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Summary Background Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies has been limited by a lack of standardization of diagnostic methods. Objectives To develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. Methods Consensus diagnostic criteria were developed through a Delphi study with international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of the available literature and the opinion of an expanded group of international experts to develop detailed, evidence‐based definitions and diagnostic methods. Results The 2020 International Alliance for the Control of Scabies (IACS) Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed scabies (level A) requires direct visualization of the mite or its products. Clinical scabies (level B) and suspected scabies (level C) rely on clinical assessment of signs and symptoms. Evidence‐based, consensus methods for microscopy, visualization and clinical symptoms and signs were developed, along with a media library. Conclusions The 2020 IACS Criteria represent a pragmatic yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardization for scabies diagnosis. Validation studies, development of training materials and development of survey methods are now required. What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical.Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common.These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts.The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings.Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis., What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical.Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common.These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts.The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings.Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis.

Scabies, a human skin infestation caused by the ectoparasitic mite Sarcoptes scabiei var. hominis, affects more than 200 million people globally. The prevailing knowledge of the disease process and host immune response mechanisms is limited. A better understanding of the host-parasite relationship is essential for the identification of novel vaccine and drug targets. Here we aimed to interrogate the transcriptomic profiles of mite-infested human skin biopsies with clinical manifestations of ordinary scabies subjects (“OS”; n = 05) and subjects naive to scabies (“control”; n = 03) using RNASeq data analysis. A combined clustering, network, and pathway mapping approach enabled us to identify key signaling events in the host immune and pro-inflammatory responses to S. scabiei infestation. The clustering patterns showed various differentially expressed genes including inflammatory responses and innate immunity genes (DEFB4A, IL-19, CXCL8, CSF3, SERPINB4, S100A7A, HRNR) and notably upregulation of the JAK-STAT pathway in scabies-infested samples. Mite-infested human skin biopsies (GSE178563) were compared with an ex-vivo porcine infested model (E-MTAB-6433) and human skin equivalents (GSE48459). Marked enrichment of immune response pathways (JAK-STAT signaling, IL-4 and IL-13 pathway, and Toll receptor cascade), chemokine ligands and receptors (CCL17, CCL18, CCL3L1, CCL3L3, CCR7), and cytokines (IL-13 and IL-20) were observed. Additionally, genes known for their role in psoriasis and atopic dermatitis were upregulated, e.g., IL-19. The detailed transcriptomic profile has provided an insight into molecular functions, biological processes, and immunological responses and increased our understanding about transcriptomic regulation of scabies in human.

Sarcoptes scabiei is a causative organism for scabies that affects an estimated global population of 300 million and remains a disease of significant concern. Recently, a number of potential drug targets were identified for scabies, including hydrolytic enzymes, inactivated paralogues of hydrolytic enzymes, inhibitors of host proteolytic enzymes and other proteins of interest. These discoveries remain confined to academic laboratories and institutions, failing to attract interest from researchers in commercial drug development. Here, we summarize the latest developments in the scabies mite biology and the drug targets that were subsequently identified, and we propose several peptide and nonpeptide ligands targeting the hot spots for protein–protein interactions. We also identify gaps in the development of ligands as inhibitors or modulators of these macromolecules.

Scabies is a neglected tropical disease of global significance. Our understanding of host-parasite interactions has been limited, particularly in crusted scabies (CS), a severe clinical manifestation involving hyper-infestation of Sarcoptes scabiei mites. Susceptibility to CS may be associated with immunosuppressive conditions but CS has also been seen in cases with no identifiable risk factor or immune deficit. Due to ethical and logistical difficulties with undertaking research on clinical patients with CS, we adopted a porcine model which parallels human clinical manifestations. Transcriptomic analysis using microarrays was used to explore scabies pathogenesis, and to identify early events differentiating pigs with ordinary (OS) and crusted scabies. Pigs with OS (n = 4), CS (n = 4) and non-infested controls (n = 4) were compared at pre-infestation, weeks 1, 2, 4 and 8 post-infestation. In CS relative to OS, there were numerous differentially expressed genes including pro-inflammatory cytokines (IL17A, IL8, IL19, IL20 and OSM) and chemokines involved in immune cell activation and recruitment (CCL20, CCL27 and CXCL6). The influence of genes associated with immune regulation (CD274/PD-L1 and IL27), immune signalling (TLR2, TLR8) and antigen presentation (RFX5, HLA-5 and HLA-DOB) were highlighted in the early host response to CS. We observed similarities with gene expression profiles associated with psoriasis and atopic dermatitis and confirmed previous observations of Th2/17 pronounced responses in CS. This is the first comprehensive study describing transcriptional changes associated with the development of CS and significantly, the distinction between OS and CS. This provides a basis for clinical follow-up studies, potentially identifying new control strategies for this severely debilitating disease., Author summary The immune response to Sarcoptes scabiei infestation is poorly defined. There have been few studies of crusted scabies, a debilitating clinical variant of the disease characterised by extremely high mite numbers. In this study, we used a pig model to explore differences in gene expression between clinical variants of scabies, including a focus on immune events occurring prior to the development of clinical signs. In early infestation, genes relating to inflammation, immune recognition and cell migration were potently suppressed in pigs with crusted scabies. This suggests that these pigs lacked the ability to mount a timely, effective immune response, allowing mites to proliferate unchecked. In later infestation, the large numbers of mites then triggered a strong inflammatory response leading to severe skin pathology. Gene expression profiles in crusted scabies shared similarities with other inflammatory skin diseases such as psoriasis. This is the first study to compare immune responses in crusted and ordinary scabies in early infestation and reveals new insights into the progression of disease. Findings may lead to the development of new approaches to diagnose and treat this important, but neglected disease.

Caerin is a family of peptides isolated from the glandular secretion of Australian tree frogs, the genusLitoria, and has been previously shown to have anticancer activity against several cancer cells. In this work, we used two host-defence peptides, caerin 1.1 and caerin 1.9, to investigate their ability to inhibit a murine derived TC-1 cell transformed with human papillomavirus 16 E6 and E7 growthin vitro. Caerin 1.9 inhibits TC-1 cell proliferation, although inhibition is more pronounced when applied in conjunction with caerin 1.1. To gain further insights into the antiproliferative mechanisms of caerin 1.9 and its additive effect with caerin 1.1, we used a proteomics strategy to quantitatively examine (i) the changes in the protein profiles of TC-1 cells and (ii) the excretory-secretory products of TC-1 cells following caerin peptides treatment. Caerin 1.9 treatment significantly altered the abundance of several immune-related proteins and related pathways, such as the Tec kinase and ILK signalling pathways, as well as the levels of proinflammatory cytokines and chemokines. In conclusion, caerin peptides inhibit TC-1 cell proliferation, associated with modification in signalling pathways that would change the tumour microenvironment which is normally immune suppressive.

Scabies is a human skin disease due to the burrowing ectoparasite Sarcoptes scabiei var. hominis resulting in intense itching and inflammation and manifesting as a skin allergy. Because of insufficient mite material and lack of in vitro propagation system for antigen preparation, scabies is a challenging disease to develop serological diagnostics. For allergen characterization, full-length S. scabiei tropomyosin (Sar s 10) was cloned, expressed in pET-15b, and assessed for reactivity with IgE antibodies from human sera. IgE binding was observed to Sar s 10 with sera collected from subjects with ordinary scabies, house dust mite (HDM)-positive and naive subjects and a diagnostic sensitivity of < 30% was observed. S. scabiei paramyosin (Sar s 11) was cloned, and expressed in pET-28a in three overlapping fragments designated Sspara1, Sspara2, and Sspara3. IgE and IgG binding was observed to Sspara2 and Sspara3 antigens with sera collected from ordinary scabies, and HDM-positive subjects, but no binding was observed with sera collected from naive subjects. Sspara2 displayed excellent diagnostic potential with 98% sensitivity and 90% specificity observed for IgE binding and 70% sensitivity for IgG. In contrast, the diagnostic sensitivity of Sspara3 was 84% for IgE binding and 40% for IgG binding. In combination, Sspara2 and Sspara3 provided an IgE sensitivity of 94%. This study shows that IgE binding to Sspara2 and Sspara3 is a highly sensitive method for diagnosis of scabies infestation in clinical practice. The developed enzyme-linked immunosorbent assay helps direct future development of a specific diagnostic tool for scabies.

Interleukin 10 (IL-10) is a cytokine that is able to downregulate inflammation. Its overexpression is directly associated with the difficulty in the clearance of chronic viral infections, such as chronic hepatitis B, hepatitis C and HIV infection, and infection-related cancer. IL-10 signaling blockade has been proposed as a promising way of clearing chronic viral infection and preventing tumor growth in animal models. Recently, we have reported that peptides with a helical repeating pattern of hydrophobic and hydrophilic residues are able to inhibit IL-10 significantly both in vitro and in vivo.1 In this work, we seek to further study the inhibiting mechanism of these peptides using sequence-modified peptides. As evidenced by both experimental and molecular dynamics simulation in concert the N-terminal hydrophobic peptide constructed with repeating hydrophobic and hydrophilic pattern of residues is more likely to inhibit IL10. In addition, the sequence length and the ability of protonation are also important for inhibition activity.

Scabies is a parasitic skin infestation caused by mite Sarcoptes scabiei and is listed as one of the top 50 epidemic diseases known to affect >200 million people globally. The scabies mites have shown resistance to the many of currently available chemotherapeutics, a prerequisite to identify potential targets for vaccine development. Paramyosin has been identified as a potential vaccine candidate for parasite control and appears as an important immunogen in S. scabiei. In the present study, we used different immune-informatics tools to analyze S. scabiei paramyosin sequence and screen potential B and T cells epitopes. Epitope prioritization was done based on reference allele coverage, antigenicity, high antigenicity, adhesive ability, non-allergenicity and potential of binding to the DRB*0101 allele. Further, it was ensured that the selected candidates were feasible for experimental cloning and expression analysis. The predicted epitopes were also used in multi-peptide vaccine construction to maximize immunogenicity and efficient recognition and processing by the host immune system. Host immune system dynamics in response to the vaccine construct antigen were also elaborated in silico, revealing robust cellular and humoral immunity. To understand cellular interaction mechanisms, molecular docking followed by molecular dynamic simulation was performed to probe the predominant binding mode of the vaccine construct to the innate immune receptor TLR5. Estimation of binding free energy for the final construct was accomplished and revealed the system highly stable with enriched electrostatic and van der Waals energy. In summary, this study provides a gateway to understand the protein function analysis of a potential vaccine candidate for S. scabiei.

No abstract available.; Errata: Analysis of IgE binding patterns to house dust mite allergens in scabies-endemic communities: insights for both diseases. Clinical and Experimental Allergy (2016), Volume 46, Issue 3, pp.508: http://dx.doi.org/10.1111/cea.12713

Moxidectin is under consideration for development as a treatment for human scabies. As some arthropods show decreased sensitivity to moxidectin relative to ivermectin, it was important to assess this for Sarcoptes scabiei . In vitro assays showed that the concentration of moxidectin required to kill 50% of mites was lower than that of ivermectin (0.5 μM versus 1.8 μM at 24 h; P < 0.0001). This finding provides further support for moxidectin as a candidate for the treatment of human scabies.

Scabies is a human skin disease due to the burrowing ectoparasite Sarcoptes scabiei var. hominis resulting in intense itching and inflammation and manifesting as a skin allergy. Because of insufficient mite material and lack of in vitro propagation system for antigen preparation, scabies is a challenging disease to develop serological diagnostics. For allergen characterization, full-length S. scabiei tropomyosin (Sar s 10) was cloned, expressed in pET-15b, and assessed for reactivity with IgE antibodies from human sera. IgE binding was observed to Sar s 10 with sera collected from subjects with ordinary scabies, house dust mite (HDM)-positive and naive subjects and a diagnostic sensitivity of < 30% was observed. S. scabiei paramyosin (Sar s 11) was cloned, and expressed in pET-28a in three overlapping fragments designated Sspara1, Sspara2, and Sspara3. IgE and IgG binding was observed to Sspara2 and Sspara3 antigens with sera collected from ordinary scabies, and HDM-positive subjects, but no binding was observed with sera collected from naive subjects. Sspara2 displayed excellent diagnostic potential with 98% sensitivity and 90% specificity observed for IgE binding and 70% sensitivity for IgG. In contrast, the diagnostic sensitivity of Sspara3 was 84% for IgE binding and 40% for IgG binding. In combination, Sspara2 and Sspara3 provided an IgE sensitivity of 94%. This study shows that IgE binding to Sspara2 and Sspara3 is a highly sensitive method for diagnosis of scabies infestation in clinical practice. The developed enzyme-linked immunosorbent assay helps direct future development of a specific diagnostic tool for scabies.

Scabies is an ectoparasitic infestation by the mite Sarcoptes scabiei. Although commonly self-limiting, a fraction of patients develop severely debilitating crusted scabies. The immune mechanisms underlying the development of crusted scabies are unclear, and undertaking longitudinal infection studies in humans is difficult. We utilized a porcine model to compare cellular immune responses in peripheral blood and skin of pigs with different clinical manifestations of scabies (n = 12), and in uninfected controls (n = 6). Although clinical symptoms were not evident until at least 4 weeks post-infestation, the numbers of peripheral IFNγ-secreting CD4(+) T cells and γδ T cells increased in infected pigs from week 1 post-infestation. γδ T cells remained increased in the blood at week 15 post-infestation. At week 15, skin cell infiltrates from pigs with crusted scabies had significantly higher CD8(+) T cell, γδ T cell and IL-17(+) cell numbers than those with ordinary scabies. Peripheral IL-17 levels were not increased, suggesting that localized skin IL-17-secreting T cells may play a critical role in the pathogenesis of crusted scabies development. Given the potential of anti-IL-17 immunotherapy demonstrated for other inflammatory skin diseases, this study may provide a novel therapeutic avenue for patients with recurrent crusted scabies.

SUMMARYScabies is an infectious disease that is endemic in poorly resourced communities, and also common in industrialized countries. Although the disease, which is caused by infestation of Sarcoptes scabiei, is generally mild, the need for a vaccine against S. scabiei is proposed. The immunological mechanisms that control S. scabiei infection are discussed and the current status of scabies vaccine development reviewed. Future directions for scabies vaccine development are also addressed.

Purpose of review: We propose that a major gap in the control, prevention, diagnosis and treatment of scabies exists because of lack of key translational understandings related to the immunopathology of scabies and the associated severe form of the disease, crusted scabies. Understanding the complex network of innate and adaptive immune responses, including the long lag period from infection to clinical symptoms, is fundamental to developing early interventions and decreasing transmission. Such interventions must be driven by clinical need and include user-friendly translational outcomes for improved control in endemic and resource-poor settings. Recent findings: In the last few years, we have seen an increase in the molecular characterization of scabies mite proteins. However, owing to limited capacity in scabies immunology-related research, little is still known regarding the immunological effects of the mite or mite products on disease progression or protection. Summary: Detailing the skin immunopathogenesis in relation to scabies, including the role of macrophages, mast cells and eosinophils, as well as the immunomodulatory effects of parasite evasion mechanisms are essential for the rational design of future therapeutic, diagnostic and preventative tools. Resolving this knowledge gap could ultimately lead to significant improvements in clinical and public health interventions. This article proposes a conceptual model for capacity building to inform future research activities in the field.;

Blockade of IL-10 signalling clears chronic viral and bacterial infections. Immunization together with blockade of IL-10 signalling or relatively low level of IL-10 further enhances viral and bacterial clearance. IL-10 functions through binding to interleukin 10 receptor (IL-10R). Here we showed that peptides P1 and P2 with the hydrophobic and hydrophilic pattern of the IL10R-binding helix in IL-10 could bind with either IL-10R1 or IL-10, and inhibit inflammatory signals with long duration and negligible cytotoxicity in vitro. Furthermore, P2 can enhance antigen specific CD8+ T cell responses in mice induced by the vaccine based on a long peptide of protein E7 in a human papillomavirus type 16.

Scabies remains one of the commonest of skin diseases seen in developing countries. Although its distribution is subject to a cycle of infection, with peaks and troughs of disease prevalence, this periodicity is often less obvious in poor communities. Scabies is a condition that affects families, particularly the most vulnerable; it also has the greatest impact on young children. Largely through the association with secondary bacterial infection caused by group A streptococci and Staphylococcus aureus, the burden of disease is compounded by nephritis, rheumatic fever and sepsis in developing countries. However, with a few notable exceptions, it remains largely neglected as an important public health problem. The purpose of this review is to provide an update on the current position of scabies with regard to its complications and control in resource-poor countries.

The following series of concise summaries addresses the evolution of infectious agents in relation to sex in animals and humans from the perspective of three specific questions: (1) what have we learned about the likely origin and phylogeny, up to the establishment of the infectious agent in the genital econiche, including the relative frequency of its sexual transmission; (2) what further research is needed to provide additional knowledge on some of these evolutionary aspects; and (3) what evolutionary considerations might aid in providing novel approaches to the more practical clinical and public health issues facing us currently and in the future?

Scabies, a mite infestation frequently sexually transmitted, dates back to antiquity but remains a challenging parasite for study in clinical practice and community settings. Its history is one of centuries of slow progress to recognize the mite and to finally establish its nexus to the clinical syndrome of pruritis with several protean manifestations and different epidemiological patterns. Contemporary methods of management are briefly reviewed, with the future promise of improved evolutionary knowledge associated with the advent of molecular and genetic technology. Current information indicates that humans and earlier protohumans were most likely the source of animal scabies, first of dogs, and later of other species with subsequent spread to wildlife. Morphologically identical variants of Sarcoptes scabiei are nonetheless host specific, as determined by recent DNA studies, and invite future investigations into the dynamics of this troublesome sexually transmissible agent, with the goal of improved recognition and control.

Introduction In remote Aboriginal communities in Australia, scabies affects 7 out of 10 children before their first birthday. This is more than six times the rate seen in the rest of the developed world. Scabies infestation is frequently complicated by bacterial infection, leading to the development of skin sores and other more serious consequences, such as septicaemia and chronic heart and kidney diseases. Tea tree oil (TTO) has been used as an antimicrobial agent for several decades with proven clinical efficacy. Preclinical investigations have demonstrated superior scabicidal properties of TTO compared with widely used scabicidal agents, such as permethrin 5% cream and ivermectin. However, current data are insufficient to warrant a broad recommendation for its use for the management of scabies because previous studies were small or limited to in vitro observations. Methods and analysis A pragmatic first trial will examine the clinical efficacy of a simple and low-cost TTO treatment against paediatric scabies and the prevention of associated secondary bacterial infections, with 1:1 randomisation of 200 participants (Aboriginal children, aged 5–16 years and living in remote Australia) into active control (permethrin 5% cream) and treatment (5% TTO gel) groups. The primary outcome for the study is clinical cure (complete resolution). Secondary outcome measures will include relief of symptoms, recurrence rate, adverse effects, adherence to treatment regimen and patient acceptability. Ethics and dissemination The project has received approvals from the University of Canberra Human Research Ethics Committee (HREC 16-133), Wurli-Wurlinjang Health Service Indigenous subcommittee and the Aboriginal Medical Services Alliance Northern Territory reference group. The results of this study will be published in core scientific publications, with extensive knowledge exchange activities with non-academic audiences throughout the duration of the project. Trial registration ACTRN12617000902392; Pre-results.

Reports of ivermectin resistance in scabies mites raise concerns regarding the sustainability of mass intervention programs for scabies worldwide and for the treatment of crusted scabies. Ligand gated ion channels (LGICs) are the primary targets of ivermectin in invertebrates. We report the molecular characterisation of SsCl--a novel LGIC from Sarcoptes scabiei var. hominis. While SsCl shows sequence similarity to other LGICs, phylogenetic analysis does not suggest strong homology to conventional glutamate, histamine or GABA gated channels. Instead, it is most similar to Drosophila pH-sensitive and group 1 clades. When expressed in Xenopus oocytes, SsCl forms a homomeric, pH-gated chloride channel that is irreversibly activated by ivermectin. These results provide the first confirmation that this group of LGIC exists in arachnids, and suggest that SsCl may be an in vivo target of ivermectin in S. scabiei.

SUMMARY Scabies is a worldwide disease and a major public health problem in many developing countries, related primarily to poverty and overcrowding. In remote Aboriginal communities in northern Australia, prevalences of up to 50% among children have been described, despite the availability of effective chemotherapy. Sarcoptic mange is also an important veterinary disease engendering significant morbidity and mortality in wild, domestic, and farmed animals. Scabies is caused by the ectoparasitic mite Sarcoptes scabiei burrowing into the host epidermis. Clinical symptoms include intensely itchy lesions that often are a precursor to secondary bacterial pyoderma, septicemia, and, in humans, poststreptococcal glomerulonephritis. Although diagnosed scabies cases can be successfully treated, the rash of the primary infestation takes 4 to 6 weeks to develop, and thus, transmission to others often occurs prior to therapy. In humans, the symptoms of scabies infestations can mimic other dermatological skin diseases, and traditional tests to diagnose scabies are less than 50% accurate. To aid early identification of disease and thus treatment, a simple, cheap, sensitive, and specific test for routine diagnosis of active scabies is essential. Recent developments leading to the expression and purification of S. scabiei recombinant antigens have identified a number of molecules with diagnostic potential, and current studies include the investigation and assessment of the accuracy of these recombinant proteins in identifying antibodies in individuals with active scabies and in differentiating those with past exposure. Early identification of disease will enable selective treatment of those affected, reduce transmission and the requirement for mass treatment, limit the potential for escalating mite resistance, and provide another means of controlling scabies in populations in areas of endemicity.

Background Scabies is an ancient disease (documented as far back as 2500 years ago). It affects about 300 million people annually worldwide, and the prevalence is as high as about 60 % in Indigenous and Torres Strait Islander children in Australia. This is more than six times the rate seen in the rest of the developed world. Scabies is frequently complicated by bacterial infection leading to the development of skin sores and other more serious consequences such as septicaemia and chronic heart and kidney diseases. This causes a substantial social and economic burden especially in resource poor communities around the world. Discussion Very few treatment options are currently available for the management of scabies infection. In this manuscript we briefly discuss the clinical consequences of scabies and the problems found (studies conducted in Australia) with the currently used topical and oral treatments. Current scabies treatment options are fairly ineffective in preventing treatment relapse, inflammatory skin reactions and associated bacterial skin infections. None have ovicidal, antibacterial, anti-inflammatory and/or anti-pruritic properties. Treatments which are currently available for scabies can be problematic with adverse effects and perhaps of greater concern the risk of treatment failure. The development of new chemical entities is doubtful in the near future. Though there may be potential for immunological control, the development of a vaccine or other immunotherapy modalities may be decades away. Summary The emergence of resistance among scabies mites to classical scabicides and ineffectiveness of current treatments (in reducing inflammatory skin reactions and secondary bacterial infections associated with scabies), raise serious concerns regarding current therapy. Treatment adherence difficulties, and safety and efficacy uncertainties in the young and elderly, all signal the need to identify new treatments for scabies.

Four new cases of sarcoptic mange in cats are described. Two cats resided in areas known to be frequented by foxes, another cohabited with a dog recently diagnosed with sarcoptic mange, while the final cat lived with a mixed breed dog that had been treated for sarcoptic mange 7 months previously. Three cases were diagnosed on the basis of characteristic mite size and morphology in skin scraping from representative lesions, situated on the head (two cases) or head and distal hind limbs (one case). Mites were highly mobile and abundant in all instances, and easily detected also in skin biopsy specimens procured from two cases. Eosinophilic inflammation, hyperkeratosis and parakeratosis were prominent in the tissue sections. In the remaining case, the diagnosis was presumptive, based on characteristic lesions, cohabitation with a canine scabies patient and positive response to scabicide therapy. Pruritus was not a prominent clinical feature in any patient and was considered to be absent in three of the four cases. Lesions in three cats with long-standing disease were reminiscent of crusted scabies (synonym: Norwegian scabies, parakeratotic scabies) as seen in human patients. In three cases, in-contact human carriers developed itchy cutaneous papular lesions. Two cases responded promptly to therapy with systemic avermectin drugs, while one responded to topical treatment with lime sulphur and the remaining cat received both a lime sulphur rinse and ivermectin. Sarcoptic mange should be considered in the differential diagnosis of cats with non-pruritic crusting skin diseases, especially when there is contact with foxes or dogs, and when owners have itchy papular lesions.

The scabies mite, Sarcoptes scabiei, is the causative agent of scabies, a disease that is common among disadvantaged populations and facilitates streptococcal infections with serious sequelae. Previously, we encountered large families of genes encoding paralogues of house dust mite protease allergens with their catalytic sites inactivated by mutation (scabies mite inactivated protease paralogues [SMIPPs]). We postulated that SMIPPs have evolved as an adaptation to the parasitic lifestyle of the scabies mite, functioning as competitive inhibitors of proteases involved in the host-parasite interaction. To propose testable hypotheses for their functions, it is essential to know their locations in the mite. Here we show by immunohistochemistry that SMIPPs exist in two compartments: 1) internal to the mite in the gut and 2) external to the mite after excretion from the gut in scybala (fecal pellets). SMIPPs may well function in both of these compartments to evade host proteases.

Scabies is a disease of considerable importance in the developing world and among disadvantaged people such as the Aborigines in Australia, as it underlies streptococcal skin infections. It has been neglected at the molecular level until very recently. However, 43,776 expressed sequence tags have now been generated at the Australian Genome Research Facility from a cDNA library we constructed. Unexpectedly, in a search for homologues of house dust mite allergens among these sequences, we discovered large families of serine and cysteine protease genes with genetically inactivated catalytic sites. These are strong candidates for parasite defences against host immunity as we did not find them in a house dust mite cDNA library. Some possible modes of action are discussed.

Permethrin, in the form of a topical cream, is being increasingly used for community-based programs to control endemic scabies. The development of resistance has reduced the use of pyrethroids for the control of many arthropods of economic and health importance. The best recognized form of pyrethroid resistance, known as knockdown resistance or kdr, has been linked to specific mutations in the target of these agents, the para-homologous voltage-sensitive sodium channel gene (Vssc). To develop tools to study resistance to pyrethroid acaricides, we cloned 3711 and 6151 bp, respectively, of cDNA and genomic fragments of the Vssc gene from scabies mite, Sarcoptes scabiei. The sequence encompasses the major polymorphic amino acid residues associated with pyrethroid resistance. A polymerase chain reaction-based strategy has been developed that enables genotyping individual scabies mites. This will facilitate early detection and monitoring of pyrethroid resistance in scabies mite populations under drug selection pressure.

The astigmatid mite Sarcoptes scabiei is the causative agent of scabies, a highly infectious parasitic disease of the skin. Although the mite causes marked hypersensitivity reactions, particularly in crusted (severe) scabies, little is known about the specific scabies mite molecules involved in such immunologic responses. We have identified six genes encoding scabies mite homologues of mu and delta-like glutathione S-transferases (GSTs) as well as novel house dust mite GSTs. A mu class S. scabiei GST was subcloned into a prokaryotic expression system. The purified recombinant protein rSsGST01 reacted strongly with IgE and IgG4 in sera from crusted scabies patients. This response was not observed with control antigens or with ordinary scabies and uninfested patient sera. In addition, the specific IgE response to rSsGST01 did not correlate with the total IgE level of the patient. These results suggest that GST may play a role in the pathophysiology associated with crusted scabies.

OBJECTIVES: To describe the clinical and immunological features of crusted scabies in a prospectively ascertained cohort of 78 patients. METHODS: All patients requiring inpatient treatment for crusted scabies in the 'top end' of the northern territory of Australia over a 10 year period were prospectively identified. Demographics, risk factors, and immunological parameters were retrospectively compiled from their medical records and pathology databases. RESULTS: More than half the patients with crusted scabies had identifiable immunosuppressive risk factors. Eosinophilia and elevated IgE levels occurred in 58% and 96% of patients, respectively, with median IgE levels 17 times the upper limit of normal. Seventeen percent had a history of leprosy but 42% had no identifiable risk factors. There was a decrease in mortality after the introduction of a treatment protocol consisting of multiple doses of ivermectin combined with topical scabicides and keratolytic therapy. CONCLUSIONS: Crusted scabies often occurs in patients with identifiable immunosuppressive risk factors. In patients without such risk factors, it is possible that the crusted response to infection results from a tendency to preferentially mount a Th2 response. The treatment regime described was associated with a reduction in mortality. This is the largest reported case series of crusted scabies.

The endosymbiont Wolbachia has been detected in a range of filarial nematodes and parasitic mites and is known to affect host reproductive compatibility and potentially evolutionary processes. PCR of Wolbachia surface protein (wsp), ftsZ and 16SrRNA genes from individual Sarcoptes scabiei mites obtained from a series of individual hosts, and database searches of an S. scabiei var. hominis EST library failed to detect Wolbachia genes. Therefore, Wolbachia appears not to be involved in the genetic subdivision observed between varieties of host-associated S. scabiei or, involved in the inflammatory disease pathogenesis of scabies unlike its activity in filarial infection.

Human scabies, caused by skin infestation with the arthropod mite, Sarcoptes scabiei, typically results in a papular, intensely pruritic eruption involving the interdigital spaces, and flexure creases. Recent research has led to a reassessment of the morbidity attributable to this parasite in endemic communities, particularly resulting from secondary skin sepsis and postinfective complications including glomerulonephritis. This has led to studies of the benefits of community based control programmes, and to concerns regarding the emergence of drug resistance when such strategies are employed. The renewed research interest into the biology of this infection has resulted in the application of molecular tools. This has established that canine and human scabies populations are genetically distinct, a finding with major implications for the formulation of public health control policies. Further research is needed to increase understanding of drug resistance, and to identify new drug targets and potential vaccine candidates.

Ivermectin is increasingly being used to treat scabies, especially crusted (Norwegian) scabies. However, treatment failures, recrudescence, and reinfection can occur, even after multiple doses. Ivermectin resistance has been documented for some intestinal helminths in animals with intensive ivermectin exposure. Ivermectin resistance has also been induced in arthropods in laboratory experiments but, to date, has not been documented among arthropods in nature. We report clinical and in vitro evidence of ivermectin resistance in 2 patients with multiple recurrences of crusted scabies who had previously received 30 and 58 doses of ivermectin over 4 and 4.5 years, respectively. As predicted, ivermectin resistance in scabies mites can develop after intensive ivermectin use.

Molecular studies on scabies, a disease of considerable human and veterinary significance, have been limited because of the difficulty of obtaining the causative organism Sarcoptes scabiei, the "itch mite." We have used skin from the bedding of crusted scabies patients as a source of mites for the construction of libraries of cDNAs from S. scabiei var. hominis in the bacteriophage lambda vector lambdaZAP express. Sequences of 145 clones established that the libraries predominantly contain sequences from S. scabiei, enabling a major sequencing program to begin. Among those sequenced to date, cDNAs encoding S. scabiei homologues of 3 house dust mite allergens-the M-177 apolipoprotein, glutathione S-transferase, and paramyosin--were identified. The availability of cDNA libraries from S. scabiei var. hominis and S. scabiei var. vulpes and the emerging public sequence databases from both opens up new possibilities in scabies research.

Sarcoptes scabiei ("itch mite") causes scabies, a disease of considerable human and veterinary significance. Little work has been done at the molecular level because of the difficulty of obtaining mites. We have used mites in skin from the bedding of crusted scabies patients for the construction of a library of 10(5) cDNAs from S. scabiei var. hominis cloned in the vector pGEX4T-2. We describe the isolation by immunoscreening of 2 clones, one of which (Ssagl) is homologous to and cross-reactive with the house dust mite Euroglyphus maynei allergen M-177, an apolipoprotein from hemolymph. Immunohistochemistry revealed that it is located around the internal organs and cuticle of the mite and in eggs. Although it was not found to be protective in a challenge trial, the rabbits did not exhibit typical crust characteristics. This work shows that it is now possible to conduct such challenge trials with cloned scabies antigens.

Background Understanding of scabies immunopathology has been hampered by the inability to undertake longitudinal studies in humans. Pigs are a useful animal model for scabies, and show clinical and immunologic changes similar to those in humans. Crusted scabies can be readily established in pigs by treatment with the glucocorticoid dexamethasone (Dex). Methodology/ Principal Findings Prospective study of 24 pigs in four groups: a) Scabies+/Dex+, b) Scabies+/Dex-, c) Scabies-/Dex+ and d) Scabies-/Dex-. Clinical symptoms were monitored. Histological profiling and transcriptional analysis of skin biopsies was undertaken to compare changes in cell infiltrates and representative cytokines. A range of clinical responses to Sarcoptes scabiei were observed in Dex treated and non-immunosuppressed pigs. An association was confirmed between disease severity and transcription of the Th2 cytokines IL-4 and IL-13, and up-regulation of the Th17 cytokines IL-17 and IL-23 in pigs with crusted scabies. Immunohistochemistry revealed marked infiltration of lymphocytes and mast cells, and strong staining for IL-17. Conclusions/ Significance While an allergic Th2 type response to scabies has been previously described, these results suggest that IL-17 related pathways may also contribute to immunopathology of crusted scabies. This may lead to new strategies to protect vulnerable subjects from contracting recurrent crusted scabies., Author Summary Scabies is a neglected tropical skin disease caused by the tiny parasitic mite Sarcoptes scabiei. Scabies is common in developing countries, and scabies outbreaks also occur in institutional settings worldwide. Scabies often underlies secondary bacterial skin infection and resulting complications, and is thus associated with considerable morbidity. Crusted scabies is a an extremely severe and debilitating clinical form of the disease, but host immune responses leading to the development of crusted or ordinary scabies are poorly understood. This is largely due to limited access to clinical samples, and the difficulty in monitoring the progression of infestation in human patients. We have overcome this challenge by using a pig model of scabies infestation, since pigs and humans with scabies display clinical and immunological similarities. In this study, we undertook longitudinal analysis of clinical, histological and molecular immunological changes in pigs experimentally infected with scabies. We confirmed that disease severity was associated with a pronounced allergic, Th2 immune response, as previously reported. In a novel finding, we showed that the Th17 associated cytokines interleukin-17 and interleukin-23 were also associated with the development of crusted scabies. This may lead to new immunotherapeutic strategies to protect vulnerable subjects from contracting recurrent crusted scabies.

Interleukin 10 is a cytokine with the ability to reduce or terminate inflammation. Chronic viral infection, such as infection of chronic hepatitis B, hepatitis C and HIV, has increased levels of interleukin 10 in peripheral blood. Serum IL-10 levels are also high in certain cancers. Blocking IL-10 signalling at the time of immunisation clears chronic viral infection and prevents tumour growth in animal models. We review recent advances in this area, with the emphasis on potential use of this novel strategy to treat chronic viral infection and cancer in human.

Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted. Refereed/Peer-reviewed

There are an estimated 0.5–1 million mite species on earth. Among the many mites that are known to affect humans and animals, only a subset are parasitic but these can cause significant disease. We aim here to provide an overview of the most recent work in this field in order to identify common biological features of these parasites and to inform common strategies for future research. There is a critical need for diagnostic tools to allow for better surveillance and for drugs tailored specifically to the respective parasites. Multi-‘omics’ approaches represent a logical and timely strategy to identify the appropriate mite molecules. Recent advances in sequencing technology enable us to generate de novo genome sequence data, even from limited DNA resources. Consequently, the field of mite genomics has recently emerged and will now rapidly expand, which is a particular advantage for parasitic mites that cannot be cultured in vitro. Investigations of the microbiota associated with mites will elucidate the link between parasites and pathogens, and define the role of the mite in transmission and pathogenesis. The databases generated will provide the crucial knowledge essential to design novel diagnostic tools, control measures, prophylaxes, drugs and immunotherapies against the mites and associated secondary infections.

Resistance of Sarcoptes scabiei to various topical therapies has been described, but clinical assessment of treatment failure is problematic and in-vitro assays are generally not available. We describe a simple in-vitro analysis used to evaluate the relative efficacy of a range of topical, oral, and herbal treatments available in Australia for the treatment of scabies. S. scabiei var. hominis mites were collected from skin scrapings obtained from 7 crusted scabies patients over a period of 2 years (1997 and 1998). Larvae, nymphal instars, and adult mites were tested within 3 h of collection and continuously exposed to selected commercially available treatment products until death, with the elapsed time recorded. Neem was the only product to show little acaricidal activity. Survival curves indicated that, of the other agents, 5% permethrin (Lyclear) had the slowest killing time, with 35% of mites still alive after 3 h, and 4% still alive after 18-22 h of constant exposure. In contrast, no mites were alive after 3 h exposure to 25% benzyl benzoate (Ascabiol), 1% lindane (Quellada), 5% tea tree oil and 100-8000 ng/g of ivermectin (Equimec). Despite the slower killing time with 5% permethrin, there was no evidence of any mite tolerance in vivo or treatment failure in any patients or contact cases.

Crusted scabies is a severe debilitating disease due to hyperinfestation with the ectoparasite Sarcoptes scabiei. Treatment protocols include oral ivermectin and topical scabicides. After single-dose ivermectin, there may be early recrudescence, whereas after 3 doses at 14-day intervals, there is an apparent cure. However, such patients often present again after 6-12 months. To clarify the biology of recurrence, we studied genetic markers in sequential populations of S. scabiei mites from treated patients with multiple episodes of crusted scabies. Individual mites were genotyped at hypervariable microsatellite loci by a fluorescence-based polymerase chain reaction. Results indicated that sequential populations of mites were genetically more similar to each other than to mites from other patients. Although the majority of recurrent scabies is probably due to reinfestation from inadequately treated contacts, there was evidence that in very severe crusted scabies, treatment with even 3 doses of ivermectin 14 days apart may be inadequate and relapse may occur.

Background Scabies is a disease of worldwide significance, causing considerable morbidity in both humans and other animals. The scabies mite Sarcoptes scabiei burrows into the skin of its host, obtaining nutrition from host skin and blood. Aspartic proteases mediate a range of diverse and essential physiological functions such as tissue invasion and migration, digestion, moulting and reproduction in a number of parasitic organisms. We investigated whether aspartic proteases may play role in scabies mite digestive processes. Methodology/Principle Findings We demonstrated the presence of aspartic protease activity in whole scabies mite extract. We then identified a scabies mite aspartic protease gene sequence and produced recombinant active enzyme. The recombinant scabies mite aspartic protease was capable of digesting human haemoglobin, serum albumin, fibrinogen and fibronectin, but not collagen III or laminin. This is consistent with the location of the scabies mites in the upper epidermis of human skin. Conclusions/Significance The development of novel therapeutics for scabies is of increasing importance given the evidence of emerging resistance to current treatments. We have shown that a scabies mite aspartic protease plays a role in the digestion of host skin and serum molecules, raising the possibility that interference with the function of the enzyme may impact on mite survival., Author Summary Scabies is an infectious disease of the skin caused by infestation with the parasitic mite Sarcoptes scabiei. It is a disease that has a considerable impact on humans and other animals, including livestock, wildlife and companion animals. Scabies mites burrow into the skin of their host, consuming host skin and blood molecules. Aspartic proteases play a key role in invasion and digestion processes in many parasitic organisms. We have identified a scabies mite aspartic protease and have shown that it is capable of digesting human haemoglobin, serum albumin, fibrinogen and fibronectin in vitro, indicating that it plays a role in mite digestive processes. This raises the possibility that interfering with the function of this digestive enzyme may impact on mite survival.

Background Crusted scabies, or hyperinfestation with Sarcoptes scabiei, occurs in people with an inadequate immune response to the mite. In recent decades, data have emerged suggesting that treatment of crusted scabies with oral ivermectin combined with topical agents leads to lower mortality, but there are no generally accepted tools for describing disease severity. Here, we describe a clinical grading scale for crusted scabies and its utility in real world practice. Methodology/Principal Findings In 2002, Royal Darwin Hospital (RDH), a hospital in tropical Australia developed and began using a clinical grading scale to guide the treatment of crusted scabies. We conducted a retrospective observational study including all episodes of admission to RDH for crusted scabies during the period October 2002–December 2010 inclusive. Patients who were managed according to the grading scale were compared with those in whom the scale was not used at the time of admission but was calculated retrospectively. There were 49 admissions in 30 patients during the study period, of which 49 (100%) were in Indigenous Australians, 29 (59%) were male and the median age was 44.1 years. According to the grading scale, 8 (16%) episodes were mild, 24 (49%) were moderate, and 17 (35%) were severe. Readmission within the study period was significantly more likely with increasing disease severity, with an odds ratio (95% CI) of 12.8 (1.3–130) for severe disease compared with mild. The patients managed according to the grading scale (29 episodes) did not differ from those who were not (20 episodes), but they received fewer doses of ivermectin and had a shorter length of stay (11 vs. 16 days, p = 0.02). Despite this the outcomes were no different, with no deaths in either group and a similar readmission rate. Conclusions/Significance Our grading scale is a useful tool for the assessment and management of crusted scabies., Author Summary Crusted scabies is a severe skin condition caused by a microscopic parasitic mite. It occurs in people whose immune system does not react properly to the mite and it leads to crusting and cracking of the skin and can cause death. The usual treatment for crusted scabies is a tablet called ivermectin combined with anti-scabies skin creams. However, there is no current method of measuring the severity of crusted scabies and thus deciding how long to continue the treatment for. We have developed a grading scale based on examination of the skin, which classifies patients as mild, moderate or severe, and uses this grading to suggest the duration of treatment. We have trialed this grading scale over an 8-year period in 49 episodes of crusted scabies requiring hospital admission, and have found that it leads to a shorter length of hospital stay and treatment, but equivalent outcomes compared to those who were treated without the use of the grading scale.

No commercial immunodiagnostic tests for human scabies are currently available, and existing animal tests are not sufficiently sensitive. The recombinant Sarcoptes scabiei apolipoprotein antigen Sar s 14.3 is a promising immunodiagnostic, eliciting high levels of IgE and IgG in infected people. Limited data are available regarding the temporal development of antibodies to Sar s 14.3, an issue of relevance in terms of immunodiagnosis. We utilised a porcine model to prospectively compare specific antibody responses to a primary infestation by ELISA, to Sar s 14.3 and to S. scabiei whole mite antigen extract (WMA). Differences in the antibody profile between antigens were apparent, with Sar s 14.3 responses detected earlier, and declining significantly after peak infestation compared to WMA. Both antigens resulted in >90% diagnostic sensitivity from weeks 8-16 post infestation. These data provide important information on the temporal development of humoral immune responses in scabies and further supports the development of recombinant antigen based immunodiagnostic tests for recent scabies infestations.

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.