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Scratching the itch: new tools to advance understanding of scabies
Review
Scratching the itch: new tools to advance understanding of scabies Kate E. Mounsey1,2, James S. McCarthy2, and Shelley F. Walton1 1
School of Health and Sport Sciences, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Locked Bag 4, Maroochydore DC, QLD 4558, Australia 2 Infectious Diseases Division, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, QLD 4029, Australia
Scabies remains a significant public health problem worldwide. Research into aspects of Sarcoptes scabiei biology and host–parasite interactions has been impeded by an inability to maintain mites in vitro and by limited access to parasite material and infected subjects. The generation of comprehensive expressed sequence tag libraries has enabled the initial characterisation of molecules of interest to diagnostics, vaccines, and drug resistance. The recent development and utilisation of animal models, combined with next-generation technologies, is anticipated to lead to new strategies to prevent, diagnose, and treat scabies, ultimately improving skin health in both human and veterinary settings. This article will summarise recent molecular and immunologic advances on scabies, and will address priorities for the exciting ‘next chapter’ of scabies research. Scabies is a common, but neglected skin disease Infestation and subsequent skin infections caused by the ectoparasitic mite Sarcoptes scabiei remain endemic in many developing, resource-poor countries. Scabies has been identified as a neglected tropical disease responsible for an underestimated and inaccurately quantified level of morbidity and global burden of disease [1]. Although it is often cited that up to 300 million people are infected with scabies at any given time [2], the accuracy of this estimate is impossible to verify. In some recent epidemiologic surveys prevalence was estimated at 8.8% in an urban slum in Brazil [3], 13.4% in an Australian indigenous community [4], 17% in Timor-Leste community clinics, schools, and hospitals [5], 18.5% in Fijian school children [6], and 31% in a Malaysian child welfare home [7]. A common theme is that the highest burden of scabies is carried in the very young in most endemic populations. For example, in two independent surveys in Australian remote indigenous communities it was found that around 70% of clinic attendances in the first year of life were for scabies [8,9]. In developed countries such as the United Kingdom a much lower prevalence (0.4–0.6%) was estimated among schoolage children [10]. Scabies outbreaks remain common in institutional settings such as child-care centres, aged care facilities, prisons, and hospital wards. Institutional outbreaks are often attributable to an index patient with unidentified crusted scabies, who may remain undiag-
nosed for prolonged periods, their condition masked and exacerbated by factors such as corticosteroid use and underlying immunodeficiency [11–14]. Such outbreaks are associated with significant economic costs (reviewed in [15]). The link between scabies, skin infections (pyoderma), and subsequent sequelae is increasingly recognised (Box 1) but, as with other neglected tropical diseases [16], the psychological burden of this disease has rarely been explored and is significantly underappreciated. In a recent study, Worth et al. [17] found that scabies substantially reduced quality of life, with 77.2% of adults with scabies reporting feelings of shame, isolation and stigmatisation. As expected, the degree of social impairment correlated with the severity of infestation. In a similar study conducted in China, 78% of scabietic patients surveyed reported an impaired quality of life [18]. Many other mammals are also host to S. scabiei, and infestation of animals is referred to as sarcoptic mange. Domestic pets (dogs), livestock (cattle, pigs, goats, camelids) and wildlife (red foxes, deer, wombats, koalas, wallabies) are commonly affected, causing significant welfare and economic costs, with management difficult, particularly in wild populations [19].
Glossary Complement system: protein cascade playing major role in elimination of pathogens, either by direct killing or by enhancing other immune pathways to remove pathogens. Eosinophils: cells important in defence against parasites, associated with inflammation and allergy. Epizootic: an increase in number of disease cases in an animal population (equivalent to an epidemic in humans). Langerhans cells: skin-resident dendritic cells that process and present antigens. Lymphocytes: key immune cells, responsible for specific immune responses and immune memory. Mast cells: important in allergic responses, releasing mediators such as histamine. Neutrophils: cells important in innate immunity and inflammatory responses to bacterial infection. Panmictic: a population where members can mate freely without genetic restriction. Sympatric: coexistence of two populations in the same environment. Th1/Th2 paradigm: Th1 and Th2 are lineages of CD4+ T cells. The ability of each to regulate the growth of the other can lead to dominance of one lineage over the other. Th1 cells are associated with the development of cell-mediated immunity, whereas Th2 cells are associated with allergy and immune responses to parasitic infection.
Corresponding author: Mounsey, K.E. ([email protected]). 1471-4922/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2012.09.006 Trends in Parasitology , January 2013, Vol. 29, No. 1
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Review Box 1. Scabies and pyoderma: epidemiologic and molecular associations In addition to the direct pathology it causes, scabies represents a major initiating factor for streptococcal pyoderma (skin infections caused by Streptococcus sp. bacteria). Thus scabies, leading to skin infections in childhood, are major predisposing factors for more serious disease in later life. For example, an evaluation of 1519 patients in a remote Australian indigenous community found scabies to underlie the majority of streptococcal infection leading to post-streptococcal glomerulonephritis (PSGN) and chronic renal disease [96]. This link between scabies and post-streptococcal sequelae is supported by intervention studies where the treatment of scabies alone resulted in significant decreases in PSGN [66]. Additional evidence suggests that skin infections occurring due to scabies contribute to the extreme levels of acute rheumatic fever and rheumatic heart disease observed in these populations [97]. Subsequently in recent years there have been renewed efforts in the control of endemic scabies to reduce this unacceptably high burden of chronic disease. Fischer and colleagues have begun to elucidate the molecular interactions between scabies mites and skin-resident bacteria, showing that several classes of mite proteins, including inactivated serine protease paralogues (SMIPP-Ss) and serine protease inhibitors, promote Streptococcus growth in vitro [98]. The molecular mechanisms behind this activity are not yet understood, but probably relate to the complement-inhibiting activity of these molecules [45]. These studies are significant because they show that skin infections are not merely related to physical skin damage, but that the mites themselves synergise with bacterial infection. It will now be important to replicate these observations in vivo to explain further the underlying pathophysiology of these wellestablished epidemiologic observations.
Clinical manifestations Although scabies can present clinically in many different forms, the two most commonly described manifestations are those of ordinary scabies (also known as classical or typical scabies) and crusted scabies (also known as Norwegian scabies, or scabies crustosa). Ordinary scabies presents as papular or vesicular lesions at the site of burrowing, as well as a generalised allergic rash accompanied by intense itching. On the basis of classical studies [20], and the great difficulty in isolating mites, it is accepted that the number of mites per patient is low (12 female mites or less), reducing further with repeat infestations, suggesting acquisition of protective immunity to control mite reproduction. Wolf et al. [21] contend that in reality the mite burden in ordinary scabies may be considerably higher. Crusted scabies is a life-threatening and poorly understood manifestation, characterised by a proliferation of mites (thousands per gram of skin) and the development of thickened skin crusts (hyperkeratosis). Crusting can be localised or extensive, and may occur outside normal predilection sites of mites, including the face, ears, and scalp. Recrudescence and reinfestation frequently occur in the same individual, with recurrent episodes of crusted scabies resulting in considerable depigmentation (Figure 1). Susceptibility to crusted scabies is commonly associated with immunosuppressive conditions, for example in transplant recipients [14], corticosteroid use, or in association with HIV or HTLV-1 infection [22]. The increasing use of immunotherapies may also predispose to crusted scabies, as recently documented in a rheumatoid arthritis patient receiving the IL-6 blocking antibody toxilizumab [23]. 36
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Notably, detailed clinical and immunologic profiling of a large case-series revealed that 42% of patients in northern Australia had no identifiable risk factor or immunological deficit [24]. Immune responses to scabies The immune response to scabies has been the subject of a recent comprehensive review [25]. Host responses to scabies have been described in the context of the Th1/Th2 paradigm (see Glossary), with crusted scabies showing features of a non-protective, Th2 polarised response. Recent evidence supporting this comes from clinical investigations on a large cohort of patients with crusted scabies showing eosinophilia and extremely high levels of IgE, often 10–100-fold higher than normal [24]. Peripheral blood mononuclear cells isolated from patients with crusted scabies secreted higher levels of IL-4, IL-5 and IL-13, and lower levels of IFN-g, compared to ordinary scabies patients, showing an increased allergic Th2 response to recombinant mite antigens [26]. It could be argued that the high levels of IgE and allergic type cytokines are simply a consequence of extreme mite burdens and subsequent circulating antigens, rather than strict causation. Other studies, however, have shown that although high levels of IL-4 were secreted after primary exposure to mite extracts, after immunization or rechallenge the IL-4 response was abrogated in favour of IFN-g [27]. This provides further support that protective immune responses to scabies may be Th1-oriented. Studies of humoral immune responses in human scabies infestation have yielded contradictory results at times, with variation possibly attributable to timing of infestation, differences in clinical severity, or confounding responses to secondary bacterial infection. In recent studies of both ordinary and crusted scabies, patients showed increases in levels of total IgE, IgM, IgG [24], IgG1, IgG3, and IgG4 [28]. Conversely, no differences in direct IgG, IgG1, or IgM reactivity specific to S. scabiei antigens were observed between infected and control groups [26]. Elevated total and S. scabiei-specific IgA appear to be associated with clinical severity of scabies [24,26] Profiling of humoral immune responses in animal S. scabiei infestation shows a steady increase in circulating IgG and IgE levels to whole-mite antigen extracts from 4–8 weeks postinfestation, before plateauing [29–32]. Seropositivity to mite antigens may persist for months following clearance of the parasite [33], a factor that may complicate diagnosis. Interestingly, S. scabiei challenge trials in goats suggest a protective role for IgE because animals with a strong IgE response upon rechallenge were resistant to reinfestation, whereas goats vaccinated with mite extracts had a strong IgG response, but no IgE response, and remained susceptible to infestation [32]. This is in conflict with the apparent lack of any protective effect of IgE in crusted scabies, and thus the functional role of IgE in scabies immunity is not clearly resolved. Direct histological examination of scabies lesions reveals a strong immune and inflammatory cell infiltrate, including neutrophils, Langerhans cells, lymphocytes, and mast cells, but few B cells or macrophages (Figure 2) [28]. In recent examination of skin biopsies from two severe
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Figure 1. Crusted scabies. Hyperkeratosis (thickening and crusting of the skin) and depigmentation (destruction of melanin) in an Aboriginal patient with recurrent crusted scabies. Acknowledgement: B. Currie, Menzies School of Health Research.
crusted scabies patients a predominant CD8+ T cell infiltrate in the dermis was observed, with minimal CD4+ T cell infiltration [28]. This is in contrast to previous findings in ordinary scabies lesions, where a cellular infiltrate dominated by CD4+ T cells has been reported [34]. The T cell subsets in the blood of these patients were within normal ranges [24]. Although these findings need to be confirmed in larger studies, they suggest that skin homing CD8+ T cells may contribute to an imbalanced inflammatory response in the dermis of crusted scabies. Immune evasion and host–parasite interactions A feature of scabies pathogenesis is the 4–6 week delay in onset of symptoms in a primary infestation. One explanation for this is that mites may secrete immunomodulatory molecules that suppress the early immune response. Arlian and colleagues have undertaken several studies measuring the effect of S. scabiei extracts on the cytokine secreting activity of numerous cell subsets (Table 1) [35–41]. The findings are variable and appear to be dependent on many factors, including the use of cell monocultures versus human skin equivalents, the presence of other cytokines, and the timing of responses. For example, mite extracts potently suppressed IL-8 secretion in dermal endothelial cells, keratinocytes, and fibroblasts; however, this cytokine was upregulated in human skin equivalents when exposed to live S. scabiei var. canis [40]. Interestingly, transcriptional profiling of host responses to psoroptic mange (a highly contagious skin infestation of sheep and goats, caused by the non-burrowing ectoparasitic mite Psoroptes ovis) reveals very strong upregulation of IL-8 early in infestation [42,43]. In this respect, a key difference between sarcoptic and psoroptic mange is the rapid development of proinflammatory responses in the latter. A potential caveat here is the use of a ‘non-matched’ host– parasite system, in other words S. scabiei var. canis mites
on human cells. It has been shown that infestation from animal-derived mites leads to a different immune response, with immediate as opposed to delayed hypersensitivity reactions [44]. Moreover, it is difficult to compare cytokine responses in cultured cell lines in isolation, to those in human skin equivalents, and to evaluate how representative these are of responses to mites in vivo. Blocking the effect of host complement is an important early survival strategy for most parasites. Recent studies suggest that the scabies mite has evolved several mechanisms to inhibit complement-mediated damage of mite gut epithelial cells. All three pathways of the complement system (classical, lectin, and alternative) have been identified as being inhibited by scabies mite inactivated protease paralogs (SMIPPs) [45]. It appears that these catalytically inactive serine proteases exert their inhibitory action by binding to the complement proteins C1q, mannose-binding lectin, and properdin, thereby preventing the initial activation of all three downstream protease cascades. A novel S. scabiei peritrophin has been postulated to be a potential target for activation of the lectin pathway [46]. In addition, scabies mite serpins (serine protease inhibitors) have also been documented as inhibiting the three complement system pathways by binding to complement proteins at different stages of activation [47]. It is hypothesised that these inhibitory mechanisms allow the mite to downregulate aspects of the host innate immune responses, and similarly contribute to the survival of scabies-associated pathogenic skin bacteria (Box 1). Is S. scabiei a single species? For many years host-associated populations of S. scabiei have been taxonomically divided into morphologically indistinguishable varieties that have a high degree of host specificity and low degree of cross-infectivity. Evidence of apparent cross-infectivity between hosts has been demonstrated in emerging epizootics in sympatric wild-animal host populations [48]. By contrast, there is limited or no evidence for cross-infestations occurring between hosts in experimental studies [49]. Immunological studies show the presence of both host-specific and cross-reactive molecules [50,51]. As such, monospecficity remains controversial. Molecular epidemiologic studies suggest that the adaptive evolution of S. scabiei varieties seem to be strongly related to the phylogenetic similarity of the host species. Evidence suggests that Sarcoptes is not a single panmictic population, and recent studies confirm genetic subdivision according to the host, with secondary subclustering according to geographical location within host groups [52,53]. In closely related parasite species, many genetic traits are determined by the demographic history of the host and its influence on the degree of gene flow and recombination within the parasite population. Understanding host specificity is important because evolutionary relatedness can inform solutions to diagnostic and treatment strategies to control infection through public health interventions. Diagnosis The diagnosis of scabies is problematic, and can be complicated by low mite burdens, atypical clinical manifestations, and possible confusion with other skin diseases such 37
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a
d
b c
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Figure 2. Skin heavily infested with S. scabiei. Skin biopsy obtained from a pig with crusted mange showing (a) hyperkeratosis, (b) epidermal thickening, (c) intense cellular infiltrate, and (d) mites burrowed in the stratum corneum. This section was stained with haematoxylin (stains nuclei blue-purple) and eosin (stains cytoplasm and other proteins pink-red) to assess general pathology.
as allergic dermatitis, fungal infections, or insect bites. Few tests currently used are sufficiently sensitive, specific, cost effective, or useful in the field (Table 2). With all current techniques, the assessment of sensitivity and to a lesser extent specificity, is severely confounded due to the absence of a true ‘gold standard’ and the inability to define true negatives (i.e., definitively exclude scabies as diagnosis) [54]. Dermoscopy-assisted skin scrapings may provide enhanced diagnostic sensitivity [49], but a limitation is that operator training is required. In reality, most diagnoses are made using clinical algorithms (e.g., presence of itching, characteristic lesions, household contact with itch) which are reported to be highly sensitive (80–100%), but lacking specificity [55]. Enzyme-linked immunosorbent assays (ELISAs) utilising crude S. scabiei extracts have been used for the detection of mange in animals [30,31,56]; however, the specificity and sensitivity of these tests are variable [29]. It appears that there is insufficient cross-reactivity between host-associated populations to use animal-derived mite extracts for the diagnosis of human scabies and that more-specific antigens are required [51]. Several recombinant proteins derived from S. scabiei have been evaluated for their immunodiagnostic potential. These include paramyosin [57], glutathione S-transferases [58,59], and atypical scabies antigen (ASA1) [60]. The recombinant apolipoprotein Sar s 14 [61] has emerged as a promising immunodiagnostic candidate. A quantitative IgE-ELISA using a fragment of Sar s 14 showed 100% sensitivity in differentiating current scabies infestation from uninfested and previously exposed patients [62]. The specificity of this assay was 93.5%, and minimal cross-reactivity was observed with the house dust mite homologue of Sar s 14 (Der p 14), or in sera from house dust mite allergic subjects. This antigen has also been identified as a dominant 38
antigen in immunoscreening of mange-infected dogs [54] and pigs [63]. A limitation in the development and optimisation of serological tests for human scabies is the difficulty in defining the antibody response at different stages of infestation. Another potential method for diagnosis of scabies is to analyse host biomarkers associated with scabies. For example, mange-infected Alpine ibex (Capra ibex) showed a highly significant increase in the acute-phase proteins serum amyloid A and a1-acid glycoprotein during infestation [64]. Similarly, auto-antibodies to the acute-phase proteins transferrin and haptoglobin were detected in mange-infested pigs [65]. An interesting recent report describes the novel use of trained dogs to detect the presence of sarcoptic mange, which may improve surveillance and control in wildlife [19]. Control of scabies and the threat of drug resistance Control of scabies is hampered by the limited number and suboptimal efficacy of available therapies. Commonly used treatments for scabies include the topical agents permethrin (5%), benzyl benzoate (25%), crotamiton (10%), malathion (0.5%) and g-benzene hexachloride (1%, lindane). Oral ivermectin (200 mg/kg) is only formally licensed for scabies in a few countries, but has been trialled in several mass drug administration programs [66,67]. The choice of treatment largely depends on cost, availability, and patient age. Lindane has been withdrawn from the market in many countries due to toxicity concerns [68], whereas ivermectin is not approved for pregnant or lactating women, or for children under 15 kg. In a recent review [69] it was concluded that permethrin is the topical treatment of choice for scabies; two doses of oral ivermectin were considered to have similar efficacy to permethrin. Alternative acaricides that show promising activity in vitro include
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Table 1. Effect of scabies mites or mite extracts on key cytokines and molecules from cultured cells in vitro Cell type(s) Human skin equivalents (HSE) Human dermal microvascular endothelial cells (HMVEC-D) Human keratinocytes, fibroblasts Spleen (from exposed/vaccinated mice) Peripheral blood mononuclear cells Dendritic cells
Cytokines " CTACK, IL-a, IL-1b, IL-1ra, IL-6, IL-8, GM-CSF, M-CSF ICAM-1
Cytokines # n/r a
Refs [40]
IL-6, IL-8, VCAM-1
[39,99]
IL-6, CTACK, TGF-a, GROa, G-CSF G-CSF, IL-2, IL-13
IL-8, GM-CSF ICAM-1, ICAM-2, L-selectin, M-CSF, TNF-a, TGF-b n/r IL-6, IL-8
[36,41] [35]
IL-10, IFN-g, IL-6, IL-8, TNF-a, IL-1b TNF-a
[37,38] [37]
a
n/r, not reported.
essential oils of tea tree (Melaleuca alternifolia), lippia (Lippia multiflora), neem (Azadirachta indica) [70], Eupatorium adenophorum [71], and eugenol compounds [72], but few have been tested in clinical trials, and the safety and efficacy of these alternative therapies have yet to be addressed. Another avenue may be the adaptation of existing veterinary products such as fluazuron for the combination treatment of sarcoptic mange [73], or the trial of alternate macrocyclic lactones such as moxidectin for human scabies, that have more attractive pharmacokinetic profiles [74,75]. In community control programs for scabies, strategies that have utilised annual mass treatments with 5% permethrin and oral ivermectin have shown varied success [4,66,67,76]. An evaluation of a recent study [4] found poor treatment-uptake of 5% permethrin by household contacts of infested children, and this may have compromised the sustainability of the program [77]. Interestingly, simulation modelling of community scabies transmission suggests that high frequency, low density control (i.e., targeted treatment of affected individuals and contacts) may be a better approach than low frequency, high density programs (i.e., annual mass drug administration) for achieving sustainable reductions in scabies prevalence [78]. Where treatment of sarcoptic mange is concerned, acaricides commonly employed include amitraz, permethrin, fipronil, or macrocyclic lactones such as ivermectin, selamectin, or doramectin [79]. Prognosis depends on the
severity of mange and host species. Gakuya [80] emphasised that a good understanding of mange by pastoralists, facilitating integrated approaches to treatment, can be beneficial to the control of mange in livestock and wildlife settings. Of increasing concern is the issue of emerging drug resistance in scabies, which has been documented for both permethrin and ivermectin. Clinical and in vitro resistance of S. scabiei to ivermectin has been documented in human crusted scabies [81,82], and treatment failures were reported in dogs [83]. Resistance to topical 5% permethrin has been observed in S. scabiei var. canis mites in an animal model [84]. Research into likely resistance mechanisms has revealed a ‘knockdown resistance’ (kdr)-type point mutation in the S. scabiei sodium channel gene associated with permethrin resistance [85] and increased transcription of a P-glycoprotein gene in mites exposed to ivermectin [86]. Metabolic detoxification, especially mediated by glutathione S-transferases, appears to play a role in resistance to both drugs. Notably, permethrin resistance could be reversed in vitro by the addition of insecticide synergists that inhibit these pathways [87]. Thus, supplementation of permethrin with synergists may represent a future therapeutic strategy for scabies, similar to approaches already undertaken for head lice. The use of P-glycoprotein inhibitors such as ketoconazole and verapamil has also been used to restore ivermectin susceptibility in resistant nematodes [88].
Table 2. An overview of techniques for diagnosis of scabiesa Method Clinical
Skin scrapings/adhesive tape test [100]
Dermoscopy [101,102]
Serological
Molecular (e.g., PCR amplification of mite DNA from patient skin) [103]
Advantages Simple Low cost Sensitive High specificity Low cost Simple Portable Low cost High specificity Good sensitivity and specificity Potential for adaptation to rapid diagnostic test/lateral flow device High specificity
Disadvantages Low specificity – hindered by atypical manifestations or differential diagnoses Low sensitivity – mites are sparsely populated in most cases of scabies Relies on technically skilled operator Relies on technically skilled operator Sensitivity debatable Burrows are not always identifiable on pigmented skin Not available for human scabies Requires laboratory equipment Poor sensitivity for diagnosis of individual animals when using mite extracts [34]. Low sensitivity – relies on sampling area where mite DNA is present Requires laboratory equipment
a
Advantages and disadvantages listed are based on the authors’ criteria.
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Priories for scabies research Beer evaluaon of new therapies Although several new lead candidates for the treatment of scabies have been idenfied through in vitro tesng, there is now a need to move beyond this into more rigorous assessment of clinical efficacy and safety in animals and humans.
Beer understanding of host–parasite interacons Beer diagnoscs For targeted control of scabies, more sensive and specific tests that can be readily used in the community seng are essenal. Serology-based diagnoscs recently shown to be of promise should now be tested in the wider community.
There is sll a paucity of informaon regarding mite molecules involved in pathogenesis and drug resistance, of potenal diagnosc or therapeuc targets, and how these molecules interact with the host. Genomic, transcriptomic and proteomic analysis, combined with focussed in vivo studies, will provide more knowledge in this area. TRENDS in Parasitology
Figure 3. Scabies research priorities. Acknowledgement: M. Flynn, Queensland Institute of Medical Research.
Research priorities and future perspectives Despite the advances made in the past 10 years, there are still large gaps in our knowledge of scabies compared to many other parasitic diseases (Figure 3). This is largely due to the lack of an in vitro culture system for S. scabiei, meaning that molecular studies have relied on opportunistic access to naturally infected hosts. The recent development of a porcine model for scabies [89] therefore represents an important resource, providing reliable access to both sufficient quantities of mites and to naturally infected hosts, thus permitting more comprehensive studies on immunology and host–parasite interactions. Current research directions that have been directly facilitated by the porcine scabies model include the temporal profiling of host immune responses in different clinical manifestations of scabies, testing of new immunodiagnostics, in vivo explorations of mite infestation on bacterial growth and complement inactivation, and testing the clinical efficacy of new therapies for scabies. Pigs in particular are considered to be an excellent model for scabies because (i) they are a natural host for S. scabiei var. suis, with infestation resulting in similar clinical manifestations to human scabies; and (ii) pigs have greater genetic, physiological, and immunological similarity to humans compared to rodents, and thus research outcomes utilising porcine models may be more readily translatable to human health [90]. The deployment of genomic, transcriptomic, and proteomic studies would facilitate the investigation of fundamental aspects of mite biology, host–parasite interactions, and pathogenesis. A historical lack of available genome sequence data on S. scabiei has been a consistent impediment to more advanced molecular scabies research. Fortunately, the advent of next-generation sequencing technologies, combined with more access to mite material, means this dearth of genetic information should be rectified in the near future. Sequencing of the S. scabiei genome has now commenced [91] and should be facilitated by its estimated small genome size (96 Mb) [92] and the recent completion of genomes of other mites (Varroa destructor, 565 Mb [93] and Tetranychus urticae, 90 Mb [94]). 40
Research to benefit directly from genome sequencing includes drug resistance studies, with the annotation of resistance-associated gene families and pathways, measurement of transcriptional responses of mites to drug exposure, and identification of resistance-associated mutations (SNPs). Significantly, the availability of sequence information introduces the capacity to identify novel mite targets for chemotherapeutic intervention. In addition, the availability of genome and transcriptome data for the related mites Psoroptes ovis [95] and Dermatophagoides pteronyssinus would enable a comparative approach, highlighting similarities and differences between parasitic and free-living mites, and provide essential information to develop specific strategies against each of these pathogens. Concluding remarks With a growing and increasingly ageing worldwide population, scabies is expected to remain as a global public health problem in the foreseeable future. Progress made in the last decade towards understanding mite molecular biology, immunology, and drug resistance has been particularly encouraging. With the availability of animal models, and the anticipated acquisition of large amounts of sequence data, we can expect a further acceleration to research outputs for scabies in the next few years. As always, the challenge and emphasis for researchers will be to translate this new knowledge into tangible improvements to the management of this neglected disease. Acknowledgements K.M. is supported by an Australian Research Council Discovery Early Career Researcher Award. J.M. is supported by a Queensland Health Clinical Research Fellowship and a National Health and Medical Research Council Practitioner Fellowship.
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Review 57 Mattsson, J.G. et al. (2001) Paramyosin from the parasitic mite Sarcoptes scabiei: cDNA cloning and heterologous expression. Parasitology 122, 555–562 58 Pettersson, E.U. et al. (2005) Functional analysis and localisation of a delta-class glutathione S-transferase from Sarcoptes scabiei. Int. J. Parasitol. 35, 39–48 59 Dougall, A. et al. (2005) Identification and characterization of Sarcoptes scabiei and Dermatophagoides pteronyssinus glutathione S-transferases: implication as a potential major allergen in crusted scabies. Am. J. Trop. Med. Hyg. 73, 977–984 60 Ljunggren, E.L. et al. (2006) Characterization of an atypical antigen from Sarcoptes scabiei containing an MADF domain. Parasitology 132, 117–126 61 Harumal, P. et al. (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. Am. J. Trop. Med. Hyg. 68, 54–60 62 Jayaraj, R. et al. (2011) A diagnostic test for scabies: IgE specificity for a recombinant allergen of Sarcoptes scabiei. Diagn. Microbiol. Infect. Dis. 71, 403–407 63 Kuhn, C. et al. (2008) Characterisation of recombinant immunoreactive antigens of the scab mite Sarcoptes scabiei. Vet. Parasitol. 153, 329–337 64 Rahman, M.M. et al. (2010) Acute phase protein response in Alpine ibex with sarcoptic mange. Vet. Parasitol. 168, 293–298 65 Zalunardo, M. et al. (2006) Identification of auto-antigens in skin scrapings from scabies-infected pigs. Int. J. Parasitol. 36, 1133–1141 66 Lawrence, G. et al. (2005) Control of scabies, skin sores and haematuria in children in the Solomon Islands: another role for ivermectin. Bull. World Health Organ. 83, 34–42 67 Kearns, T. et al. (2009) Beating scabies and strongyloidiasis in the Northern Territory, Australia with an ivermectin MDA. Trop. Med. Int. Health 14, 196 68 Nolan, K. et al. (2012) Lindane toxicity: a comprehensive review of the medical literature. Pediatr. Dermatol. 29, 141–146 69 Strong, M. and Johnstone, P.W. (2007) Interventions for treating scabies. Cochrane Database Syst. Rev. 3, CD000320 70 Deng, Y. et al. (2012) Acaricidal activity of petroleum ether extract of neem (Azadirachta indica) oil and its four fractions separated by column chromatography against Sarcoptes scabiei var. cuniculi larvae in vitro. Exp. Parasitol. 130, 475–477 71 Nong, X. et al. (2012) Acaricidal activity of extract from Eupatorium adenophorum against the Psoroptes cuniculi and Sarcoptes scabiei in vitro. Vet. Parasitol. 187, 345–349 72 Pasay, C. et al. (2010) Acaricidal activity of eugenol based compounds against scabies mites. PLoS ONE 5, e12079 73 Pasay, C. et al. (2012) An exploratory study to assess the activity of the acarine growth inhibitor, fluazuron, against Sarcoptes scabei infestation in pigs. Parasit. Vectors 5, 40 74 Astiz, S. et al. (2011) Efficacy of long-acting moxidectin against sarcoptic mange in naturally infested sheep. Vet. Rec. 169, 637a 75 Korth-Bradley, J.M. et al. (2012) Relative bioavailability of liquid and tablet formulations of the antiparasitic moxidectin. Clin. Pharmacol. Drug Dev. 1, 32 76 Wong, L. et al. (2001) Outcome of an interventional program for scabies in an indigenous community. Med. J. Aust. 175, 367–370 77 La Vincente, S. et al. (2009) Community management of endemic scabies in remote Aboriginal communities of northern Australia: low treatment uptake and high ongoing aquisition. PLoS Negl. Trop. Dis. 3, e444 78 Gilmore, S.J. (2011) Control strategies for endemic childhood scabies. PLoS ONE 6, e15990 79 Beugnet, F. and Franc, M. (2012) Insecticide and acaricide molecules an/or combinations to prevent pet infestation by ectoparasites. Trends Parasitol. 28, 267–279
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80 Gakuya, F. et al. (2012) Knowledge of mange amongst Masai pastoralists in Kenya. PLoS ONE 7, e43342 81 Currie, B.J. et al. (2004) First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei. Clin. Infect. Dis. 39, e8–e12 82 Mounsey, K. et al. (2009) Longitudinal evidence of increasing in vitro tolerance of scabies mites to ivermectin in scabies-endemic communities. Arch. Dermatol. 145, 840 83 Terada, Y. et al. (2010) Sarcoptes scabiei var. canis refractory to ivermectin treatment in two dogs. Vet. Dermatol. 21, 608–612 84 Pasay, C. et al. (2006) PCR-based assay to survey for knockdown resistance to pyrethroid acaricides in human scabies mites (Sarcoptes scabiei var. hominis). Am. J. Trop. Med. Hyg. 74, 649–657 85 Pasay, C. et al. (2008) High-resolution melt analysis for the detection of a mutation associated with permethrin resistance in a population of scabies mites. Med. Vet. Entomol. 22, 82–88 86 Mounsey, K.E. et al. (2010) Increased transcription of glutathione Stransferases in acaricide exposed scabies mites. Parasit. Vectors 3, 43 87 Pasay, C. et al. (2009) The effect of insecticide synergists on the response of scabies mites to pyrethroid acaricides. PLoS Negl. Trop. Dis. 3, e354 88 Bartley, D.J. et al. (2009) P-glycoprotein interfering agents potentiate ivermectin susceptibility in ivermectin sensitive and resistant isolates of Teladorsagia circumcincta and Haemonchus contortus. Parasitology 136, 1081–1088 89 Mounsey, K. et al. (2010) A tractable experimental model for study of human and animal scabies. PLoS Negl. Trop. Dis. 4, e756 90 Meurens, F. et al. (2012) The pig: a model for human infectious diseases. Trends Microbiol. 20, 50–57 91 Dean, T. (2011) Catching the sequencing bug. Aust. Life Scientist 8, 48–50 92 Mounsey, K.E. et al. (2012) Quantitative PCR-based genome size estimation of the astigmatid mites Sarcoptes scabiei, Psoroptes ovis and Dermatophagoides pteronyssinus. Parasit. Vectors 5, 3 93 Cornman, S.R. et al. (2010) Genomic survey of the ectoparasitic mite Varroa destructor, a major pest of the honey bee Apis mellifera. BMC Genomics 11, 602 94 Grbic, M. et al. (2011) The genome of Tetranychus urticae reveals herbivorous pest adaptations. Nature 479, 487–492 95 Burgess, S. et al. (2012) Development of a cDNA microarray for the measurement of gene expression in the sheep scab mite Psoroptes ovis. Parasit. Vectors 5, 30 96 Hoy, W.E. et al. (2012) Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life. Kidney Int. 81, 1026–1032 97 McDonald, M. et al. (2004) Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect. Dis. 4, 240–245 98 Mika, A. et al. (2012) Complement inhibitors from scabies mite promote streptococcal growth – a novel mechanism in infected epidermis. PLoS Negl. Trop. Dis. 6, e1563 99 Elder, B. et al. (2006) Sarcoptes scabiei (Acari: Sarcoptidae) mite extract modulates expression of cytokines and adhesion molecules by human dermal microvascular endothelial cells. J. Med. Entomol. 43, 910–915 100 Walter, B. et al. (2011) Comparison of dermoscopy, skin scraping and the adhesive tape test for the diagnosis of scabies in a resource poor setting. Arch. Dermatol. 147, 468–473 101 Park, J.H. et al. (2012) The diagnostic accuracy of dermoscopy for scabies. Ann. Dermatol. 24, 194–199 102 Dupuy, A. et al. (2007) Accuracy of standard dermoscopy for diagnosing scabies. J. Am. Acad. Dermatol. 56, 53–62 103 Fukuyama, S. et al. (2010) Diagnostic usefulness of a nested polymerase chain reaction assay for detecting Sarcoptes scabiei DNA in skin scrapings from clinically suspected scabies. Br. J. Dermatol. 163, 875–899
Scratching the itch: new tools to advance understanding of scabies Kate E. Mounsey1,2, James S. McCarthy2, and Shelley F. Walton1 1
School of Health and Sport Sciences, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Locked Bag 4, Maroochydore DC, QLD 4558, Australia 2 Infectious Diseases Division, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, QLD 4029, Australia
Scabies remains a significant public health problem worldwide. Research into aspects of Sarcoptes scabiei biology and host–parasite interactions has been impeded by an inability to maintain mites in vitro and by limited access to parasite material and infected subjects. The generation of comprehensive expressed sequence tag libraries has enabled the initial characterisation of molecules of interest to diagnostics, vaccines, and drug resistance. The recent development and utilisation of animal models, combined with next-generation technologies, is anticipated to lead to new strategies to prevent, diagnose, and treat scabies, ultimately improving skin health in both human and veterinary settings. This article will summarise recent molecular and immunologic advances on scabies, and will address priorities for the exciting ‘next chapter’ of scabies research. Scabies is a common, but neglected skin disease Infestation and subsequent skin infections caused by the ectoparasitic mite Sarcoptes scabiei remain endemic in many developing, resource-poor countries. Scabies has been identified as a neglected tropical disease responsible for an underestimated and inaccurately quantified level of morbidity and global burden of disease [1]. Although it is often cited that up to 300 million people are infected with scabies at any given time [2], the accuracy of this estimate is impossible to verify. In some recent epidemiologic surveys prevalence was estimated at 8.8% in an urban slum in Brazil [3], 13.4% in an Australian indigenous community [4], 17% in Timor-Leste community clinics, schools, and hospitals [5], 18.5% in Fijian school children [6], and 31% in a Malaysian child welfare home [7]. A common theme is that the highest burden of scabies is carried in the very young in most endemic populations. For example, in two independent surveys in Australian remote indigenous communities it was found that around 70% of clinic attendances in the first year of life were for scabies [8,9]. In developed countries such as the United Kingdom a much lower prevalence (0.4–0.6%) was estimated among schoolage children [10]. Scabies outbreaks remain common in institutional settings such as child-care centres, aged care facilities, prisons, and hospital wards. Institutional outbreaks are often attributable to an index patient with unidentified crusted scabies, who may remain undiag-
nosed for prolonged periods, their condition masked and exacerbated by factors such as corticosteroid use and underlying immunodeficiency [11–14]. Such outbreaks are associated with significant economic costs (reviewed in [15]). The link between scabies, skin infections (pyoderma), and subsequent sequelae is increasingly recognised (Box 1) but, as with other neglected tropical diseases [16], the psychological burden of this disease has rarely been explored and is significantly underappreciated. In a recent study, Worth et al. [17] found that scabies substantially reduced quality of life, with 77.2% of adults with scabies reporting feelings of shame, isolation and stigmatisation. As expected, the degree of social impairment correlated with the severity of infestation. In a similar study conducted in China, 78% of scabietic patients surveyed reported an impaired quality of life [18]. Many other mammals are also host to S. scabiei, and infestation of animals is referred to as sarcoptic mange. Domestic pets (dogs), livestock (cattle, pigs, goats, camelids) and wildlife (red foxes, deer, wombats, koalas, wallabies) are commonly affected, causing significant welfare and economic costs, with management difficult, particularly in wild populations [19].
Glossary Complement system: protein cascade playing major role in elimination of pathogens, either by direct killing or by enhancing other immune pathways to remove pathogens. Eosinophils: cells important in defence against parasites, associated with inflammation and allergy. Epizootic: an increase in number of disease cases in an animal population (equivalent to an epidemic in humans). Langerhans cells: skin-resident dendritic cells that process and present antigens. Lymphocytes: key immune cells, responsible for specific immune responses and immune memory. Mast cells: important in allergic responses, releasing mediators such as histamine. Neutrophils: cells important in innate immunity and inflammatory responses to bacterial infection. Panmictic: a population where members can mate freely without genetic restriction. Sympatric: coexistence of two populations in the same environment. Th1/Th2 paradigm: Th1 and Th2 are lineages of CD4+ T cells. The ability of each to regulate the growth of the other can lead to dominance of one lineage over the other. Th1 cells are associated with the development of cell-mediated immunity, whereas Th2 cells are associated with allergy and immune responses to parasitic infection.
Corresponding author: Mounsey, K.E. ([email protected]). 1471-4922/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2012.09.006 Trends in Parasitology , January 2013, Vol. 29, No. 1
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Review Box 1. Scabies and pyoderma: epidemiologic and molecular associations In addition to the direct pathology it causes, scabies represents a major initiating factor for streptococcal pyoderma (skin infections caused by Streptococcus sp. bacteria). Thus scabies, leading to skin infections in childhood, are major predisposing factors for more serious disease in later life. For example, an evaluation of 1519 patients in a remote Australian indigenous community found scabies to underlie the majority of streptococcal infection leading to post-streptococcal glomerulonephritis (PSGN) and chronic renal disease [96]. This link between scabies and post-streptococcal sequelae is supported by intervention studies where the treatment of scabies alone resulted in significant decreases in PSGN [66]. Additional evidence suggests that skin infections occurring due to scabies contribute to the extreme levels of acute rheumatic fever and rheumatic heart disease observed in these populations [97]. Subsequently in recent years there have been renewed efforts in the control of endemic scabies to reduce this unacceptably high burden of chronic disease. Fischer and colleagues have begun to elucidate the molecular interactions between scabies mites and skin-resident bacteria, showing that several classes of mite proteins, including inactivated serine protease paralogues (SMIPP-Ss) and serine protease inhibitors, promote Streptococcus growth in vitro [98]. The molecular mechanisms behind this activity are not yet understood, but probably relate to the complement-inhibiting activity of these molecules [45]. These studies are significant because they show that skin infections are not merely related to physical skin damage, but that the mites themselves synergise with bacterial infection. It will now be important to replicate these observations in vivo to explain further the underlying pathophysiology of these wellestablished epidemiologic observations.
Clinical manifestations Although scabies can present clinically in many different forms, the two most commonly described manifestations are those of ordinary scabies (also known as classical or typical scabies) and crusted scabies (also known as Norwegian scabies, or scabies crustosa). Ordinary scabies presents as papular or vesicular lesions at the site of burrowing, as well as a generalised allergic rash accompanied by intense itching. On the basis of classical studies [20], and the great difficulty in isolating mites, it is accepted that the number of mites per patient is low (12 female mites or less), reducing further with repeat infestations, suggesting acquisition of protective immunity to control mite reproduction. Wolf et al. [21] contend that in reality the mite burden in ordinary scabies may be considerably higher. Crusted scabies is a life-threatening and poorly understood manifestation, characterised by a proliferation of mites (thousands per gram of skin) and the development of thickened skin crusts (hyperkeratosis). Crusting can be localised or extensive, and may occur outside normal predilection sites of mites, including the face, ears, and scalp. Recrudescence and reinfestation frequently occur in the same individual, with recurrent episodes of crusted scabies resulting in considerable depigmentation (Figure 1). Susceptibility to crusted scabies is commonly associated with immunosuppressive conditions, for example in transplant recipients [14], corticosteroid use, or in association with HIV or HTLV-1 infection [22]. The increasing use of immunotherapies may also predispose to crusted scabies, as recently documented in a rheumatoid arthritis patient receiving the IL-6 blocking antibody toxilizumab [23]. 36
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Notably, detailed clinical and immunologic profiling of a large case-series revealed that 42% of patients in northern Australia had no identifiable risk factor or immunological deficit [24]. Immune responses to scabies The immune response to scabies has been the subject of a recent comprehensive review [25]. Host responses to scabies have been described in the context of the Th1/Th2 paradigm (see Glossary), with crusted scabies showing features of a non-protective, Th2 polarised response. Recent evidence supporting this comes from clinical investigations on a large cohort of patients with crusted scabies showing eosinophilia and extremely high levels of IgE, often 10–100-fold higher than normal [24]. Peripheral blood mononuclear cells isolated from patients with crusted scabies secreted higher levels of IL-4, IL-5 and IL-13, and lower levels of IFN-g, compared to ordinary scabies patients, showing an increased allergic Th2 response to recombinant mite antigens [26]. It could be argued that the high levels of IgE and allergic type cytokines are simply a consequence of extreme mite burdens and subsequent circulating antigens, rather than strict causation. Other studies, however, have shown that although high levels of IL-4 were secreted after primary exposure to mite extracts, after immunization or rechallenge the IL-4 response was abrogated in favour of IFN-g [27]. This provides further support that protective immune responses to scabies may be Th1-oriented. Studies of humoral immune responses in human scabies infestation have yielded contradictory results at times, with variation possibly attributable to timing of infestation, differences in clinical severity, or confounding responses to secondary bacterial infection. In recent studies of both ordinary and crusted scabies, patients showed increases in levels of total IgE, IgM, IgG [24], IgG1, IgG3, and IgG4 [28]. Conversely, no differences in direct IgG, IgG1, or IgM reactivity specific to S. scabiei antigens were observed between infected and control groups [26]. Elevated total and S. scabiei-specific IgA appear to be associated with clinical severity of scabies [24,26] Profiling of humoral immune responses in animal S. scabiei infestation shows a steady increase in circulating IgG and IgE levels to whole-mite antigen extracts from 4–8 weeks postinfestation, before plateauing [29–32]. Seropositivity to mite antigens may persist for months following clearance of the parasite [33], a factor that may complicate diagnosis. Interestingly, S. scabiei challenge trials in goats suggest a protective role for IgE because animals with a strong IgE response upon rechallenge were resistant to reinfestation, whereas goats vaccinated with mite extracts had a strong IgG response, but no IgE response, and remained susceptible to infestation [32]. This is in conflict with the apparent lack of any protective effect of IgE in crusted scabies, and thus the functional role of IgE in scabies immunity is not clearly resolved. Direct histological examination of scabies lesions reveals a strong immune and inflammatory cell infiltrate, including neutrophils, Langerhans cells, lymphocytes, and mast cells, but few B cells or macrophages (Figure 2) [28]. In recent examination of skin biopsies from two severe
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Figure 1. Crusted scabies. Hyperkeratosis (thickening and crusting of the skin) and depigmentation (destruction of melanin) in an Aboriginal patient with recurrent crusted scabies. Acknowledgement: B. Currie, Menzies School of Health Research.
crusted scabies patients a predominant CD8+ T cell infiltrate in the dermis was observed, with minimal CD4+ T cell infiltration [28]. This is in contrast to previous findings in ordinary scabies lesions, where a cellular infiltrate dominated by CD4+ T cells has been reported [34]. The T cell subsets in the blood of these patients were within normal ranges [24]. Although these findings need to be confirmed in larger studies, they suggest that skin homing CD8+ T cells may contribute to an imbalanced inflammatory response in the dermis of crusted scabies. Immune evasion and host–parasite interactions A feature of scabies pathogenesis is the 4–6 week delay in onset of symptoms in a primary infestation. One explanation for this is that mites may secrete immunomodulatory molecules that suppress the early immune response. Arlian and colleagues have undertaken several studies measuring the effect of S. scabiei extracts on the cytokine secreting activity of numerous cell subsets (Table 1) [35–41]. The findings are variable and appear to be dependent on many factors, including the use of cell monocultures versus human skin equivalents, the presence of other cytokines, and the timing of responses. For example, mite extracts potently suppressed IL-8 secretion in dermal endothelial cells, keratinocytes, and fibroblasts; however, this cytokine was upregulated in human skin equivalents when exposed to live S. scabiei var. canis [40]. Interestingly, transcriptional profiling of host responses to psoroptic mange (a highly contagious skin infestation of sheep and goats, caused by the non-burrowing ectoparasitic mite Psoroptes ovis) reveals very strong upregulation of IL-8 early in infestation [42,43]. In this respect, a key difference between sarcoptic and psoroptic mange is the rapid development of proinflammatory responses in the latter. A potential caveat here is the use of a ‘non-matched’ host– parasite system, in other words S. scabiei var. canis mites
on human cells. It has been shown that infestation from animal-derived mites leads to a different immune response, with immediate as opposed to delayed hypersensitivity reactions [44]. Moreover, it is difficult to compare cytokine responses in cultured cell lines in isolation, to those in human skin equivalents, and to evaluate how representative these are of responses to mites in vivo. Blocking the effect of host complement is an important early survival strategy for most parasites. Recent studies suggest that the scabies mite has evolved several mechanisms to inhibit complement-mediated damage of mite gut epithelial cells. All three pathways of the complement system (classical, lectin, and alternative) have been identified as being inhibited by scabies mite inactivated protease paralogs (SMIPPs) [45]. It appears that these catalytically inactive serine proteases exert their inhibitory action by binding to the complement proteins C1q, mannose-binding lectin, and properdin, thereby preventing the initial activation of all three downstream protease cascades. A novel S. scabiei peritrophin has been postulated to be a potential target for activation of the lectin pathway [46]. In addition, scabies mite serpins (serine protease inhibitors) have also been documented as inhibiting the three complement system pathways by binding to complement proteins at different stages of activation [47]. It is hypothesised that these inhibitory mechanisms allow the mite to downregulate aspects of the host innate immune responses, and similarly contribute to the survival of scabies-associated pathogenic skin bacteria (Box 1). Is S. scabiei a single species? For many years host-associated populations of S. scabiei have been taxonomically divided into morphologically indistinguishable varieties that have a high degree of host specificity and low degree of cross-infectivity. Evidence of apparent cross-infectivity between hosts has been demonstrated in emerging epizootics in sympatric wild-animal host populations [48]. By contrast, there is limited or no evidence for cross-infestations occurring between hosts in experimental studies [49]. Immunological studies show the presence of both host-specific and cross-reactive molecules [50,51]. As such, monospecficity remains controversial. Molecular epidemiologic studies suggest that the adaptive evolution of S. scabiei varieties seem to be strongly related to the phylogenetic similarity of the host species. Evidence suggests that Sarcoptes is not a single panmictic population, and recent studies confirm genetic subdivision according to the host, with secondary subclustering according to geographical location within host groups [52,53]. In closely related parasite species, many genetic traits are determined by the demographic history of the host and its influence on the degree of gene flow and recombination within the parasite population. Understanding host specificity is important because evolutionary relatedness can inform solutions to diagnostic and treatment strategies to control infection through public health interventions. Diagnosis The diagnosis of scabies is problematic, and can be complicated by low mite burdens, atypical clinical manifestations, and possible confusion with other skin diseases such 37
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a
d
b c
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Figure 2. Skin heavily infested with S. scabiei. Skin biopsy obtained from a pig with crusted mange showing (a) hyperkeratosis, (b) epidermal thickening, (c) intense cellular infiltrate, and (d) mites burrowed in the stratum corneum. This section was stained with haematoxylin (stains nuclei blue-purple) and eosin (stains cytoplasm and other proteins pink-red) to assess general pathology.
as allergic dermatitis, fungal infections, or insect bites. Few tests currently used are sufficiently sensitive, specific, cost effective, or useful in the field (Table 2). With all current techniques, the assessment of sensitivity and to a lesser extent specificity, is severely confounded due to the absence of a true ‘gold standard’ and the inability to define true negatives (i.e., definitively exclude scabies as diagnosis) [54]. Dermoscopy-assisted skin scrapings may provide enhanced diagnostic sensitivity [49], but a limitation is that operator training is required. In reality, most diagnoses are made using clinical algorithms (e.g., presence of itching, characteristic lesions, household contact with itch) which are reported to be highly sensitive (80–100%), but lacking specificity [55]. Enzyme-linked immunosorbent assays (ELISAs) utilising crude S. scabiei extracts have been used for the detection of mange in animals [30,31,56]; however, the specificity and sensitivity of these tests are variable [29]. It appears that there is insufficient cross-reactivity between host-associated populations to use animal-derived mite extracts for the diagnosis of human scabies and that more-specific antigens are required [51]. Several recombinant proteins derived from S. scabiei have been evaluated for their immunodiagnostic potential. These include paramyosin [57], glutathione S-transferases [58,59], and atypical scabies antigen (ASA1) [60]. The recombinant apolipoprotein Sar s 14 [61] has emerged as a promising immunodiagnostic candidate. A quantitative IgE-ELISA using a fragment of Sar s 14 showed 100% sensitivity in differentiating current scabies infestation from uninfested and previously exposed patients [62]. The specificity of this assay was 93.5%, and minimal cross-reactivity was observed with the house dust mite homologue of Sar s 14 (Der p 14), or in sera from house dust mite allergic subjects. This antigen has also been identified as a dominant 38
antigen in immunoscreening of mange-infected dogs [54] and pigs [63]. A limitation in the development and optimisation of serological tests for human scabies is the difficulty in defining the antibody response at different stages of infestation. Another potential method for diagnosis of scabies is to analyse host biomarkers associated with scabies. For example, mange-infected Alpine ibex (Capra ibex) showed a highly significant increase in the acute-phase proteins serum amyloid A and a1-acid glycoprotein during infestation [64]. Similarly, auto-antibodies to the acute-phase proteins transferrin and haptoglobin were detected in mange-infested pigs [65]. An interesting recent report describes the novel use of trained dogs to detect the presence of sarcoptic mange, which may improve surveillance and control in wildlife [19]. Control of scabies and the threat of drug resistance Control of scabies is hampered by the limited number and suboptimal efficacy of available therapies. Commonly used treatments for scabies include the topical agents permethrin (5%), benzyl benzoate (25%), crotamiton (10%), malathion (0.5%) and g-benzene hexachloride (1%, lindane). Oral ivermectin (200 mg/kg) is only formally licensed for scabies in a few countries, but has been trialled in several mass drug administration programs [66,67]. The choice of treatment largely depends on cost, availability, and patient age. Lindane has been withdrawn from the market in many countries due to toxicity concerns [68], whereas ivermectin is not approved for pregnant or lactating women, or for children under 15 kg. In a recent review [69] it was concluded that permethrin is the topical treatment of choice for scabies; two doses of oral ivermectin were considered to have similar efficacy to permethrin. Alternative acaricides that show promising activity in vitro include
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Table 1. Effect of scabies mites or mite extracts on key cytokines and molecules from cultured cells in vitro Cell type(s) Human skin equivalents (HSE) Human dermal microvascular endothelial cells (HMVEC-D) Human keratinocytes, fibroblasts Spleen (from exposed/vaccinated mice) Peripheral blood mononuclear cells Dendritic cells
Cytokines " CTACK, IL-a, IL-1b, IL-1ra, IL-6, IL-8, GM-CSF, M-CSF ICAM-1
Cytokines # n/r a
Refs [40]
IL-6, IL-8, VCAM-1
[39,99]
IL-6, CTACK, TGF-a, GROa, G-CSF G-CSF, IL-2, IL-13
IL-8, GM-CSF ICAM-1, ICAM-2, L-selectin, M-CSF, TNF-a, TGF-b n/r IL-6, IL-8
[36,41] [35]
IL-10, IFN-g, IL-6, IL-8, TNF-a, IL-1b TNF-a
[37,38] [37]
a
n/r, not reported.
essential oils of tea tree (Melaleuca alternifolia), lippia (Lippia multiflora), neem (Azadirachta indica) [70], Eupatorium adenophorum [71], and eugenol compounds [72], but few have been tested in clinical trials, and the safety and efficacy of these alternative therapies have yet to be addressed. Another avenue may be the adaptation of existing veterinary products such as fluazuron for the combination treatment of sarcoptic mange [73], or the trial of alternate macrocyclic lactones such as moxidectin for human scabies, that have more attractive pharmacokinetic profiles [74,75]. In community control programs for scabies, strategies that have utilised annual mass treatments with 5% permethrin and oral ivermectin have shown varied success [4,66,67,76]. An evaluation of a recent study [4] found poor treatment-uptake of 5% permethrin by household contacts of infested children, and this may have compromised the sustainability of the program [77]. Interestingly, simulation modelling of community scabies transmission suggests that high frequency, low density control (i.e., targeted treatment of affected individuals and contacts) may be a better approach than low frequency, high density programs (i.e., annual mass drug administration) for achieving sustainable reductions in scabies prevalence [78]. Where treatment of sarcoptic mange is concerned, acaricides commonly employed include amitraz, permethrin, fipronil, or macrocyclic lactones such as ivermectin, selamectin, or doramectin [79]. Prognosis depends on the
severity of mange and host species. Gakuya [80] emphasised that a good understanding of mange by pastoralists, facilitating integrated approaches to treatment, can be beneficial to the control of mange in livestock and wildlife settings. Of increasing concern is the issue of emerging drug resistance in scabies, which has been documented for both permethrin and ivermectin. Clinical and in vitro resistance of S. scabiei to ivermectin has been documented in human crusted scabies [81,82], and treatment failures were reported in dogs [83]. Resistance to topical 5% permethrin has been observed in S. scabiei var. canis mites in an animal model [84]. Research into likely resistance mechanisms has revealed a ‘knockdown resistance’ (kdr)-type point mutation in the S. scabiei sodium channel gene associated with permethrin resistance [85] and increased transcription of a P-glycoprotein gene in mites exposed to ivermectin [86]. Metabolic detoxification, especially mediated by glutathione S-transferases, appears to play a role in resistance to both drugs. Notably, permethrin resistance could be reversed in vitro by the addition of insecticide synergists that inhibit these pathways [87]. Thus, supplementation of permethrin with synergists may represent a future therapeutic strategy for scabies, similar to approaches already undertaken for head lice. The use of P-glycoprotein inhibitors such as ketoconazole and verapamil has also been used to restore ivermectin susceptibility in resistant nematodes [88].
Table 2. An overview of techniques for diagnosis of scabiesa Method Clinical
Skin scrapings/adhesive tape test [100]
Dermoscopy [101,102]
Serological
Molecular (e.g., PCR amplification of mite DNA from patient skin) [103]
Advantages Simple Low cost Sensitive High specificity Low cost Simple Portable Low cost High specificity Good sensitivity and specificity Potential for adaptation to rapid diagnostic test/lateral flow device High specificity
Disadvantages Low specificity – hindered by atypical manifestations or differential diagnoses Low sensitivity – mites are sparsely populated in most cases of scabies Relies on technically skilled operator Relies on technically skilled operator Sensitivity debatable Burrows are not always identifiable on pigmented skin Not available for human scabies Requires laboratory equipment Poor sensitivity for diagnosis of individual animals when using mite extracts [34]. Low sensitivity – relies on sampling area where mite DNA is present Requires laboratory equipment
a
Advantages and disadvantages listed are based on the authors’ criteria.
39
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Priories for scabies research Beer evaluaon of new therapies Although several new lead candidates for the treatment of scabies have been idenfied through in vitro tesng, there is now a need to move beyond this into more rigorous assessment of clinical efficacy and safety in animals and humans.
Beer understanding of host–parasite interacons Beer diagnoscs For targeted control of scabies, more sensive and specific tests that can be readily used in the community seng are essenal. Serology-based diagnoscs recently shown to be of promise should now be tested in the wider community.
There is sll a paucity of informaon regarding mite molecules involved in pathogenesis and drug resistance, of potenal diagnosc or therapeuc targets, and how these molecules interact with the host. Genomic, transcriptomic and proteomic analysis, combined with focussed in vivo studies, will provide more knowledge in this area. TRENDS in Parasitology
Figure 3. Scabies research priorities. Acknowledgement: M. Flynn, Queensland Institute of Medical Research.
Research priorities and future perspectives Despite the advances made in the past 10 years, there are still large gaps in our knowledge of scabies compared to many other parasitic diseases (Figure 3). This is largely due to the lack of an in vitro culture system for S. scabiei, meaning that molecular studies have relied on opportunistic access to naturally infected hosts. The recent development of a porcine model for scabies [89] therefore represents an important resource, providing reliable access to both sufficient quantities of mites and to naturally infected hosts, thus permitting more comprehensive studies on immunology and host–parasite interactions. Current research directions that have been directly facilitated by the porcine scabies model include the temporal profiling of host immune responses in different clinical manifestations of scabies, testing of new immunodiagnostics, in vivo explorations of mite infestation on bacterial growth and complement inactivation, and testing the clinical efficacy of new therapies for scabies. Pigs in particular are considered to be an excellent model for scabies because (i) they are a natural host for S. scabiei var. suis, with infestation resulting in similar clinical manifestations to human scabies; and (ii) pigs have greater genetic, physiological, and immunological similarity to humans compared to rodents, and thus research outcomes utilising porcine models may be more readily translatable to human health [90]. The deployment of genomic, transcriptomic, and proteomic studies would facilitate the investigation of fundamental aspects of mite biology, host–parasite interactions, and pathogenesis. A historical lack of available genome sequence data on S. scabiei has been a consistent impediment to more advanced molecular scabies research. Fortunately, the advent of next-generation sequencing technologies, combined with more access to mite material, means this dearth of genetic information should be rectified in the near future. Sequencing of the S. scabiei genome has now commenced [91] and should be facilitated by its estimated small genome size (96 Mb) [92] and the recent completion of genomes of other mites (Varroa destructor, 565 Mb [93] and Tetranychus urticae, 90 Mb [94]). 40
Research to benefit directly from genome sequencing includes drug resistance studies, with the annotation of resistance-associated gene families and pathways, measurement of transcriptional responses of mites to drug exposure, and identification of resistance-associated mutations (SNPs). Significantly, the availability of sequence information introduces the capacity to identify novel mite targets for chemotherapeutic intervention. In addition, the availability of genome and transcriptome data for the related mites Psoroptes ovis [95] and Dermatophagoides pteronyssinus would enable a comparative approach, highlighting similarities and differences between parasitic and free-living mites, and provide essential information to develop specific strategies against each of these pathogens. Concluding remarks With a growing and increasingly ageing worldwide population, scabies is expected to remain as a global public health problem in the foreseeable future. Progress made in the last decade towards understanding mite molecular biology, immunology, and drug resistance has been particularly encouraging. With the availability of animal models, and the anticipated acquisition of large amounts of sequence data, we can expect a further acceleration to research outputs for scabies in the next few years. As always, the challenge and emphasis for researchers will be to translate this new knowledge into tangible improvements to the management of this neglected disease. Acknowledgements K.M. is supported by an Australian Research Council Discovery Early Career Researcher Award. J.M. is supported by a Queensland Health Clinical Research Fellowship and a National Health and Medical Research Council Practitioner Fellowship.
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