is high and this seems to indicate
transmission is mediated by close personal contact with an infected
person, such as embracing or sharing a bed (Sachdev et al., 1982).
Among adults, sexual contacts are perhaps the most important means
of transmission (Shrank and Alexander, 1967; Elgart, 1990).
Molecular studies in northern Australia provided the first genetic
evidence of intra-family transmission of S. scabiei mites (Walton
et al., 1999a). Although the numbers were small, on three separate
occasions mites collected from two or more members of the same
‘‘family group’’ demonstrated only minor deviations from genotypic
homogeneity while showing large differences between groups.
In endemic areas intra-familial incidence of scabies is frequently
reported and these genotyping results confirm long held beliefs that
transmission is mediated by close personal contact with an infected
person. This hypothesis is further supported by the lack of genotypic
clustering between mites collected from individuals living in separate
households within a community (Walton et al., 1999b). Current
results indicate that transmission events for S. scabiei tend to be
localised in time/or space and suggest that the family/household is the
focus of transmission.
6.5. Significance in Indigenous Communities
In some northern Australian Aboriginal communities, conditions

of reduced socioeconomic status, inadequate medical facilities and
overcrowding appear to be contributing to the high levels of endemic
scabies (Munoz et al., 1992; Currie and Carapetis, 2000). A large pro-
portion of Aboriginal people in northern Australia live in substandard
and overcrowded housing with poor water supplies and sanitary
facilities. Recent reports indicate up to 30 people per household
and a 50% incidence of scabies (Currie et al., 1994; Fraser, 1994).
Similarly Sachdev et al. (1982) observed that overcrowding and

limited sleeping space were some of the factors associated
with scabies in resettlement colonies of Delhi. The prevalence of
dermatoses in children in rural Africa was reported to not only
depend on treatment schemes within the primary health care system,
but also on the socio-economic conditions (Schmeller and Dzikus,
2001). Nair et al. (1977) found a significant association between
high prevalence of scabies and poor nutritional status in a scabies
epidemic in an Indian village.
Within tropical northern Australia the intensely pruritic lesions
of scabies are reported to underlie between 50 and 70% of group
A streptococcus (GAS) skin infection (Currie and Carapetis, 2000;
Wong et al., 2002; see Section 7.3). The resulting pyoderma is
believed to be an important progenitor for the high levels of renal
disease reported in these communities with post-streptococcal disease
rates in Aboriginal Australians amongst the highest in the world
(Carapetis et al., 1997; Currie and Carapetis, 2000). Rates of end-
stage renal failure in the Aboriginal people of the Northern Territory
are 21 times that seen in the general Australian population and have
recently been shown to be associated with post-streptococcal
glomerulonephritis in childhood (Cass et al., 2001; White et al.,
2001). Significantly throat infections with GAS are rare in these
northern Australian Aboriginal communities and it is now considered
likely that GAS infections of the skin, by relevant GAS strains, may
directly lead to rheumatic fever and potentially contribute to the
highest rates of rheumatic heart disease recorded worldwide
(Carapetis and Currie, 1996; Currie and Brewster, 2002).
7. CLINICAL PRESENTATION
Classical scabies in the adult presents as a generalised pruritis

which is frequently more intense at night. Two forms of skin eruption
occur concurrently: (1) the papular or vesicular lesions associated
with the site or vicinity of burrows and which in some cases become
pustular or bullous and (2) a more generalised itchy papular eruption
unrelated to obvious mite activity. This more generalised skin rash

is most commonly seen around the axillae, the peri-areolar regions,
abdomen, buttocks and thighs.
Localisation of the mite in humans is classically in the webs of the
fingers, the volar aspects of the wrists and arms, and the extensor
aspect of the elbow, periumbilical skin, pelvic girdle including
buttocks, ankles, the penis in males and the peri-areolar region
in females. Currently definitive diagnosis is via microscopic exami-
nation of skin scrapings but this has low sensitivity. The classical
clinical sign for the diagnosis of scabies is the burrow. The adult
female, approximately 0.3 mm in length, makes the burrow as it
digests and consumes the horny layer of the epidermis. Burrows
present as a serpiginous greyish line approximately 5 mm long and
are generally found where the stratum corneum is thin and soft and
where there are few or no hair follicles. Unfortunately, these burrows
are often not visible with an unaided eye and various techniques have
been developed to enhance their visibility (Alexander, 1984; Brodell
and Helms, 1991). Experiences in scabies-endemic communities in
northern Australia and Panama indicate that burrows are often not
detectable in the tropics (Walton, S.F., unpublished observations and
Taplin, D., personal communication). Mellanby (1944) observed that
the number of adult female mites per patient was approximately 11
and both he and Arlian et al. (1994a, b) have reported that with
repeated infestations this number reduces substantially. Therefore,
with subsequent infestations, burrows would be even more difficult to
find. Mellanby (1944) observed that individuals with subsequent
infestations experienced intense local irritation and erythema around
the mite, with the mite frequently becoming undetectable within
a couple of days. Additionally excoriation, eczematisation, and
pyoderma (secondary bacterial infection) may obscure presentation.
In humans the clinical signs and symptoms of scabies infestation
can mimic other skin diseases such as eczema, impetigo, dermatitis
herpetiformis, furunculosis, papular urticaria, other allergic reac-
tions, eczema herpeticum and other viral exanthems, syphilis and
response to other ectoparasitic mites and insects such as chiggers, lice,
fleas, and bedbugs (Alexander, 1984). In approximately 7% of cases
a nodular reaction occurs which may persist for months after suc-
cessful treatment of the disease. The red/brown nodules are about
5–8 mm in diameter, can be extremely pruritic, and develop most
frequently on the anterior fold of the axillae, the groin region, the
genitalia, the buttocks, and around the navel (Burgess, 1994).
Classical scabies in children follows a similar pattern to adults
but may also present with a different distribution of lesions and
variations in symptoms. The primary difference is with the involve-
ment of the face, neck, scalp, feet and the post-auricular fold being
sometimes seen in children (Paller, 1993). This different distribu-
tion is also commonly seen in adults as well as children in tropical
regions.
7.1. Immunodiagnosis
Scabies is a challenging disease to diagnose due to difficulties in

isolating sarcoptic mites on the host and clinical symptoms imitating
other skin diseases. However, many studies document that scabies
mite infestation cause the production of measurable antibodies in
infested host species (Hoefling and Schroeter, 1980; Falk and Bolle,
1980b; Bornstein and Zakrisson, 1994; Morgan and Arlian, 1994;
Arlian et al., 1994a, 1996a, b; Bornstein et al., 1996; Bornstein and
Wallgren, 1997). Based on this Enzyme-linked ImmunoSorbent
Assays (ELISA) have now been developed for the detection of
antibodies to S. scabiei in pigs and dogs (Bornstein et al., 1996;
Hollanders et al., 1997; Jacobson et al., 1999; Lower et al., 2001) and
are commercially available in Europe (Van der Heijden et al., 2000).
These assays rely on whole mite antigen preparations derived from
S. scabiei var. suis, and the itch-mite of the red fox S. scabiei var.
vulpes. Arlian et al. (1996a) describe immunological cross reactivity
between various strains of S. scabiei, and this has been demonstrated
in the accurate diagnosis of mange in dogs and sheep using
the var. vulpes ELISA (Bornstein et al., 1996; Hollanders et al.,
1997; Lower et al., 2001). However, there has been no reported
evaluation of the var. suis and var. vulpes ELISAs in the diagnosis
of human scabies. Normaznah et al. (1996) developed an ELISA

based on S. scabiei var. canis whole mite extract and determined
the seroprevalence of anti-var. canis antibodies in the Indigenous
Orang Asli in Peninsular Malaysia. The 24.7% positive result
observed was surprising considering there were few patients with
clinical manifestations (3/312). As yet there has been no docu-
mentation on the development of an assay based on var. hominis
whole mite extract. This latter situation would certainly relate to
the lack of an in vitro culture system or animal model for var.
hominis limiting access to large numbers of mites, and perhaps
more importantly, the previous lack of recombinant purified mite
antigens.
Associated difficulties with the development of an ELISA for
diagnosis of human scabies also include: problems with documented
host cross reactivity to house dust mite allergens (see Section 8.2);
high background caused by contamination of whole mite antigen
extract with host immunoglobulin (Van der Heijden et al., 2000
and Harumal, P., personal communication); and lack of knowledge
on the induction and time course of the specific humoral response
in both immunological naı̈ve or sensitised human hosts. However,
a serological test would be advantageous in that it can be cost
effective and suitable for both large and small scale application.
With the recent progress in scabies molecular research and the
cloning of both scabies mite homologues of house dust mite
allergens and novel molecules, the development of an ELISA
specific for human scabies may now be a real possibility in the near
future.
7.2. Reinfestation
The severe itching and papular rash of the primary infestation

are reported to take 4–6 weeks to develop (Mellanby, 1944).
With subsequent infestations however skin sensitisation develops
rapidly and the associated lesions and pruritus are evident within
24–48 h.
7.3. Secondary Infection
Untreated scabies is often associated with pyoderma primarily caused

by secondary infection with group A streptococcus (GAS) and
Staphlococcus aureus (Brook, 1995; Currie and Carapetis, 2000).
More significant however are the associated sequelae of cellulitis,
lymphangitis and acute glomerulonephritis (AGN) (Hersch, 1967;
Svartman et al., 1972). The recent studies by Wong et al. (2001, 2002)
and that of Carapetis et al. (1997) and Taplin et al. (1991) demon-
strated that community control programs directed at scabies with no
antibiotic intervention have a significant impact on the prevalence
and severity of streptococcal pyoderma. In epidemics of AGN in
Trinidad it was recorded that the outbreaks had been preceded by an
increase in the incidence of scabies (Svartman et al., 1972; Poon-King
et al., 1973). GAS was also isolated from skin lesions of dogs with
mange found in the area. Staphlococcus spp. have been isolated from
skin burrows as well as from mite faecal pellets suggesting the mites
themselves may contribute to the spread of pathogenic bacteria
(Shelley et al., 1988).
7.4. Crusted (Norwegian) Scabies
Crusted scabies is an extreme form of the disease and characterised

by large numbers of mites, high IgG and IgE levels, and the
development of hyperkeratotic skin crusts that may be loose, scaly
and flaky or thick and adherent (Figure 4; see colour plate section).
The distribution over the body is extensive including neck, scalp, face,
and nails. Fissuring and secondary bacterial skin lesions are common
and regional lymphadenopathy is frequently present. Examination of
the crusts microscopically reveals large numbers of mites and eggs.
Currie et al. (1995) report up to 4700 mites per gram of skin.
Consequently, crusted scabies is considerably more infectious than
ordinary scabies, as evidenced with nosocomial outbreaks of ordinary
scabies from index cases of crusted scabies (Moberg et al., 1984;
Holness et al., 1992; Estes and Estes, 1993b). Patients with crusted
Figure 4 Fatal sepsis secondary to crusted scabies. (See Plate 5.4 in

colour plate section.)
scabies may also remain infectious for long periods of time because of
the difficulty in eradicating mites from heavily crusted areas of skin
(Currie et al., 1997).
Crusted scabies is caused by the same variety of mite that causes
typical scabies, S. scabiei. Progression from ordinary scabies to
crusted scabies is uncommon and susceptibility to the more severe
form of the disease has been associated with a number of
predisposing conditions. Crusted scabies has been observed in
patients with cognitive deficiency and in institutionalised patients
who are unable to properly interpret the associated pruritis or are
unable to physically respond to the itching (Kolar and Rapini, 1991).
Scratching is thought to be important to the removal of mites
and patients with poor cutaneous sensation due to neuropathy
or systemic disease are at risk for worsening infestation (Carslaw,
1975). Recent reports have increasingly linked crusted scabies with
immunosuppression and human immunodeficiency virus (HIV)
infection (Patterson et al., 1973; Glover et al., 1987). Crusted scabies
in northern Australia is seen in previously treated leprosy patients
but is also associated with substance abuse, systemic lupus erythe-
matosus, pulmonary tuberculosis, diabetes mellitus and Hepatitis B.
In a series of nine Aboriginal cases treated at the Alice Springs

Hospital in the Northern Territory of Australia, all of the patients
were infected with human T-lymphotropic virus type I (HTLV-I),
compared to 10–15% in the general local Aboriginal community
(Mollison et al., 1993). The association between HTLV-I and scabies
has similarly been observed in Dominica (Adedayo et al., 2003) and
Brazil (Brites et al., 2002). Importantly crusted scabies has also been
recognised in people with no known immunological deficit (Gogna
et al., 1985; Currie et al., 1995).
7.5. Genetic Composition of S. scabiei Populations in

Sequential Crusted Scabies
Recurrent crusted scabies is of significant concern both for individual

patient outcome as well as for public health. Current treatment
protocols for crusted scabies in northern Australia include oral doses
of ivermectin in combination with a topical therapy of scabicides
(Huffam and Currie, 1998). Preliminary data from 20 patients with
crusted scabies supports early recrudescence of the disease following
a single dose of ivermectin at 200 mg/kg, whereas three doses 2 weeks
apart resulted in an apparent ‘‘cure’’. However, half these latter cases
relapsed 6–12 months later, suggesting either recrudescence of the
disease or reinfestation.
Genetic analysis undertaken by Walton et al. (1999a, b) investi-
gated whether successive populations of mites on a single individual
were genetically similar and thus descended from the same founder
group or whether a new and genetically distinct population had
become established post treatment. As a consequence, treatment
protocols could be reassessed on an individual basis as well as
providing definitive guidelines for best practice. Studies on popu-
lations of mites collected from different people revealed highly
significant genotypic differences. A study on individuals with recur-
rent infestations showed that mites from sequential infestations
were genetically closer to each other than to mites from other
patients (Figure 5) (Walton et al., 1999b). This suggested that some
Figure 5 Multi-locus clustering based on the proportion of shared alleles

of S. scabiei populations collected from four crusted scabies patients
(C1–C4) with sequential infestations (Walton et al., 1999b). In total 151
mites were analysed from C1, 134 mites from C2, 31 mites from C3 and
13 mites from C4. Mites were partitioned into subpopulations based on
individual hosts and the time of collection. Assumes all single alleles
are homozygous.
of the mites had survived treatment or that reinfestation had been

from the same or a similar source. The analysis of the mite
subpopulations obtained from two sisters suggested reinfestation
from one sister to the other, or alternatively, from a person infected
with genotypically similar mites (Figure 5, C3.1 and C4).
Current management protocols for crusted scabies patients in
northern Australia include environmental measures such as house
insecticide bombs and the washing of bed-linen etc., additional to all
family/household members receiving treatment for scabies. These
procedures, if carried out adequately, should reduce considerably
the risk of reinfestation in the patient. However Walton et al. (1999b)
describe one case of severe sequential crusted scabies, during which
an individual received 20 doses of ivermectin over four years, and
in which mites, collected at six monthly episodes, showed only
minor changes in genotypic diversity. In vitro sensitivity testing
undertaken during this period indicated mites were not resistant
to ivermectin. Furthermore, the analysis of mites collected at two

successive relapses, during which time the patient remained iso-
lated from his family, implied reinfestation with mites derived from
the same gene pool was considered unlikely to be the cause of the
relapse. These results signify that in some cases of severe crusted
scabies current treatment protocols are probably insufficient. Recent
changes in treatment schedules at the Royal Darwin Hospital include
increasing the number of doses of ivermectin (200 mg/kg) to 7 doses,
for the most severe crusted scabies cases, (days 0, 1, 7, 8, 14, 21 and
28), together with topical scabicides (full body application initially
every 2–3 days) and topical keratolytic creams. Concerns about
possible emergence of parasite resistance and drug toxicity necessi-
tate the continued surveillance on patient response and mite sensi-
tivity studies to a variety of active substances.
8. HOST IMMUNE RESPONSE
To understand more clearly the pathogenicity of scabies an

understanding of the immune response mechanisms to scabies mites
in both naı̈ve and sensitised hosts is essential. In his classical studies
Mellanby (1944) demonstrated that the clinical signs and symptoms
of scabies are the result of an immune response. Studies by Arlian
(1989) using a dog mite/rabbit ear model suggest naı̈ve hosts have no
apparent immunity. Immunity develops when the host immune
system encounters scabies antigens introduced during the lifecycle of
S. scabiei. The time required to induce immunity in primary infes-
tations may account for the latent period of four weeks during which
no symptoms are present and may relate to the amount of antigenic
stimuli (Estes and Estes, 1993a). Continuous exposure for more than
100 days appears to raise immunity and reduce the number of infest-
ing mites. Mellanby (1944) demonstrated immunological memory to
mite antigens by reporting an induction time of only 24 h for
hypersensitivity with patients infested for a second time. Additionally
the parasite rate was significantly reduced and in approximately
60% of the cases reinfestation of sensitised hosts was unsuccessful.
Arlian et al. (1994a, 1996b) have also demonstrated induced immu-

nity to S. scabiei var. canis in both rabbits and dogs. Immunity
in experimental Psoroptes ovis (Acari: Psoroptidae) infestation of
naive and sensitised Hereford cattle likewise indicated acquired
resistance and reduced mite numbers on previously exposed calves
(Stromberg and Fisher, 1986). The direct and indirect effects of
immunity on mite mortality, natality rates and emigration are still
unclear however due to a historical lack of scabies-specific antigens.
8.1. Scabies Specific Immune Response
Classical studies of the symptoms and signs of scabies pointed to the

development of host immunity but until the recent Scabies Gene
Discovery Project the antigens responsible for the immune reactions
in scabies remained principally undefined (Fischer et al., 2003a).
Consequently there is a dearth of literature reporting human scabies-
specific humoral or cellular immunity. The limited investigations to
date of humoral immunity in scabietic patients give contradictory
results and have used scabietic extracts from other hosts such as the
dog (Morgan et al., 1997; Arlian et al., 2004). In Darwin, patients
with crusted scabies were noted to have extremely high serum
levels of total IgE and IgG. Of 52 cases all but two had elevated IgE,
with a median of 1700 mg/L (normal is <150 mg/L). 38/52 (73%) had
levels >10 times normal and 5/52 (10%) had levels >1000 times
normal (i.e. over 100,000 mg/L). In addition 34/59 (58%) had
eosinophilia, with 7/54 (12%) having levels over 10 times normal
(Roberts, L.J. and Currie, B.J., unpublished observations). The
reasons for this extreme non-protective antibody response are as
yet unknown and may relate to an inappropriate Th2-polarised
immune response.
To date cell-mediated host immune responses have been primarily
identified by histopathological examination of skin biopsies from
scabietic lesions. Mite burrows are surrounded by inflammatory
cell infiltrates comprising eosinophils, lymphocytes and histiocytes.
While predominantly CD4 þ T-cells dominate the lymphocytic
infiltrate in ordinary scabies (Cabrera and Dahl, 1993), interestingly

limited immunohistology studies on crusted scabies patients in
Darwin suggest the inflammatory skin response comprises predomi-
nantly CD8 þ T-cells (Currie, B.J., Bradley, J., Beroukas, D., and
Walton, S.F., unpublished observations). The proportion of
lymphocytes in the blood of scabietic patients and the T-cell subsets
were normal. The ratio of T-cells to B-cells was greater in infiltrates
than peripheral blood suggesting a selective movement of T-cells into
the dermis and signifying their role in a cell mediated response to
scabies. There are currently no documented studies on scabietic
patients’ in vitro T-cell responses to scabies mite antigens.
Preliminary studies on cytokine production using RNase-protec-
tion assays on mRNA obtained from fresh PBMC collected from
crusted scabies patients and uninfested controls in northern
Australia, demonstrated a statistically significant elevation of IL-4
in crusted scabies (Figure 6). That elevated IL-4 production is
observed in unstimulated PBMC is similar to the highly Th2-
polarised immune response seen in atopic dermatitis (Leung, 2000).
Perhaps not only is the Th2 response ineffective at removing the
mite infestation, but the IL-4 produced in this response may
Figure 6 IL-4 mRNA levels in crusted scabies compared with non-

infested control ( p ¼ 0.03).
contribute to the hyperproliferative skin disease characteristic

of crusted scabies. It has been shown that IL-4 can stimulate
keratinocyte proliferation (Yang et al., 1996), that epidermal cells
have IL-4 receptors, and that IL-4R expression is elevated in
psoriasis, a disease with some clinical similarities to crusted scabies
(Prens et al., 1996).
8.2. Similarities Between Scabies Mite Infections and

Allergy to House Dust Mite Antigens
Since the house dust mite and scabies mite are related arthropods
with similar nutritional requirements, it is not unlikely that they
or their excretions or secretions have allergens in common.
Immunochemical studies have demonstrated that antisera to house
dust mite allergens cross-react with extracts of S. scabiei (Falk
and Bolle, 1980a; Falk et al., 1981; Arlian et al., 1988c, 1991, 1995;
Morgan et al., 1997). Allergens from house dust mite are recog-
nised as major causes of human respiratory disease (Thomas et al.,
2002). Many different species of dust mites have been reported but
the allergens of the pyroglyphid mites (Dermatophagoides pteronys-
sinus, D. farinae and Euroglyphus maynei) predominate. Allergens
have been identified in the midgut, the hindgut and the cuticle
(Mumcuoglu and Rufli, 1979), but the faecal pellet is the major
allergen source (Tovey et al., 1981).
Sera obtained from nine house dust mite skin test positive patients,
with no previous history of scabies, exhibited strong binding to
a variety of S. scabiei proteins using SDS-PAGE and 125I-labelled
anti-human IgE detection (Arlian et al., 1991). Furthermore western
blotting and radioallergosorbent assays demonstrated that indivi-
duals with scabies showed strong IgE binding to both scabies
mite and house dust mite protein extract (Falk and Bolle, 1980a and
Walton, S.F., unpublished observations). These findings are
important as they demonstrate the presence of a high level of IgE
cross-reactivity between scabies mite and house dust mite antigens
and that patients sensitive to house dust mite but with no history
of scabies exhibit circulating antibodies that recognise S. scabiei

antigens.
Finally, immunisation of rabbits with an extract of D. farinae/
D. pteronyssinus resulted in reduced levels of S. scabiei var. canis
infestation in 71% of the hosts when they were challenged with
scabies mites. This resistance was evidenced by a marked reduction in
the parasite load compared to the control rabbits and suggests
the development of cross-protective immunity (Arlian et al., 1995).
These results contrast with those of Falk and Bolle (1980a) who
observed patients with skin sensitivity to D. pteronyssinus had a more
severe rash from scabies than non allergic persons. In point of
fact immunity to the scabies mite is a confounding factor in skin
testing for Dermatophagoides allergy in scabies endemic Aboriginal
communities in northern Australia. The prevalence of a positive
response ( 3 mm wheal) to dust mite antigen (DPT) in subjects with
a reactive positive/histamine control was 49.8% (104/209), possibly
reflecting scabies exposure and not true atopy (Maguire, G., personal
communication). These findings are supported by data suggesting
that the prevalence of atopy, as measured by positive skin prick test
result to a panel of antigens, is lower in Indigenous compared with
non-Indigenous Australian communities, (Veale et al., 1996; Bremner
et al., 1998 and Macguire, G., personal communication). Although
data for Indigenous Australian are limited, previous surveys in
Indigenous and non-Indigenous Australian communities would
suggest that asthma and airway hyper-responsiveness are no more
common in Indigenous Australian communities than non-Indigenous
and may well be less prevalent (Peat et al., 1992; Veale et al., 1996).
However the prevalence of scabies in some Aboriginal communities
is reported as amongst the highest in the world (Currie et al., 1994;
Veale et al., 1996). An editorial in The Lancet cites evidence for
an inverse relation between parasites and allergy and quote ‘‘asthma
and hayfever are rare in parts of the world where the population is
heavily parasitised’’. The article goes on to suggest that some factor
associated with parasite infection may block or inactivate immediate-
hypersensitivity reactions (Editorial, 1976). The relationship between
susceptibility to and severity of symptoms with scabies and asthma
are as yet unknown and conceivably may be interdependent. Those

who suffer from house dust mite allergy may have reduced (or
possibly increased) symptoms of scabies and presumably the reverse –
those with scabies have a reduced (or increased) susceptibility to
house dust mite antigens.
9. GENETICS
A significant increase in the frequency of HLA A11 (28.3%)

compared to healthy controls (10.4%) was found when 60 patients
with scabies were typed for 33 antigens of the HLA A, B, and C series
(Falk and Thorsby, 1981). HLA typing by Morsy et al. (1990)
confirmed this, revealing an HLA A11 frequency of 29.03% in
patients with scabies compared to 9.5% in the controls. To date no
geographical or ethnic group has been associated with an increased
genetic susceptibility to scabies.
10. CHEMOTHERAPY
Topical application of active substances is the primary means of

effective treatment for scabies, although oral ivermectin is increas-
ingly used (Glaziou et al., 1993; Lawrence et al., 1994; del Giudice
et al., 2003; Santoro et al., 2003). There are a number of materials
available on the market, and choice is largely based on the age of the
patient, state of their health, degree of excoriation or eczematisation,
potential toxicity, cost and availability.
(1) Sulphur compounds have been used for centuries with
reasonable results, but can cause skin irritation, are messy
and smelly and require repeated application, making them
less acceptable to the patient. Mellanby et al. (1942) observed
that sulphur itself was not toxic to mites, noting the survival
of mites in sulphur ointment on a glass slide for several days.
However, mites did not survive contact with the active
products on human skin. The active forms of sulphur,

possibly pentathionic acid, therefore appear to be produced
either by skin microorganisms or epidermal cells (Burgess,
1994).
(2) Benzyl benzoate 25% has been used effectively for some years
although at therapeutic concentrations it is often unsuitable
due to severe stinging. Consequently for use on children it
needs to be diluted thus possibly reducing its efficacy.
(3) Crotamiton 10% has been widely used on children but
requires multiple applications and its antiscabicidal pro-
perties are extremely variable (Taplin et al., 1990; Burgess,
1994).
(4) Gammabenzene hexachloride 1% (Lindane) is an organo-
chlorine with a demonstrated cure rate of 98% (Taplin and
Rivera, 1983). It has been successfully used in the United
States of America for many years but recent reports indicate
the development of possible mite tolerance (Hernandez-Perez,
1983; Taplin and Meinking, 1990; Orkin and Maibach, 1993;
Fraser, 1994). Additionally there have been multiple reports
of systemic toxicity, primarily related to misuse in children,
but nevertheless leading to its removal from the market in
Australia and some other countries (Davies et al., 1983;
Commens, 1994).
(5) Permethrin, although more expensive than other agents, is
now considered the treatment of choice in many parts of the
world including Australia, the United Kingdom and the
United States of America. The standard treatment is topical
application of permethrin in a concentration of 5%. It is well
accepted by the patient, has low toxicity, is poorly absorbed
by the skin and rapidly metabolised. A single overnight
application was shown to be equally as effective as lindane
(Schultz et al., 1990; Taplin et al., 1991). However, in vitro
mite tolerance to permethrin has now been documented
(Walton et al., 2000) alongside increasing reports of treatment
failure in endemic indigenous communities in northern
Australia (Currie, B.J., unpublished observations).
(6) Ivermectin is a chemically modified avermectin. It has a broad

spectrum of activity against numerous nematodes and
arthropod parasites. It has been widely used for treatment
of sarcoptic mange in animals in topical, oral and parenteral
preparations. In humans it has been used since the mid
1980s, most commonly for the treatment of the filarial worm
Onchocerca volvulus, but also for Wuchereria bancrofti and
Brugia malayi with few adverse effects (Campbell, 1991;
Dunne et al., 1991). In addition, oral ivermectin for sca-
bies is increasingly used worldwide, particularly for crusted
scabies (hyperinfestation) (Glaziou et al., 1993; Kar et al.,
1994; Lawrence et al., 1994; Meinking et al., 1995; Currie
et al., 1997) and was recently approved for treatment of
ordinary scabies in France (del Giudice et al., 2003). A recent
report by Barkwell and Shields (1997) however has indicated
possible toxicity in the elderly.
10.1. Drug Resistance in Scabies
The contribution of drug resistance to treatment failure has been

largely unexplored. To date, treatment failures have been attributed
to incorrect application of the acaricide, failure to treat all contacts
leading to reinfestation, or to so called core-transmitter crusted
scabies patients (Wong et al., 2002). Taplin et al. (1983) and
Carapetis et al. (1997) have demonstrated that fomites are not a
major source of transmission confirming earlier reports by Mellanby
(1941). However, there are increasing reports internationally of
treatment failure, likely to be caused by resistance (Coskey, 1979;
Hernandez-Perez, 1983; Roth, 1991). In scabies-endemic commu-
nities in the Northern Territory of Australia, public health prevention
strategies are increasingly based on mass community treatment.
In studies evaluating such community control programs, significant
success has been demonstrated, with a major reduction in the
prevalence of symptomatic scabies and of pyoderma. For example,
the rate of pyoderma fell from 29% to 3% in 18 months in one study
where antibiotics were not used (Carapetis et al., 1997), and from
11.5% to 0.5% in 15 months in another study (Wong et al., 2002).
However increasing reports of tolerance of the scabies mite to
permethrin has been described and careful monitoring of S. scabiei
resistance to current treatments by epidemiological assessments and
in vitro testing will be required to ensure successful eradication of
scabies in endemic areas.
10.2. Permethrin Resistance
Permethrin was first approved for human use in 1986 in the United
States of America for treatment of head lice (Pediculus capitis).
Today, permethrin resistance in head lice is widespread, with clinical
failures now reported in Australia, Israel, England, France and the
Czech Republic (Bailey and Prociv, 2000; Witkowski and Parish,
2002). Permethrin (5%) was introduced in northern Australia in
1994 for treatment of scabies. At that time an in vitro study
showed that after 1 h of exposure to 5% permethrin all the mites
were dead (Fraser, 1994). Since then permethrin has been extensively
used across central and northern Australia. Walton et al. (2000)
recently repeated an in vitro study using similar methodology to
test mites also collected from northern Australia. In contrast to the
100% efficacy observed 5 years earlier, 35% of mites were still viable
after 3 h of in vitro permethrin exposure (Figure 7). These results
therefore raise concerns about the development of permethrin
resistance.
Synthetic pyrethroids including permethrin constitute one of
the most important classes of insecticides, accounting for over 25%
of the world insecticide market (Georghiou, 1990). Their intensive use
over the last 25 years has led to the development of drug resistance
in many arthropods (Georghiou, 1990), such that resistance now
constitutes a serious threat to the many programs for control of
pests and ectoparasites of importance in agriculture, veterinary and
human practice.
Figure 7 Kaplin–Meier survival curves of mites treated with 5%

permethrin, benzyl benzoate and control compound BP88 (Walton
et al., 2000).
Like dichlorodiphenyltrichloroethane (DDT), permethrin acts on

the insect nervous system to slow decay of the action potential,
thereby initiating repetitive discharges in motor and sensory axons
(Narahashi, 1989). The paralysis of flying insects induced by
such agents has given them the name of ‘‘knockdown’’ insecticides.
Electrophysiological studies have determined that these phenomena
result from slowing the gating kinetics of a neuronal, voltage-sensitive
sodium channel (Narahashi, 2000).
10.2.1. Mechanisms of permethrin resistance
As for all chemotherapeutic agents, the mechanisms of pyrethroid

resistance can be caused by: (a) target alteration to render it less
susceptible, (b) removal of the drug by an efflux pump, such as
P-glycoprotein or (c) by enzymatic degradation of the drug. Of these,
target alteration and enzymatic degradation are well-established
causes of pyrethroid resistance in a range of arthropod pests and
ectoparasites but have not yet been studied in S. scabiei.
10.3. Ivermectin Resistance
Ivermectin is a macrocyclic lactone antibiotic that has a broad

spectrum of activity against numerous nematodes and arthropods.
It has been widely used for treatment of sarcoptic mange in animals
in topical, oral and parenteral preparations. In humans it has
been used since the mid 1980s for treatment of filarial infection
and strongyloidiasis. More recently, it has been shown to be effi-
cacious as an oral treatment for scabies in humans. It is particularly
useful in institutional outbreaks, and for treatment of crusted
scabies. However, clinical and in vitro ivermectin resistance have
now been observed in mites collected from two patients who
had recurrent episodes of crusted scabies over a 10-year period
(Currie et al., in press). These patients had received 30 and 58 doses
of ivermectin over 4 and 4.5 years, respectively.
10.3.1. Mechanisms of ivermectin resistance
Ivermectin resistance has become a major problem in veterinary

practice where resistance among gastrointestinal nematodes is
now widespread. This has led to intensive investigation of the
mechanism of resistance (Prichard, 2001). Available evidence
indicates that the mechanism of resistance in nematodes is likely
to be complex, and perhaps mulifactorial. However, two candidate
mechanisms are well-established: firstly, mutations in glutamate-
gated chloride channels (GluCl), where for example, ivermectin
resistance in the ruminant gut nematode Haemonchus contortus
has been associated with two alternatively spliced GluCl cDNAs
(Prichard, 2001); and secondly, alteration in P-glycoprotein (Pgp)
expression (Prichard, 2001).
Ivermectin is known to be both a substrate for, and an inhibitor
of the Pgp family of membrane transport proteins. Pgp’s are
members of the superfamily of ATP-binding Cassettes (ABC
transporters), and pump a large range of substances, including
heavy metals and xenobiotics out of cells. Their hyperproduction has
been associated with broad spectrum resistance to cytotoxic cancer

drugs, hence the term multi-drug resistant genes (MDR). In some
isolates of the malaria parasite Plasmodium falciparum, amplification
or mutation of a Pgp gene ( pfmdr1) is associated with chloroquine
resistance (Foote et al., 1990; Reed et al., 2000). The association of
Pgp with ivermectin resistance in parasitic nematodes has been
demonstrated at the level of allelic polymorphism in a number of
studies (Blackhall et al., 1998; Xu et al., 1998; Sangster and Gill,
1999; Le Jambre et al., 2000). Increased transcription of Pgp mRNA
among ivermectin-resistant strains of H. contortus has also been
reported (Xu et al., 1998).
Which of these two mechanisms causes ‘‘field’’ resistance to
ivermectin in arthropods, such as the scabies mite, is undetermined as
to date only laboratory strains produced by chemical mutagenesis
have been studied (Kane et al., 2000). Support for a possible role
of Pgp in ivermectin resistance in arthropods comes from a study
of the effect of the Pgp inhibitor verapamil, on the effect of ivermectin
resistance on the mosquito Culex pipiens, where addition of the
drug resulted in a reduction of the LD50 of ivermectin by 50% (Buss
et al., 2002).
10.4. Consequences of Drug Resistance
Experience with both acarid and insect pests, as demonstrated

in human head lice, shows that once drug resistance becomes
established management is difficult. Detection of resistance in scabies
mites is currently dependent on the analysis of clinical efficacy and/or
in vitro drug sensitivity assay. Clinical diagnosis of resistance is
hampered by difficulties confirming the diagnosis through identifica-
tion of mites or eggs, and by difficulties in distinguishing between
active infestation, residual skin reaction, or reinfestation. This is
particularly so given the frequent dissociation between resolution
of symptoms such as itching, and cure. Thus the evaluation of
the efficacy of acaricides in both individual patients and in controlled
clinical trials is troublesome, costly, time consuming and unreliable.
The establishment of an in vitro assay has now provided a more

sensitive approach than clinical observation (Walton et al., 2000).
However, unless the patient has crusted scabies, there are often fewer
than 10 mites per individual thus hampering the use of the in vitro
test. To define the extent of permethrin and ivermectin resistance in
scabies mites there is an urgent need to develop better tools
to monitor for drug resistance. Such molecular tools have
been developed and successfully applied to monitor for pesticide
resistance in many agricultural and veterinary settings, (including the
phylogenetically-related cattle tick) (Guerrero et al., 2002). However,
little work has been undertaken in human scabies.
11. NOVEL ACARICIDES
Management of drug resistance is difficult and clearly, development

of novel therapies to protect against the emergence of acaricide
resistance would be highly advantageous to the individual and to
society at large. The essential oil of the Tea tree is an Australian
Aboriginal traditional medicine for bruises, insect bites, and skin
infections (Budhiraja et al., 1999) and is a membrane active biocide
extracted from the tree Melaleuca alternifolia. It was rediscovered
in the 1920s as a topical antiseptic which was more effective than
phenol (Mantle et al., 2001). Numerous studies have demonstrated
its antimicrobial activity against Gram-positive bacteria (e.g.
Staphylococcus aureus) (Raman et al., 1995), Gram-negative bacteria
(e.g. Escherichia coli), yeast (e.g. Candida albicans) and viral
organisms (e.g. Herpes simplex viruses) (Carson and Riley, 1995)
and recently its anti-ectoparasitic activity (Walton et al., in press;
Walton et al., 2000). The chemical composition of Tea tree oil (TTO)
is well defined and the primary active components are the oxygenated
terpenoids (Cox et al., 2001). A large variation in oil composition
occurs naturally but two identified significant components include
terpinen-4-ol and 1,8-cineole. Terpinen-4-ol can constitute up to
approximately 40% of some TTOs (Cox et al., 2001). Recent in vitro
results suggest Tea tree oil has a potential role as a new topical
acaricide and that terpinen-4-ol is the primary active component

(Walton et al., in press).
Terpenoid compounds which are chemical constituents of essential
oils have long been known to be insect repellent. The essential oil
from the leaves of Lippia multiflora Moldenke (Verbenaceae), a
shrub found growing in West Africa Savannah, also contains the
active components of terpineol, alpha- and beta-pinene and has been
tested for its pediculocidal and scabicidal activites (Oladimeji et al.,
2000). A 20% v/v preparation of lippia oil applied to scabietic
subjects for five consecutive days gave 100% cure compared with
87.5% cure obtained for benzyl benzoate preparation of the same
concentration.
12. RECOMBINANT DNA TECHNOLOGY APPLICATIONS IN

SCABIES RESEARCH
12.1. Identification of Clones by Screening Expression

Libraries With Antibodies
Recombinant DNA technology has had a major impact on our

understanding of many organisms and biological processes over the
past three decades. The polymerase chain reaction (PCR) has greatly
enhanced the power of recombinant DNA by providing a sensitivity
which can allow the detection of as little as one molecule in some
circumstances. Cloned complementary DNA (cDNA) copies of
mRNAs are amenable to expression of individual gene products in
other organisms, for example Eschericia coli, and an ever widening
array of eukaryotic cells. In order to identify gene products that were
antigens from infectious agents, Kemp et al. (1983) introduced the
approach of screening libraries of expression clones with serum from
people or animals who had been heavily exposed to the agent, using
serum from people who had not been exposed to the disease as
controls.
Since the isolation of malaria antigens by expression screening
(Kemp et al., 1983), cDNA libraries have been widely used in the
field of parasitology as a means for isolating and characterising

antigenic proteins. They have been used in studies involving parasites
including the sheep scab mite Psoroptes ovis (Lee et al., 1999), cattle
tick Boophilus microplus (Rand et al., 1989), Schistosoma spp.
(Simpson and Knight, 1986; Scott and McManus, 1999), Onchocerca
volvulus (Unnasch et al., 1988; Lizotte-Waniewski et al., 2000),
Leishmania spp. (Kidane et al., 1989; Melby et al., 2000) and the
house dust mites D. pteronyssinus (Chua et al., 1990; Greene et al.,
1991; Chua et al., 1993), D. farinae (Dilworth et al., 1991; Aki et al.,
1994; Fujikawa et al., 1996) and E. maynei (Epton et al., 1999).
Because of the lack of an in vitro culture system and the difficulty
in obtaining large numbers of mites, such libraries of cloned
cDNA molecules were not been generated for S. scabiei until recently.
As a consequence immunological studies have lagged far behind
those on many other parasites, relying on crude antigen extracts
prepared from whole mite bodies. While it is clear that there are
antibodies to molecules in such extracts, their identity is unknown.
The availability of cloned DNA molecules will also stimulate
other areas of study. In the first report of cloned DNA from
S. scabiei, Walton et al. (1997) utilised shed skin from the bedding
of hospitalised crusted scabies patients as a non-invasive source
of up to 4000 mites per gram of skin. EcoRI genomic fragments of
S. scabiei var. hominis DNA obtained from this material were cloned
in the vector gt10 (Walton et al., 1997) and used to isolate
microsatellite sequences. The availability of microsatellite DNA
fingerprinting of individual scabies mites has led to important insights
in the understanding of the structure of scabies mite populations
(see Section 5.3).
A library of cDNA clones was constructed in the vector ZAP,
using mRNA from S. scabiei var. vulpes (Mattsson et al., 2001).
The red fox (Vulpes vulpes) is highly susceptible to scabies and a total
of 160 mg of mites were obtained. A highly efficient packaging
system enabled the generation of 106 plaque-forming units. This
vector expresses polypeptides fused to a fragment of galactosidase.
The library was screened with hyperimmune rabbit serum and
cDNA clones encoding paramyosin and myosin were identified.
The complete sequence of paramyosin was determined (accession

number AF317670, Mattsson et al., 2001). Western blotting studies
demonstrated that the recombinant paramyosin protein was recog-
nised by sera from infected animals, the first demonstration at least
in principle, of a cloned immunodiagnostic reagent for scabies.
More recently Harumal et al. (2003) and Fisher et al. (2003a) have
overcome the problem of obtaining sufficient S. scabiei var hominis.
Several hundred mites from skin fragments in the bedding of crusted
scabies patients were used for preparation of mRNA. A fraction of
this was copied into cDNA, amplified by PCR and cloned in the
expression vector pGEX4T-2. Libraries of about 105 clones were
obtained both from cDNA primed with oligo dT and from randomly-
primed cDNA (Harumal et al., 2003). The remainder of the mRNA
was used to construct a ZAP library, again using a highly effici-
ent packaging system. About 3 105 plaque forming units were
obtained (Fischer et al., 2003a). These libraries are suitable for
isolation of candidate allergens, immunodiagnostic molecules and
vaccine molecules by antibody screening. Harumal et al. (2003)
described the isolation of two clones using immunoscreening of the
pGEX4T-2 randomly-primed library with serum from rabbits hyper-
infested with S. scabiei var. canis. These were designated Sarcoptes
scabiei antigen 1 (Ssag1, accession number BM176880) and Ssag2
(BM176881). The sequence of Ssag2 was found to be almost identi-
cal to a var. vulpes EST of unknown identity (BG817678), however
it showed no other significant matches in GenBank (Harumal et al.,
2003). Ssag1 was determined to be the S. scabiei homologue of the
major house dust mite allergen M-177. The cloned polypeptide was
expressed as a glutathione S-transferase fusion, purified by affinity
chromatography on immobilised glutathione and used to prepare
antibodies in rabbits. The antisera reacted specifically with mites in
sections through highly infested human skin. The staining was spread
over a number of internal organs and eggs, consistent with its
identification by sequencing as the homologue of a haemolymph
apolipoprotein of house dust mites. Purified Ssag1 reacted with sera
from rabbits infested with S. scabiei var. canis and the immunopre-
cipitate bound human IgE from a patient with crusted scabies,
demonstrating the presence of an IgE epitope. Sera from rabbits

immunised with D. farinae, D. pteronyssinus and E. maynei also
reacted with purified Ssag1, as might be expected from the sequence
homology. Rabbits immunised with Ssag1 did not show protection
against S. scabiei var. canis but the rabbits did not exhibit typical
crust characteristics (Harumal et al., 2003). Nevertheless this
experiment is important as it demonstrates that it is now possible
to carry out such challenge trials with cloned scabies antigens.
12.2. S. scabiei Gene Discovery
By far the most powerful current approach to the discovery of genes

in such cDNA libraries is automated high-throughput random
sequencing generating so called ‘‘Expressed Sequence Tag’’ (EST)
libraries. A pilot scale EST approach with 156 cDNA clones of
the S. scabiei var. hominis ZAP library was undertaken (Fischer
et al., 2003a). Of these, 11 ESTs failed the specified sequence quality
criteria while three were considered to be contaminating DNA of
human origin. Thirty-nine sequences showed no significant homology
to any sequence in the GenBank non redundant database. These
ESTs were submitted to the GenBank EST database as probable
S. scabiei var. hominis sequences and were assigned the accession
numbers BM276682 to BM276719. A further 94 sequences showed
significant matches to sequences in the GenBank non redundant
database and these were submitted to the EST database with the
accession numbers BM276587–BM276681. Of particular interest
was the identification of S. scabiei homologues of the known house
dust mite allergens glutathione S-transferase (assigned accession
number AF462190) and paramyosin (AF452195). In addition, three
clones representing a longer segment of Ssag1 (the combined
sequence has the accession number AF462196) were found. Other
clones showed a high level of identity to the cysteine protease
cathepsin L (AF462189), vitellogenin (AF462194) and the mito-
chondrial sequences cytochrome oxidase subunits I (AF462191), II
(AF462192) and cytochrome Bc1 (AF462193) (Fischer et al., 2003a).
Further libraries were derived from the var. hominis ZAP libraries
after a process of normalisation, in which the most abundant
transcripts were removed (Fischer et al., 2003b). A total of 43,776
cDNA clones from the var. hominis ZAP and normalised ZAP
libraries have now been sequenced at the Australian Genome
Research Facility and analysis of these sequences is underway.
This has identified many important genes including candidate
allergens and immunodiagnostic molecules, molecules of value in
understanding the population structure of scabies and candidate
vaccine molecules (Holt, D.C., Fischer, K., Walton, S.F. and Kemp,
D.J., unpublished observations).
EST analysis has also now been undertaken on the var. vulpes
cDNA library (Ljunggren et al., 2003). Over 1000 clones with inserts
over 500 bp were sequenced, resulting in 904 additional sequences
being made available in the GenBank EST database under the
accession numbers BG817579–BG817974, BM521860–BM522350,
BM564941–BM564942 and CA305267–CA305281. The sequences
were grouped into 76 clusters (67% of which contained two or three
sequences) and 576 singletons. A putative identity was assigned to
48% of the sequences and of these, over half could be classified as
being involved in metabolism (28%), cellular organisation (14%) or
protein synthesis (10%). Homologues of the house dust mite group 1
(cysteine protease), 8 (glutathione S-transferase), 10 (tropomyosin)
and 13 (fatty acid binding protein) allergens were identified, as were
another cysteine protease cathepsin L, and an aspartic protease
cathepsin D. Many sequences were found to contain known protein
motifs, including a large group of transcripts which contained
trypsin inhibitor-like cysteine rich domains. The function of these S.
scabiei molecules is not known but the high number of transcripts
(3%) indicates that it is highly expressed in the mites and may have
an important role which warrants further investigation (Mattsson
et al., 2001).
A useful comparison to the S. scabiei EST libraries may be the
EST sequencing project for the sheep scab mite Psoroptes ovis
(Kenyon et al., 2003). This project analysed the sequences of 507
P. ovis cDNA clones with inserts over 500 bp in length. A total of
49 clusters containing more than one sequence, and 231 singletons

were identified. Forty-five of the ESTs (9%) showed homology to
sequences of known house dust mite allergens. Homologues of the
group 1 (cysteine protease), 2, 5, 7, 8 (glutathione S-transferase),
10 (tropomyosin), 11 (paramyosin) and 13 (fatty acid binding
protein) allergens were identified. The most abundant transcripts
(20 ESTs-4%) were the homologues of the group 2 house dust
mite allergens. This is a significant contrast to what has been seen
in S. scabiei, in which no homologues of this allergen have
been reported in either the var. hominis or var. vulpes EST projects
so far.
A number of other interesting genes were identified including free
radical scavenging enzymes, a heat shock protein and additional
cysteine proteases cathepsin L and cathepsin B, which may be
involved in lesion development. A total of 47.5% of the ESTs did not
show significant homology to any sequence in the GenBank non-
redundant database and were thus considered to be novel sequences.
Interestingly, this included six clusters which contained at least eight
sequences indicating that some of these are highly expressed genes
(Kenyon et al., 2003).
The differences in expression levels of homologous genes, as well as
the presence or absence of particular genes, may help to identify
those gene products which are especially important in the differing
host immune responses and disease aetiology caused by related mite
species. EST projects have allowed the observation of large
differences in the gene expression levels of certain allergens between
S. scabiei and D. pteronyssinus, which may well reflect the differences
in their respective parasitic and non-parasitic habits (Holt et al.,
in press).
12.3. The Scabies Mite Inactivated Protease

Paralogues (SMIPPs)
The group 3 allergens of house dust mites have been extensively

studied. They are trypsin-like serine proteases which are secreted into
the gut of the mites where they are presumably involved in digestion
(Stewart et al., 1992; Ando et al., 1993; Smith et al., 1994). They are
excreted in faecal pellets which can become aerosols and a high
proportion of asthma patients have been shown to have a strong IgE
reaction to house dust mite group 3 allergens (Stewart et al., 1992;
Ando et al., 1993).
A total of 19,488 EST sequences from the S. scabiei var. hominis
libraries were analysed to identify those clones with homology to the
group 3 house dust mite allergens (Holt et al., 2003). Fifty-four clones
were identified which fell into 24 distinct contigs. One of these contigs
appeared to encode the scabies mite orthologue of house dust mite
group 3 allergens and hence it was designated Sar s 3. It has an
identical pattern of six conserved cysteine residues and a conserved
proenzyme cleavage site, as well as the catalytic triad of histidine,
aspartic acid and serine essential for catalytic activity of serine
proteases (Holt et al., 2003).
All other scabies mite group 3 allergen homologues examined
lacked the same two of the six conserved cysteine residues, namely
those which flank the active serine (Rawlings and Barrett, 1994) in the
house dust mite proteins and the putative Sar s 3. However, their
most remarkable feature was that with the exception of Sar s 3, not
one of them encoded a putative protein with an intact catalytic triad.
In each of the contigs the serine residue of the catalytic triad has been
substituted, most commonly by an alanine. In all but one of those
contigs, the catalytic histidine and/or the aspartic acid residues have
also been substituted. This indicates that these molecules cannot
function as serine proteases using any known mechanism.
These inactivated proteases were designated Scabies Mite
Inactivated Protease Paralogues (SMIPPs). Limited studies with
single mites suggested multiple genes in individual mites (Holt et al.,
2003). The size of this gene family in S. scabiei was not anticipated
as the D. pteronyssinus group 3 allergen Der p 3 has been considered
to be the product of a single gene (Smith and Thomas, 1996), even
though genomes of comparable organisms encode many serine
proteases (Rubin et al., 2000). Southern blotting experiments of
seven available Der p 3 sequences indicated four were identical in
the coding region while another two showed 98.7% identity. The
partial sequence of the remaining clone only showed 84.4% amino
acid identity to the other sequences and appeared to encode a more
distantly related gene (Smith and Thomas, 1996). The transcripts
encoding these inactivated molecules in S. scabiei are collectively
much more abundant than the putative active molecule for which a
single transcript was found in the 19,488 sequences examined (Holt
et al., 2003).
Phylogenetic analysis of the SMIPP genes indicated that at least
some of the genes had duplicated after inactivation of the proteolytic
activity had occurred. In addition, synonymous changes greatly
exceeded non-synonymous changes. This suggests that although these
molecules no longer function as active proteases, they must be under
selection for some other function.
The SMIPPs retain significant homology to the active serine
proteases and may well retain the ability to bind to peptides while not
being capable of cleaving them. Thus they may act as antagonists of
active proteases by competing for their peptide substrates. House
dust mite group 3 and group 9 (also serine proteases) allergens are
known to bind to and activate protease activated receptor (PAR) 2
on the surface of human pulmonary epithelial cells, inducing cytokine
release (Sun et al., 2001). PAR-2 is also present on the surface of
keratinocytes (Shpacovitch et al., 2002). Therefore SMIPPs may be
capable of binding to PAR-2 but not activating it thus protecting the
scabies mite from the inflammatory response resulting from
activation of these receptors. Another possibility is that SMIPPs
may bind to host serine protease inhibitors thus protecting Sar s 3
from inactivation by these molecules (Holt et al., 2003).
Initial analysis of S. scabiei cysteine protease homologues of the
house dust mite group 1 allergens revealed that inactivated cysteine
proteases are also found. Marked differences in the transcript levels
of group 1 allergens between the S. scabiei and D. pteronyssinus were
also detected (Holt et al., in press). The presence of SMIPPs of
both serine and cysteine proteases in S. scabiei which have not
been reported in house dust mites, may well represent an adaptation
of the scabies mite to parasitism.
13. CONCLUSION
Despite scabies being a public health and veterinary concern

worldwide for many thousands of years there, is relatively negligible
information available on the host-parasite interactions of this
important parasitic mite. Research has been hampered by limitations
associated with obtaining mites from infested human and animal
hosts, lack of an in vitro culture system and difficulties in establishing
animal models. Identification of the specific host immune responses
which are effective in clearing infestation have been unobtainable due
to lack of purified S. scabiei antigens/allergens. With molecular
information now defining the taxonomy of scabies mites and the
public availability of libraries of cDNA clones and EST databases
derived from human and fox mites, recent progress in scabies
molecular research has significantly contributed to the increased
understanding of S. scabiei biology. More importantly with many
scabies mite homologues of house dust mite allergens already cloned
and the identification of many more novel molecules imminent,
fascinating and unexpected molecular discoveries will soon emerge.
Parasite secretions and hidden antigens are recognised as playing key
roles in stimulating and modulating host tissue responses and the
discovery of new S. scabiei gene families and their products can only
further provide interesting insights into molecular biology and host
immune evasion strategies of the scabies mite. Scabies research has
indeed taken a leap into the molecular era and recent molecular
advances provides the potential for novel strategies aimed towards
the prevention, diagnosis, treatment, control and immunotherapy of
this important but neglected parasite.
ACKNOWLEDGEMENTS
This work was supported by the Australian National Health and

Medical Research Council grants 137205, 137206 and 219175, the
Channel 7 Children’s Research Foundation of South Australia and
the Cooperative Research Centre for Aboriginal and Tropical

Health.
REFERENCES
Adedayo, O., Grell, G. and Bellot, P. (2003). Hospital admissions for

human T-cell lymphotropic virus type-1 (HTLV-1) associated diseases
in Dominica. Postgradate Medical Journal 79, 341–344.
Aki, T., Ono, K., Paik, S.Y., Wada, T., Jyo, T., Shigeta, S., Murooka, Y.
and Oka, S. (1994). Cloning and characterization of cDNA coding for
a new allergen from the house dust mite Dermatophagoides farinae.
International Archives of Allergy and Immunology 103, 349–356.
Alexander, J.O. (1984). Arthropods and Human Skin, p. 227. Berlin and
Heidelberg: Springer-Verlag.
Al-Rawashdeh, O.F., Al-Ani, F.K., Sharrif, L.A., Al-Qudah, K.M.,
Al-Hami, Y. and Frank, N. (2000). A survey of camel (Camelus
dromedarius) diseases in Jordan. Journal of Zoology and Wildlife Medicine
31, 335–338.
Anderson, T.J.C., Romero-Abal, M.E. and Jaenike, J. (1993). Genetic
structure and epidemiology of Ascaris populations: patterns of host
affiliation in Guatemala. Parasitology 107, 319–334.
Anderson, T.J.C., Romero-Abal, M.E. and Jaenike, J. (1995).
Mitochondrial DNA and Ascaris microepidemiology: the composition
of parasite populations from individual hosts, families, and villages.
Parasitology 110, 221–229.
Ando, T., Homma, R., Ino, Y., Ito, G., Miyahara, A., Yanagihara, T.,
Kimura, H., Ikeda, S., Yamakawa, H., Iwaki, M., et al. (1993).
Trypsin-like protease of mites: purification and characterization of
trypsin-like protease from mite faecal extract Dermatophagoides farinae.
Relationship between trypsin-like protease and Der f III. Clinical and
Experimental Allergy 23, 777–784.
Andrews, J.R.H. (1991). Epidemiology of scabies Sarcoptes scabiei.
In: Modern Acarology (F. Dusbabek and V. Bukva, eds.), Vol. 1,
pp. 281–285. Prague: Academia.
Arlian, L.G. (1989). Biology, host relations, and epidemiology of Sarcoptes
scabiei. Annual Review of Entomology 34, 139–161.
Arlian, L.G., Estes, S.A. and Vyszenski-Moher, D.L. (1988a). Prevalence
of Sarcoptes scabiei in the homes and nursing homes of scabietic pati-
ents. The Journal of the American Academy of Dermatology 19, 806–811.
Arlian, L.G., Morgan, M.S. and Arends, J.J. (1996a). Immunologic cross-
reactivity among various strains of Sarcoptes scabiei. Journal of
Arlian, L.G., Morgan, M.S., Estes, S.A., Walton, S.F., Kemp, D.J. and
Currie, B.J. (2004). Circulating IgE in patients with ordinary and crusted
scabies. Journal of Medical Entomology 41, 74–77.
Arlian, L.G., Morgan, M.S., Rapp, C.M. and Vyszenski-Moher, D.L.
(1996b). The development of protective immunity in canine scabies.
Veterinary Parasitology 62, 133–142.
Arlian, L.G., Morgan, M.S., Vyszenski-Moher, D.L. and Stemmer, B.L.
(1994a). Sarcoptes scabiei: The circulating antibody response and
induced immunity to scabies. Experimental Parasitology 78, 37–50.
Arlian, L.G., Rapp, C.M. and Morgan, M.S. (1995). Resistance and imm-
une response in scabies-infested hosts immunised with Dermatophagoides
mites. American Journal of Tropical Medicine and Hygiene 52, 539–545.
Arlian, L.G., Rapp, C.M., Vyszenski-Moher, D.L. and Morgan, M.S.
(1994b). Sarcoptes scabiei: Histopathological changes associated with
acquisition and expression of host immunity to scabies. Experimental
Arlian, L.G., Runyan, R.A., Achar, S. and Estes, S.A. (1984a). Survival and
infestivity of Sarcoptes scabiei var. canis and var. hominis. The Journal of
the American Academy of Dermatology 11, 210–215.
Arlian, L.G., Runyan, R.A. and Estes, S.A. (1984b). Cross infestivity of
Sarcoptes scabiei. Journal of the American Academy of Dermatology 10,
979–986.
Arlian, L.G., Runyan, R.A., Sorlie, L.B. and Estes, S.A. (1984c). Host-
seeking behaviour of Sarcoptes scabiei. The Journal of the American
Academy of Dermatology 11, 594–598.
Arlian, L.G. and Vyszenski-Moher, D.L. (1988). Life Cycle of Sarcoptes
scabiei var canis. Journal of Parasitology 74, 427–430.
Arlian, L.G., Vyszenski-Moher, D.L., Ahmed, S.G. and Estes, S.A. (1991).
Cross-antigenicity between the scabies mite, Sarcoptes scabiei, and the
house dust mite, Dermatophagoides pteronyssinus. Journal of Investigative
Dermatology 96, 349–354.
Arlian, L.G., Vyszenski-Moher, D.L. and Cordova, D. (1988b). Host
specificity of S. scabiei var. canis (Acari: Sarcoptidae) and the role of
host odour. Journal of Medical Entomology 25, 52–56.
Arlian, L.G., Vyszenski-Moher, D.L. and Gilmore, A.M. (1988c). Cross-
antigenicity between Sarcoptes scabiei and the house dust mite,
Dermatophagoides farinae (Acari: Sarcoptidae and Pyroglyphidae).
Journal of Medical Entomology 25, 240–247.
Avise, J. (1994). Molecular Markers, Natural History, and Evolution,
pp. 324–326. New York: Chapman & Hall.
Backhouse, T.C. (1929). Sarcoptic skin disease in natives of the territory of
New Guinea. Transactions of the Royal Society of Tropical Medicine 23,
173–178.
Bailey, A.M. and Prociv, P. (2000). Persistent head lice following multiple
treatments: evidence for insecticide resistance in Pediculus humanus
capitis. Australasian Journal of Dermatology 41, 250–254.
Barkwell, R. and Shields, S. (1997). Deaths associated with ivermectin
treatment for scabies. The Lancet 349, 1144–1145.
Bates, P. (2003). Sarcoptic mange (Sarcoptes scabiei var. vulpes) in a red fox
(Vulpes vulpes) population in north-west Surrey. Veterinary Records 152,
112–114.
Beck, A.L. (1965). Animal scabies affecting man. Archives of Dermatology
91, 54–55.
Berrilli, F., D’Amelio, S. and Rossi, L. (2002). Ribosomal and mitochon-
drial DNA sequence variation in Sarcoptes mites from different hosts
and geographical regions. Parasitology Research 88, 772–777.
Blackhall, W., Liu, H., Xu, M., Prichard, R. and Beech, R. (1998). Selection
at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains
of Haemonchus contortus. Molecular and Biochemical Parasitology 95,
193–201.
Bornstein, S., Thebo, P. and Zakrisson, G. (1996). Evaluation of an enzyme-
linked immunosorbant (ELISA) for the serological diagnosis of canine
sarcoptic mange. Veterinary Dermatology 7, 21–27.
Bornstein, S. and Wallgren, P. (1997). Serodiagnosis of sarcoptic mange in
pigs. Veterinary Record 141, 8–12.
Bornstein, S. and Zakrisson, G. (1994). Humoral antibody response to
experimental Sarcoptes scabiei var. vulpes infection in the dog. Veterinary
Bremner, P.R., de Klerk, N.H., Ryan, G.F., James, A.L., Musk, M.,
Murray, C., Le Souef, P.N., Young, S., Spargo, R. and Musk, A.W.
(1998). Respiratory symptoms and lung function in aborigines from
tropical Western Australia. American Journal of Respiratory and Critical
Care Medicine 158, 1724–1729.
Brites, C., Weyll, M., Pedroso, C. and Badaro, R. (2002). Severe and
Norwegian scabies are strongly associated with retroviral (HIV-1/HTLV-
1) infection in Bahia, Brazil. Aids 16, 1292–1293.
Brodell, R.T. and Helms, M.D. (1991). Office dermatolgic testing: the
scabies preparation. American Family Physician 44, 505–508.
Brook, I. (1995). Microbiology of secondary bacterial infection in scabies
lesions. Journal of Clinical Microbiology 33, 2139–2140.
Budhiraja, S.S., Cullum, M.E., Sioutis, S.S., Evangelista, L. and
Habanova, S.T. (1999). Biological activity of Melaleuca alternifola
(Tea Tree) oil component, terpinen-4-ol, in human myelocytic cell line
HL-60. Journal of Manipulative and Physiological Therapeutics 22, 447–453.
Burgess, I. (1994). Sarcoptes scabiei and scabies. Advances in Parasitology
33, 235–292.
Bush, G. (1975). Modes of animal speciation. Annual Review of Ecological

Systems 6, 339–364.
Buss, D., McCaffery, A. and Callaghan, A. (2002). Evidence for p-glyco-
protein modification of insecticide toxicity in mosquitoes of the Culex
pipiens complex. Medical and Veterinary Entomology 16, 218–222.
Cabrera, R. and Dahl, M.V. (1993). The immunology of scabies. Seminars
in Dermatology 12, 15–21.
Campbell, W. (1991). Ivermectin as an antiparasitic agent for use in
humans. Annual Review of Microbiology 45, 445–474.
Carapetis, J., Connors, C., Yarrmirr, D., Krause, V. and Currie, B. (1997).
Success of a scabies control program in an Australian Aboriginal
community. Pediatric Infectious Disease Journal 16, 494–499.
Carapetis, J. and Currie, B. (1996). Group A streptococcus, pyoderma, and
rheumatic fever. The Lancet 347, 1271–1272.
Cargill, C.F., Pointon, A.M., Davies, P.R. and Garcia, R. (1997). Using
slaughter inspections to evaluate sarcoptic mange infestation of finishing
swine. Veterinary Parasitology 70, 191–200.
Carslaw, R.W. (1975). Scabies in spinal injuries ward. British Medical
Journal 2, 617.
Carson, C. and Riley, T. (1995). Antimicrobial activity of the major
components of the essential oil of Melaleuca alternifolia. Journal of
Applied Bacteriology 78, 264–269.
Cass, A., Cunningham, J., Wang, Z. and Hoy, W. (2001). Regional
variation in the incidence of end-stage renal disease in Indigenous
Australians. Medical Journal of Australia 175, 24–27.
Chakrabarti, A., Chatterjee, A., Chakrabarti, K. and Sengupta, D.N.
(1981). Human scabies from contact with water buffaloes infested
with Sarcoptes scabiei var. bubalis. Annals of Tropical Medicine and
Charlesworth, E.N. and Johnson, J.L. (1974). An epidemic of canine scabies
in man. Archives of Dermatology 110, 572–574.
Chosidow, O. (2000). Scabies and pediculosis. The Lancet 355, 819–826.
Chosidow, O. Ivermectin: main results of efficacy and safety data in scabies.
20th World Congress of Dermatology.
Chua, K.Y., Doyle, C.R., Simpson, R.J., Turner, K.J., Stewart, G.A. and
Thomas, W.R. (1990). Isolation of cDNA coding for the major mite
allergen Der P II by IgE plaque immunoassay. International Archives of
Allergy and Applied Immunology 91, 118–123.
Chua, K.Y., Kehal, P.K. and Thomas, W.R. (1993). Sequence polymor-
phisms of cDNA clones encoding the mite allergen Der p I. International
Archives of Allergy and Applied Immunology 101, 364–368.
Commens, C. (1994). We can get rid of scabies: new treatment available
soon. The Medical Journal of Australia 160, 317–318.
Coskey, R. (1979). Scabies-resistance to treatment with crotamiton. Archives

of Dermatology 115, 109.
Cox, S.D., Mann, C.M. and Markham, J.L. (2001). Interactions between
components of the essential oil of Melaleuca alternifolia. Journal of
Applied Microbiology 91, 492–497.
Croom, H.B., Gillespie, R.G. and Palumbi, S.R. (1991). Mitochondrial
DNA sequences coding for a portion of the RNA of the small ribosomal
subunits of Tetragnatha mandibulata and Tetragnatha hawaiensi (Arenae,
Tetragnathidae). The Journal of Arachnology 19, 210–214.
Currie, B. and Carapetis, J. (2000). Skin infections and infestations in
Aboriginal communities in northern Australia. Australian Journal of
Currie, B., Huffam, S., O’Brien, D. and Walton, S. (1997). Ivermectin for
scabies. The Lancet 350, 1551.
Currie, B.J. and Brewster, D.R. (2002). Rheumatic fever in Aboriginal
children. J Paediatr Child Health 38, 223–225.
Currie, B.J., Connors, C.M. and Krause, V.L. (1994). Scabies programs
in Aboriginal communities. The Medical Journal of Australia 161, 636–637.
Currie, B.J., Harumal, P., McKinnon, M. and Walton, S.F. (in press). First
documentation of in vivo and in vitro ivermectin resistance in Sarcoptes
scabiei. Clinical Infectious Diseases.
Currie, B.J., Maguire, G.P. and Wood, Y.K. (1995). Ivermectin and crusted
(Norwegian) scabies. The Medical Journal of Australia 163, 559–560.
Davies, J.E., Dedhia, H.V., Morgade, C., Barquet, A. and Maibach, H.I.
(1983). Lindane poisonings. Archives of Dermatology 119, 142–144.
Davies, P.R., Bahnson, P.B., Grass, J.J., Marsh, W.E., Garcia, R.,
Melancon, J. and Dial, G.D. (1996). Evaluation of the monitoring of
papular dermatitis lesions in slaughtered swine to assess sarcoptic mite
infestation. Veterinary Parasitology 62, 143–153.
Davis, D.P. and Moon, R.D. (1990). Dynamics of swine mange: a critical
review of the literature. Journal of Medical Entomology 27, 727–737.
del Giudice, P., Chosidow, O. and Caumes, E. (2003). Ivermectin in
dermatology. Journal of Drugs in Dermatology 2, 13–21.
Dilworth, R.J., Chua, K.Y. and Thomas, W.R. (1991). Sequence analysis of
cDNA coding for a major house dust mite allergen, Der f I. Clinical and
Experimental Allergy 21, 25–32.
Dunne, C.L., Malone, C.J. and Whitworth, J.A.G. (1991). A field study of
the effects of ivermectin on ectoparasites of man. Transactions of the
Royal Society of Tropical Medicine 85, 550–551.
Eason, R.J. and Tasman-Jones, T. (1985). Resurgent yaws and other skin
diseases in the Western province of the Solomon Islands. Papua New
Guinea Medical Journal 28, 247–250.
Editorial (1976). IgE, parasites, and allergy. The Lancet 1, 894–895.
Elbers, A.R., Rambags, P.G., van der Heijden, H.M. and Hunneman, W.A.
(2000). Production performance and pruritic behaviour of pigs naturally
infected by Sarcoptes scabiei var. suis in a contact transmission
experiment. Veterinary Quarterly 22, 145–149.
Elgart, M.L. (1990). Scabies. Dermatologic Clinics 8, 253–263.
Elgart, M.L. and Higdon, R.S. (1972). Canine scabies: report of a family
outbreak. Southern Medical Journal 3, 375–376.
Epton, M., Dilworth, R., Smith, W., Hart, B. and Thomas, W. (1999). High-
molecular weight allergens of the house dust mite: an apolipophorin-
like cDNA has sequence identity with the major M-177 allergen and the
IgE-binding peptide fragments Mag1 and Mag3. International Archives
of Allergy and Immunology 120, 185–191.
Estes, S.A. and Estes, J. (1993a). Scabies research: Another dimension.
Seminars in Dermatology 12, 34–38.
Estes, S.A. and Estes, J. (1993b). Therapy of scabies: Nursing homes,
hospitals, and the homeless. Seminars in Dermatology 12, 26–33.
Estes, S.A., Kummel, B. and Arlian, L.G. (1983). Experimental canine
scabies in humans. Journal of the American Academy of Dermatology 9,
397–401.
Fain, A. (1978). Epidemiological problems of scabies. International Journal
of Dermatology 17, 20–30.
Falk, E. and Bolle, R. (1980a). IgE antibodies to house dust mite in patients
with scabies. British Journal of Dermatology 102, 283–288.
Falk, E. and Thorsby, E. (1981). HLA antigens in patients with scabies.
British Journal of Dermatology 104, 317–320.
Falk, E.S. and Bolle, R. (1980b). In vitro demonstration of specific immu-
nological hypersensitivity to scabies mite. British Journal of Dermatology
103, 367–373.
Falk, E.S., Dale, S., Bolle, R. and Haneberg, B. (1981). Antigens common
to scabies and house dust mites. Allergy 36, 233–238.
Fischer, K., Holt, D., Harumal, P., Currie, B., Walton, S. and Kemp, D.
(2003a). Generation and characterisation of cDNA clones from
Sarcoptes scabiei var. hominis for an expressed sequence tag library:
identification of homologues of house dust mite allergens. American
Journal of Tropical Medicine and Hygiene 68, 61–64.
Fischer, K., Holt, D.C., Wilson, P., Davis, J., Hewitt, V., Johnson, M.,
McGrath, A., Currie, B.J., Walton, S.F. and Kemp, D.J. (2003b). Nor-
malization of a library of Sarcoptes scabiei cDNAs cloned in ZAP by a
long PCR and cDNA reassociation procedure. Biotechniques 34, 250–254.
Foote, S., Kyle, D., Martin, R., Oduola, A., Forsyth, K., Kemp, D. and
Cowman, A. (1990). Several alleles of the multidrug-resistance gene are
closely linked to chloroquine resistance in Plasmodium falciparum. Nature
345, 255–258.
Fraser, J. (1994). Permethrin: a top end viewpoint and experience. The

Medical Journal of Australia 160, 806.
Fthenakis, G.C., Karagiannidis, A., Alexopoulos, C., Brozos, C. and
Papadopoulos, E. (2001). Effects of sarcoptic mange on the reproductive
performance of ewes and transmission of Sarcoptes scabiei to newborn
lambs. Veterinary Parasitology 95, 63–71.
Fujikawa, A., Ishimaru, N., Seto, A., Yamada, H., Aki, T.,
Shigeta, S., Wada, T., Jyo, T., Murooka, Y., Oka, S. and
Ono, K. (1996). Cloning and characterization of a new allergen,
Mag 3, from the house dust mite Dermatophagoides farinae: cross-
reactivity with high-molecular-weight allergen. Molecular Immunology
33, 311–319.
Funaki, B. and Elpern, D.J. (1987). Scabies epidemiology, Kauai, Hawaii,
1981–1985. International Journal of Dermatology 26, 590–592.
Funk, D.J. (1999). Molecular systematics of cytochrome oxidase I and 16S
from Neochlamisus leaf beetles and the importance of sampling.
Molecular Biology and Evolution 16, 67–82.
Georghiou, G.P. (1990). Overview of insecticide resistance. In: Managing
Resistance to Agrochemicals (M.B. Green, H.M. LeBaron, and W.K.
Moberg, eds.), Vol. 421, pp. 18–41. Washington DC: American Chemical
Society.
Gillepsie, R.G., Croom, H.B. and Palumbi, S.R. (1994). Multiple origins of
spider radiation in Hawaii. Proceedings of the National Academy of
Science USA 91, 2290–2294.
Glaziou, P., Cartel, J.L., Alzieu, P., Briot, C., Moulia-Pelat, J.P. and
Martin, P.M.V. (1993). Comparison of ivermectin and benzyl
benzoate for treatment of scabies. Tropical Medicine and Parasitology
44, 331–332.
Glover, R., Young, L. and Goltz, R. (1987). Norwegian scabies in acquired
immunodeficiency syndrome: Report of a case resulting in death
from associated sepsis. Journal of the American Academy of
Gogna, N.K., Lee, K.C. and Howe, D.W. (1985). Norwegian scabies in
Australian Aborigines. The Medical Journal of Australia 142, 140–142.
Green, M.S. (1989). Epidemiology of scabies. Epidemiologic Reviews 11,
126–150.
Greene, W.K., Cyster, J.G., Chua, K.Y., Obrien, R.M. and Thomas, W.R.
(1991). IgE and IgG binding of the peptides expressed from fragments of
cDNA encoding the major house dust mite allergen Der p I. The Journal
of Immunology 147, 3768–3773.
Guerrero, F.D., Li, A.Y. and Hernandez, R. (2002). Molecular diagnosis of
pyrethroid resistance in Mexican strains of Boophilus microplus (Acari:
Ixodidae). Journal of Medical Entomology 39, 770–776.
Harumal, P., Morgan, M.S., Walton, S.F., Holt, D.C., Rode, J.,
Arlian, L.G., Currie, B.J. and Kemp, D.J. (2003). Identification of a
homologue of a house dust mite allergen in a cDNA library from
Sarcoptes scabiei var. hominis and evaluation of its vaccine potential in a
rabbit/S. scabiei var. canis model. American Journal of Tropical Medicine
and Hygiene 68, 54–60.
Henderson, C. and Nykia, M. (1992). Treatment of scabies in rural East
Africa—a comparative study of two regimens. Tropical Doctor 22,
165–167.
Hernandez-Perez, E. (1983). Resistance to antiscabietic drugs. The Journal
of the American Academy of Dermatology 8, 1121–1122.
Hersch, C. (1967). Acute glomerulonephritis due to skin disease, with special
reference to scabies. South African Medical Journal 41, 29–34.
Hillis, D., Moritz, C. and Mable, B., eds. (1996). Molecular Systematics,
p. 521. Sunderland, MA: Sinauer Associates, Inc.
Hoefling, K.K. and Schroeter, A.L. (1980). Dermatoimmunopathology of
scabies. The Journal of the American Academy of Dermatology 3, 237–240.
Hollanders, W., Vercruysse, J., Raes, S. and Bornstein, S. (1997).
Evaluation of an enzyme-linked immunosorbent assay (ELISA) for the
serological diagnosis of sarcoptic mange in swine. Veterinary
Holness, L., DeKoven, J.G. and Nethercott, J.R. (1992). Scabies in chronic
health care institutions. Archives of Dermatology 128, 1257–1260.
Holt, D.C., Fischer, K., Allen, G.E., Wilson, D., Wilson, P., Slade, R.,
Currie, B.J., Walton, S.F. and Kemp, D.J. (2003). Mechanisms for a
novel immune evasion strategy in the scabies mite Sarcoptes scabiei: A
multigene family of inactivated serine proteases. Journal of Investigative
Holt, D.C., Fischer, K., Pizzutto, S.J., Currie, B.J., Walton, S.F. and Kemp,
D.J. (in press). A multigene family of inactivated cysteine proteases in
Sarcoptes scabiei. Journal of Investigative Dermatology.
Hopkins, R.M., Meloni, B.P., Groth, D.M., Wetherall, J.D.,
Reynoldson, J.A. and Thompson, R.C. (1997). Ribosomal RNA
sequencing reveals differences between the genotypes of Giardia isolates
recovered from humans and dogs living in the same locality. Journal of
Hoy, W. (1996). Renal disease in Australian Aboriginals. Medical Journal of
Australia 165, 126–127.
Huffam, S.E. and Currie, B.J. (1998). Ivermectin for Sarcoptes scabiei
hyperinfestation. International Journal of Infectious Disease 2, 152–154.
Jacobson, M., Bornstein, S. and Wallgren, P. (1999). The efficacy of simpli-
fied eradication strategies against sarcoptic mange mite infections in swine
herds monitored by an ELISA. Veterinary Parasitology 81, 249–258.
Jensen, J.C., Nielsen, L.H., Arnason, T. and Cracknell, V. (2002).

Elimination of mange mites Sarcoptes scabiei var. suis from two naturally
infested Danish sow herds using a single injection regime with
doramectin. Acta Veterineria Scandinavica 43, 75–84.
Kane, N.S., Hirschberg, B., Qian, S., Hunt, D., Thomas, B., Brochu, R.,
Ludmerer, S.W., Zheng, Y., Smith, M., Arena, J.P., Cohen, C.J.,
Schmatz, D., Warmke, J. and Cully, D.F. (2000). Drug-resistant
Drosophila indicate glutamate-gated chloride channels are targets for
the antiparasitics nodulisporic acid and ivermectin. Proceedings of the
National Academy Science USA 97, 13949–13954.
Kar, S.K., Mania, J. and Patnaik, S. (1994). The use of ivermectin for
scabies. The National Medical Journal of India 7, 15–16.
Kemp, D.J., Coppel, R.L., Cowman, A.F., Saint, R.B., Brown, G.V. and
Anders, R.F. (1983). Expression of Plasmodium falciparum blood-stage
antigens in Escherichia coli: detection with antibodies from immune
humans. Proceedings of the National Academy of Science USA 80,
3787–3791.
Kenyon, F., Welsh, M., Parkinson, J., Whitton, C., Blaxter, M.L. and
Knox, D.P. (2003). Expressed sequence tag survey of gene expression in
the scab mite Psoroptes ovis-allergens, proteases and free-radical
scavengers. Parasitology 126, 451–460.
Kettle, D.S. (1984). Acari-Astigmata, and Oribatida. In: Medical and
Veterinary Entomology, pp. 356–379. London and Sydney: Croom Helm.
Kidane, G.Z., Samaras, N. and Spithill, T.W. (1989). Cloning of
developmentally regulated genes from Leishmania major and expres-
sion following heat induction. Journal of Biological Chemistry 264,
4244–4250.
Kocher, T.D., Thomas, W.K., Meyer, A., Edwards, S.V., Paabo, S.,
Villablanca, F.X. and Wilson, A.C. (1989). Dynamics of mitochondrial
DNA evolution in animals: amplification and sequencing with conserved
primers. Proceedings of the National Academy of Science USA 86,
6196–6200.
Kolar, K.A. and Rapini, R.P. (1991). Crusted (Norwegian) scabies.
American Family Practice 44(4), 1317–1321.
Lawrence, G.W., Sheridan, J.W. and Speare, R. (1994). We can get rid
of scabies: new treatment available soon. Medical Journal of Australia
161, 232.
Le Jambre, L.F., Gill, J.H., Lenane, I.J. and Baker, P. (2000). Inheritance of
avermectin resistance in Haemonchus contortus. International Journal for
Lee, A.J., Isaac, R.E. and Coates, D. (1999). The construction of a cDNA
expression library for the sheep scab mite Psoroptes ovis. Veterinary
Leung, D.Y. (2000). Atopic dermatitis: new insights and opportunities for
therapeutic intervention. Journal of Allergy and Clinical Immunology 105,
860–876.
Lines, D.R. (1977). An Auckland high school health survey. The Australian
and New Zealand Journal of Medicine 7, 143–147.
Lizotte-Waniewski, M., Tawe, W., Guiliano, D.B., Lu, W., Liu, J.,
Williams, S.A. and Lustigman, S. (2000). Identification of potential
vaccine and drug target candidates by expressed sequence tag analysis
and immunoscreening of Onchocerca volvulus larval cDNA libraries.
Infection and Immunity 68, 3491–3501.
Ljunggren, E.L., Nilsson, D. and Mattsson, J.G. (2003). Expressed sequence
tag analysis of Sarcoptes scabiei. Parasitology 127, 139–145.
Loukas, A. and Prociv, P. (2001). Immune responses in hookworm
infections. Clinical Microbiology Reviews 14, 689–703.
Lower, K.S., Medleau, L.M., Hnilica, K. and Bigler, B. (2001). Evaluation
of an enzyme-linked immunosorbent assay (ELISA) for the serological
diagnosis of sarcoptic mange in dogs. Veterinary Dermatology 12,
315–320.
Lymbery, A., Thompson, R. and Hobbs, R. (1990). Genetic diversity and
genetic differentiation in Echinococcus granulosus (Batsch, 1786) from
domestic and sylvatic hosts on the mainland of Australia. Parasitology
101, 283–289.
MacDonald, R.A.S. (1922). Observations on an extensive human infection
by sarcoptic mange of the horse. The Lancet April 15, 738–739.
Mantle, D., Gok, M.A. and Lennard, T.W. (2001). Adverse and beneficial
effects of plant extracts on skin and skin disorders. Adverse Drug
Reaction and Toxicology Reviews 20, 89–103.
Martin, R.W., Handasyde, K.A. and Skerratt, L.F. (1998). Current distri-
bution of sarcoptic mange in wombats. Australian Veterinary Journal 76,
411–414.
Mattsson, J.G., Ljunggren, E.L. and Bergstrom, K. (2001). Paramyosin
from the parasitic mite Sarcoptes scabiei: cDNA cloning and hetero-
logous expression. Parasitology 122, 555–562.
Meinking, T., Taplin, D., Hermida, J., Pardo, R. and Kerdel, F. (1995).
The treatment of scabies with ivermectin. The New England Journal of
Medicine 333, 26–30.
Melby, P.C., Ogden, G.B., Flores, H.A., Zhao, W., Geldmacher, C.,
Biediger, N.M., Ahuja, S.K., Uranga, J. and Melendez, M. (2000).
Identification of vaccine candidates for experimental visceral leishman-
iasis by immunization with sequential fractions of a cDNA expression
library. Infection and Immunity 68, 5595–5602.
Mellanby, K. (1941). The transmission of scabies. British Medical Journal 2,
405–406.
Mellanby, K. (1944). The development of symptoms, parasitic infection and

immunity in human scabies. Parasitology 35, 197–206.
Mellanby, K., Johnson, C. and Bartley, W. (1942). The treatment of scabies.
British Medical Journal 4252–4255.
Mercier, P., Cargill, C.F. and White, C.R. (2002). Preventing transmission
of sarcoptic mange from sows to their offspring by injection of
ivermectin. Effects on swine production. Veterinary Parasitology 110,
25–33.
Moberg, S.A., Lowhagen, G.B.E. and Hersle, K.S. (1984). An epidemic of
scabies with unusual features and treatment resistance in nursing home.
Journal of the American Academy of Dermatology 11, 242–244.
Mollison, L.C., Lo, S.T.H. and Marning, G. (1993). HTLV-1 and scabies in
Australian Aborigines. The Lancet 341, 1281–1282.
Montesu, M., Cottoni, F., Bonomo, G.C. and Cestoni, D. (1991).
Discoverers of the parasitic origin of scabies. The American Journal of
Dermatopathology 13, 425–427.
Morgan, M.S. and Arlian, L.G. (1994). Serum antibody profiles of
Sarcoptes scabiei infested or immunized rabbits. Folia Parasitologica
(Praha) 41, 223–227.
Morgan, M.S., Arlian, L.G. and Estes, S.A. (1997). Skin test and
radioallergosorbent test characteristics of scabietic patients. American
Journal of Tropical Medicine and Hygiene 57, 190–196.
Morner, T. (1992). Sarcoptic mange in Swedish wildlife. Reviews in Science
and Technology 11, 1115–1121.
Morsy, T.A., Romia, S.A., Al-Ganayni, G.A., Abu-Zakham, A.A., Al-
Shazly, A.M. and Rezk, R.A. (1990). Histocompatibility (HLA)
antigens in Egyptians with two parasitic skin diseases (scabies and
leishmaniasis). Journal of the Egyptian Society of Parasitology 20,
565–572.
Mumcuoglu, Y. and Rufli, T. (1979). Immunological investigations of
house-dust and house-dust mites II. Localization of the antigen in the
body of the house-dust mite Dermatophagoides pteronyssinus by means
of the indirect immunofluorescence method. In: Recent Advances in
Acarology, Vol. 2, pp. 205–210. Academic Press Inc.
Munoz, E., Powers, J., Nienhuys, T. and Mathews, J. (1992). Social and
environmental factors in 10 Aboriginal communities in the Northern
Territory: relationship to hospital admissions of children. The Medical
Journal of Australia 156, 529–533.
Nair, B.K.H., Kandamuthan, A.J. and Kandamuthan, M. (1977). Epidemic
scabies. Indian Journal of Medical Research 65, 513–518.
Narahashi, T. (1989). The role of ion channels in insecticide action.
In: Insecticide Action: From Molecule to Organism (T. Narahashi and J.E.
Chambers, eds.), pp. 55–84. New York: Plenum Press.
Narahashi, T. (2000). Neuroreceptors and ion channels as the basis for

drug action: past, present, and future. Journal of Pharmacology and
Experimental Therapy 294, 1–26.
Navajas, M., Gutierrez, J., Bonato, O., Bolland, H. and Mapangou-
Divassa, S. (1994). Intraspecific diversity of the cassava green mite
Mononychellus progresivus (Acari: Tetranychidae) using comparisons of
mitochondrial and nuclear ribosomal DNA sequences and cross-
breeding. Experimental and Applied Acarology 18, 351–360.
Norins, A.L. (1969). Canine scabies in children. American Journal of
Diseased Children 117, 239–242.
Normaznah, Y., Saniah, K., Nazma, M., Mak, J.W., Krishnasamy, M. and
Hakim, S.L. (1996). Seroprevalence of Sarcoptes scabiei var. canis
antibodies among aborigines in peninsular Malaysia. Southeast Asian
Journal of Tropical Medicine and Public Health 27, 53–56.
Oladimeji, F.A., Orafidiya, O.O., Ogunniyi, T.A. and Adewunmi, T.A.
(2000). Pediculocidal and scabicidal properties of Lippia multiflora
essential oil. Journal of Ethnopharmacology 72, 305–311.
Orkin, M. (1971). Resurgence of scabies. The Journal of the American
Medical Association 217(5), 593–597.
Orkin, M. (1975). Today’s scabies. The Journal of the American Medical
Association 233(8), 882–885.
Orkin, M. and Maibach, H.I. (1993). Scabies therapy—1993. Seminars in
Dermatology 12(1), 22–25.
Paller, A.S. (1993). Scabies in infants and small children. Seminars in
Dermatology 12(1), 3–8.
Patterson, W.D., Allen, B.R. and Beveridge, G.W. (1973). Norwegian
scabies during immunosuppressive therapy. British Medical Journal 4,
211–212.
Peat, J.K., Haby, M., Spijker, J., Berry, G. and Woolcock, A.J. (1992).
Prevalence of asthma in adults in Busselton, Western Australia. British
Medical Journal 305, 1326–1329.
Pence, D. and Ueckermann, E. (2002). Sarcoptic mange in wildlife. Reviews
in Science and Technology 21, 385–398.
Pence, D.B., Windberg, L.A., Pence, B.C. and Sprowls, R. (1983). The
epizootiology and pathology of sarcoptic mange in coyotes, Canis
latrans, from south Texas. Journal of Parasitology 69, 1100–1115.
Poon-King, T., Svartman, M., Mohammed, I., Potter, E.V., Achong, J.,
Cox, R. and Earle, D.P. (1973). Epidemic acute nephritis with reappear-
ance of M-type 55 streptococci in Trinidad. The Lancet 1, 475–479.
Prens, E., Hegmans, J., Lien, R.C., Debets, R., Troost, R., van Joost, T. and
Benner, R. (1996). Increased expression of interleukin-4 receptors
on psoriatic epidermal cells. American Journal of Pathology 148,
1493–1502.
Prichard, R. (2001). Genetic variability following selection of Haemonchus

contortus with anthelmintics. Trends in Parasitology 17, 445–453.
Raman, A., Weir, U. and Bloomfield, S.F. (1995). Antimicrobial effects of
tea-tree oil and its major components on Staphylococcus aureus, Staph.
epidermidis and Propionibacterium acnes. Letters in Applied Microbiology
21, 242–245.
Rand, K.N., Moore, T., Sriskantha, A., Spring, K., Tellam, R.,
Willadsen, P. and Cobon, G.S. (1989). Cloning and expression of a
protective antigen from the cattle tick Boophilus microplus. Proceedings
of the National Academy of Science USA 86, 9657–9661.
Rawlings, N.D. and Barrett, A.J. (1994). Families of serine peptidases.
Methods in Enzymology 244, 19–61.
Reed, M., Sallba, K., Caruana, S., Kirk, K. and Cowman, A. (2000). Pgh1
modulates sensitivity and resistance to multiple antimalarials in
Plasmodium falciparum. Nature 403, 906–909.
Rehbein, S., Visser, M., Winter, R., Trommer, B., Matthes, H.F.,
Maciel, A.E. and Marley, S.E. (2003). Productivity effects of bovine
mange and control with ivermectin. Veterinary Parasitology 114,
267–284.
Richard, K., Dillon, M., Whitehead, H. and Wright, J. (1996). Patterns of
kinship in groups of free-living sperm whales (Physeter macrocephalus)
revealed by multiple molecular genetic analysis. Proceedings of the
National Academy of Science USA 93, 8792–8795.
Roth, W. (1991). Scabies resistant to lindane 1% lotion and crotamiton
10% cream. Journal of American Academy of Dermatology 24, 502–503.
Rubin, G.M., Yandell, M.D., Wortman, J.R., Gabor Miklos, G.L.,
Nelson, C.R., Hariharan, I.K., Fortini, M.E., Li, P.W., Apweiler, R.,
Fleischmann, W., Cherry, J.M., Henikoff, S., Skupski, M.P., Misra, S.,
Ashburner, M., Birney, E., Boguski, M.S., Brody, T., Brokstein, P.,
Celniker, S.E., Chervitz, S.A., Coates, D., Cravchik, A., Gabrielian, A.,
Galle, R.F., Gelbart, W.M., George, R.A., Goldstein, L.S., Gong, F.,
Guan, P., Harris, N.L., Hay, B.A., Hoskins, R.A., Li, J., Li, Z.,
Hynes, R.O., Jones, S.J., Kuehl, P.M., Lemaitre, B., Littleton, J.T.,
Morrison, D.K., Mungall, C., O’Farrell, P.H., Pickeral, O.K., Shue, C.,
Vosshall, L.B., Zhang, J., Zhao, Q., Zheng, X.H. and Lewis, S. (2000).
Comparative genomics of the eukaryotes. Science 287, 2204–2215.
Ruiz-Maldonado, R., Tamayo, L. and Dominguez, J. (1977). Norwegian
scabies due to Sarcoptes scabiei var. canis. Archives of Dermatology 113,
1733.
Sachdev, T.R., Gulati, P.V. and Prasad, P. (1982). A study on prevalence
of scabies in a resettlement colony (slum area) and its association
with some sociocultural and environmental factors. Journal of Indian
Association for Communicable Diseases 5, 88–91.
Salomone, N., Frati, F. and Bernini, F. (1996). Investigation on the

taxonomic status of Steganacarus magnus and Steganacarus anomalus
(Acari: Oribatida) using mitochondrial DNA sequences. Experimental
and Applied Acarology 20, 607–615.
Sangster, N. and Gill, J. (1999). Pharmacology of anthelmintic resistance.
Parasitology Today 15, 141–146.
Santoro, A.F., Rezac, M.A. and Lee, J.B. (2003). Current trend in
ivermectin usage for scabies. Journal of Drugs in Dermatology 2, 397–401.
Schmeller, W. and Dzikus, A. (2001). Skin diseases in children in
rural Kenya: long-term results of a dermatology project within
the primary health care system. British Journal of Dermatology 144,
118–124.
Schultz, M., Gomez, M., Hansen, R., Mills, J., Menter, A., Rodgers, H.,
Judson, F., Mertz, G. and Handsfield, H. (1990). Comparative study
of 5% permethrin cream and 1% lindane lotion for the treatment of
scabies. Archives of Dermatology 126, 167–170.
Schwartzman, R.M. (1983). Scabies in animals. In: Cutaneous Infestations of
Man and Animals (L.C. Parish, W.B. Nutting, and R.M. Schwartzman,
eds.), pp. 90–99. New York: Praeger Scientific.
Scott, D.W. and Horn, R.T. (1987). Zoonotic dermatoses of dogs and cats.
Veterinary Clinic of North America 17, 117–144.
Scott, J.C. and McManus, D.P. (1999). Identification of novel 70-kDa heat
shock protein-encoding cDNAs from Schistosoma japonicum.
International Journal for Parasitology 29, 437–444.
Seddon, H.R. and Albiston, H.E. (1968). Mites. In: Diseases of Domestic
Animals in Australia, Part 3, Arthropod Infestations (ticks and mites),
Vol. 3, pp. 98–140. Commonwealth of Australia, Service publications
(veterinary hygiene), Number 7.
Shelley, W., Shelley, E. and Burmeister, V. (1988). Staphlococcus aureus
colonisation of burrows in erythrodermic Norwegian scabies. A case
study of iatrogenic contagion. Journal of the American Academy of
Shpacovitch, V.M., Brzoska, T., Buddenkotte, J., Stroh, C.,
Sommerhoff, C.P., Ansel, J.C., Schulze-Osthoff, K., Bunnett, N.W.,
Luger, T.A. and Steinhoff, M. (2002). Agonists of proteinase-activated
receptor 2 induce cytokine release and activation of nuclear transcription
factor kappaB in human dermal microvascular endothelial cells. Journal
of Investigative Dermatology 118, 380–385.
Shrank, A.B. and Alexander, S.L. (1967). Scabies: another epidemic? British
Medical Journal 1, 669–671.
Simon, C. (1991). Molecular systematics at the species boundary: exploiting
conserved and variable regions of the mitochondrial genome of animals
via direct sequencing from amplified DNA. In: Molecular Techniques
in Taxonomy (G.M. Hewitt, ed.), Vol. H57, pp. 33–71. Berlin and
Heidelberg: Springer-Verlag.
Simpson, A.J. and Knight, M. (1986). Cloning of a major developmentally
regulated gene expressed in mature females of Schistosoma mansoni.
Molecular and Biochemical Parasitology 18, 25–35.
Skerratt, L.F., Campbell, N.J.H., Murrell, A., Walton, S., Kemp, D. and
Barker, S.C. (2002). The mitochondrial 12S gene is a suitable marker of
populations of Sarcoptes scabei from wombats, dogs and humans in
Australia. Parasitology Research 88, 376–379.
Skerratt, L.F., Martin, R.W. and Handasyde, K.A. (1998). Sarcoptic mange
in wombats. Australian Veterinary Journal 76, 408–410.
Smith, W.A., Chua, K.Y., Kuo, M.C., Rogers, B.L. and Thomas, W.R.
(1994). Cloning and sequencing of the Dermatophagoides pteronyssinus
group III allergen, Der p III. Clinical and Experimental Allergy 24,
220–228.
Smith, W.A. and Thomas, W.R. (1996). Sequence polymorphisms of the
Der p 3 house dust mite allergen. Clinical and Experimental Allergy 26,
571–579.
Smits, J.M. and Merks, J.W. (2001). The importance of different pig diseases
in the Netherlands. Tijdschr Diergeneeskd 126, 2–8.
Stevenson, W.J. and Hughes, K.L. (1988). Synopsis of Zoonoses in Australia,
p. 154. Canberra, Australia: Commonwealth Department of Community
Services.
Stewart, G.A., Ward, L.D., Simpson, R.J. and Thompson, P.J. (1992). The
group III allergen from the house dust mite Dermatophagoides
pteronyssinus is a trypsin-like enzyme. Immunology 75, 29–35.
Stromberg, P.C. and Fisher, W.F. (1986). Dermatopathology and immunity
in experimental Psoroptes ovis (Acari: Psoroptidae) infestation of naive
and previously exposed Hereford cattle. American Journal of Veterinary
Research 47(7), 1551–1559.
Sun, G., Stacey, M., Schmidt, M., Mori, L. and Mattoli, S. (2001).
Interaction of mite allergens Der P3 and Der P9 with protease-activated
receptor-2 expressed by lung epithelial cells. Journal of Immunology 167,
1014–1021.
Svartman, M., Potter, E., Finklea, J. and Poon-King, T. (1972). Epidemic
scabies and acute glomerulonephritis in Trinidad. The Lancet 1, 249–251.
Tannenbaum, M.H. (1965). Canine scabies in man: a report of human
mange. Journal of the American Medical Association 193, 141–142.
Taplin, D., Arrue, C., Walker, J.G., Roth, W.I. and Rivera, A. (1983).
Eradication of scabies with a single treatment schedule. Journal of the
American Academy of Dermatology 9, 546–550.
Taplin, D. and Meinking, T. (1990). Pyrethrins and pyrethroids in
dermatology. Archives of Dermatology 126, 213–221.
Taplin, D., Meinking, T.L., Chen, J.A. and Sanchez, R. (1990). Comparison
of crotamiton 10% cream (eurax) and permethrin 5% cream
(elimite) for the treatment of scabies in children. Pediatric Dermatology
7, 67–73.
Taplin, D., Porcelain, S.L., Meinking, T.L., Athey, R.L., Chen, J.A.,
Castillero, P.M. and Sanchez, R. (1991). Community control of
scabies: a model based on use of permethrin cream. The Lancet 337,
1016–1018.
Taplin, D. and Rivera, A. (1983). A comparative trial of three treatment
schedules for the eradication of scabies. Journal of the American Academy
of Dermatology 9, 550–554.
Thomas, W.R., Smith, W.A., Hales, B.J., Mills, K.L. and O’Brien, R.M.
(2002). Characterization and immunobiology of house dust mite
allergens. International Archives of Allergy and Immunology 129, 1–18.
Thompson, R.C.A. and Lymbery, A.J. (1996). Genetic variability in
parasites and host-parasite interactions. Parasitology 112, 1–16.
Tovey, E.R., Chapman, M.D. and Platts-Mills, T.A.E. (1981). Mite faeces
are a major source of house dust allergens. Nature 289, 592–593.
Unnasch, T.R., Gallin, M.Y., Soboslay, P.T., Erttmann, K.D. and
Greene, B.M. (1988). Isolation and characterization of expression
cDNA clones encoding antigens of Onchocerca volvulus infective larvae.
Journal of Clinical Investigation 82, 262–269.
Van der Heijden, H.M.J.F., Rambags, P.G., Elbers, A.R., van Maanen, C.
and Hunneman, W.A. (2000). Validation of ELISAs for the detection
of antibodies to Sarcoptes scabiei in pigs. Veterinary Parasitology 89,
95–107.
Veale, A.J., Peat, J.K., Tovey, E.R., Salome, C.M., Thompson, J.E. and
Woolcock, A.J. (1996). Asthma and atopy in four rural Australian
Aboriginal communities. The Medical Journal of Australia 165, 192–196.
Walton, S., Low Choy, J., Bonson, A., Valle, A., McBroom, J., Taplin, D.,
Arlian, L., Mathews, J., Currie, B. and Kemp, D. (1999a). Genetically
distinct dog-derived and human-derived Sarcoptes scabiei in scabies-
endemic communities in northern Australia. American Journal of
Tropical Medicine and Hygiene 61, 542–547.
Walton, S., McBroom, J., Mathews, J., Kemp, D. and Currie, B. (1999b).
Crusted scabies: a molecular analysis of Sarcoptes scabiei var. hominis
populations in patients with repeated infestations. Clinical Infectious
Diseases 29, 1226–1230.
Walton, S.F., Currie, B.J. and Kemp, D.J. (1997). A DNA fingerprinting
system for the ectoparasite Sarcoptes scabiei. Molecular and Biochemical
Walton, S.F., Dougall, A., Pizzutto, S., Hott, D.C., Toplin, D., Arlian,
L.G., Morgan, M., Currie, B.J. and Kemp, D.J. (in press). Genetic
epidemiology of Sarcoptes scabiei (Acari: Sarcoptidae) in northern

Australia. International Journal for Parasitology.
Walton, S.F., McKinnon, M., Pizzutto, S., Dougall, A., Williams, E. and
Currie, B.J. (in press). Acaricidal activity of Melaleuca alternifolia (Tea
Tree) oil. Archives of Dermatology.
Walton, S.F., Myerscough, M.R. and Currie, B.J. (2000). Studies in vitro on
the relative efficacy of current acaricides for Sarcoptes scabiei var.
hominis. Transactions of the Royal Society of Tropical Medicine and
Hygiene 94, 1–5.
White, A.V., Hoy, W.E. and McCredie, D.A. (2001). Childhood post-
streptococcal glomerulonephritis as a risk factor for chronic renal disease
in later life. Medical Journal of Australia 174, 492–496.
Witkowski, J.A. and Parish, L.C. (2002). Pediculosis and resistance: the
perennial problem. Clinical Dermatology 20, 87–92.
Wong, L., Amega, B., Barker, R., Connors, C., Ninnal, M.D.A.,
Cumaiyi, M., Kolumboort, L. and Currie, B. (2002). Factors supporting
sustainability of a community-based scabies control program.
Australasian Journal of Dermatology 43, 274–277.
Wong, L.C., Amega, B., Connors, C., Barker, R., Dulla, M.E., Ninnal, A.,
Kolumboort, L., Cumaiyi, M.M. and Currie, B.J. (2001). Outcome of an
interventional program for scabies in an Indigenous community. Medical
Journal of Australia 175, 367–370.
Xu, M., Molento, M., Blackhall, W., Ribeiro, P., Beech, R. and Prichard, R.
(1998). Ivermectin resistance in nematodes may be caused by alteration of
P-glycoprotein homolog. Molecular and Biochemical Parasitology 91,
327–335.
Yang, Y., Yoo, H., Choi, I., Pyun, K., Byun, S. and Ha, H. (1996).
Interleukin 4-induced proliferation in normal human keratinocytes is
associated with c-myc gene expression and inhibited by genistein. Journal
of Investigative Dermatology 107, 367–372.
Zahler, M., Essig, A., Gothe, R. and Rinder, H. (1999). Molecular analyses
suggest monospecificity of the genus Sarcoptes (Acari: Sarcoptidae).
International Journal for Parasitology 29, 759–766.

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Scabies: New Future for a Neglected Disease

Shelley F. Walton1,*, Deborah C. Holt2, Bart J. Currie1,3 and

*Author for correspondence. E-mail: Shelley.Walton@menzies.edu.au

ADVANCES IN PARASITOLOGY VOL 57 Copyright ß 2004 Elsevier Inc.

6.4. Poverty, Overcrowding and Poor Hygiene . . . . . . . . . . . . 328

Scabies is a disease of global proportions in both human and animal

and poverty have been identiﬁed as signiﬁcant confounding factors

The burrowing ectoparasitic mite Sarcoptes scabiei is regarded as

contribute to the extreme levels of renal disease and rheumatic heart

Scabies is believed to be the ﬁrst disease of man with a known cause

Cottoni, 1991). This represented the ﬁrst mention of the parasitic

Sarcoptes scabiei is a member of the class Arachnida, subclass

Sarcoptes scabiei is a creamy white colour with brown sclerotised legs

Figure 1 Ventral view of Sarcoptes scabiei var. hominis. Male adult.

The lifecycle of S. scabiei includes three active developmental

Figure 2 Scanning electron micrograph (JEOLJSM-T330) of upper leg

to four days the larvae moult into protonymphs which develop

3.4. Transfer of Mites

Mellanby (1944) believed the stage responsible for transmission was

to the skin surface. During active infestation immature mites

3.5. Survival and Infestivity

Detailed studies by Arlian et al. (1984a) have demonstrated that

Worldwide S. scabiei causes mange in many companion and livestock

with S. scabiei (Cargill et al., 1997). Veterinary concerns include

Many animal scabies mite infestations have been recorded as

report a case of a 14-year-old girl with Turners syndrome and crusted

5. TAXONOMY AND POPULATION STRUCTURE

5.1. Determination of a Single Species

Fain (1978) made a comparative study of the morphology of various

Studies published subsequently indicate physiological diﬀerences

5.2. Population Genetics of Host Specificity

Nucleic acid methodologies are becoming an increasingly important

such as genetic variability, gene ﬂow, hybridisation, recognition of

5.3. Population Genetics of S. scabiei

A number of studies investigating genetic variation in host-associated

Figure 3 Multi-locus clustering analysis of S. scabiei populations using

that interbreeding or cross-infection appeared to be extremely rare

people were treated, and prevalence rates were reduced to around 5%

6.1. Cyclical Pattern of Infection

Early accounts of the epidemiology of human scabies described large

1944; Shrank and Alexander, 1967). The principal peaks coincided

6.2. Sex and Age

Alexander (1984) concluded that scabies is generally commonest in

A number of studies suggest some racial groups may be more

epidemiological study of scabies in Hawaii observed much higher

6.4. Poverty, Overcrowding and Poor Hygiene

The relationship between scabies and relative levels of poverty,

observed to coincide with evidence of poor nutrition and beri beri

6.5. Significance in Indigenous Communities

In some northern Australian Aboriginal communities, conditions

Similarly Sachdev et al. (1982) observed that overcrowding and

Classical scabies in the adult presents as a generalised pruritis

unrelated to obvious mite activity. This more generalised skin rash

Scabies is a challenging disease to diagnose due to diﬃculties in

of human scabies. Normaznah et al. (1996) developed an ELISA

The severe itching and papular rash of the primary infestation

7.3. Secondary Infection

Untreated scabies is often associated with pyoderma primarily caused

7.4. Crusted (Norwegian) Scabies

Crusted scabies is an extreme form of the disease and characterised

Figure 4 Fatal sepsis secondary to crusted scabies. (See Plate 5.4 in

In a series of nine Aboriginal cases treated at the Alice Springs

7.5. Genetic Composition of S. scabiei Populations in

Recurrent crusted scabies is of signiﬁcant concern both for individual