ISSN 0001-5555 ActaDV Volume 100 2020 Theme issue

Advances in Dermatology and Venereology

A Non-profit International Journal for Interdisciplinary Skin Research, Clinical and Experimental Dermatology and Sexually Transmitted Diseases

Frontiers in Dermatology and Venereology - A series of theme issues in relation to the 100-year anniversary of ActaDV

Official Journal of - European Society for Dermatology and Psychiatry

Affiliated with - The International Forum for the Study of Itch

Immediate Open Access

Acta Dermato-Venereologica

www.medicaljournals.se/adv ACTA DERMATO-VENEREOLOGICA The journal was founded in 1920 by Professor Johan Almkvist. Since 1969 ownership has been vested in the Society for Publication of Acta Dermato-Venereologica, a non-profit organization. Since 2006 the journal is published online, independently without a commercial publisher. (For further information please see the journal’s website https://www. medicaljournals.se/acta)

ActaDV is a journal for clinical and experimental research in the field of dermatology and venereology and publishes high- quality papers in English dealing with new observations on basic dermatological and venereological research, as well as clinical investigations. Each volume also features a number of review articles in special areas, as well as Correspondence to the Editor to stimulate debate. New books are also reviewed. The journal has rapid publication times.

Editor-in-Chief: Olle Larkö, MD, PhD, Gothenburg Former Editors: Johan Almkvist 1920–1935 Deputy Editors: Sven Hellerström 1935–1969 Anette Bygum, MD, PhD, Odense Nils Thyresson 1969–1987 Magnus Lindberg, MD, PhD, Örebro Lennart Juhlin 1987–1999 Elisabet Nylander, MD, PhD, Umeå Anders Vahlquist 1999–2017 Kaisa Tasanen-Määttä, MD, PhD, Oulu Artur Schmidtchen 2018–2019

Section Editors: Tasuku Akiyama, Miami (Neurodermatology and Itch - Experimental) Annamari Ranki, Helsinki (Cutaneous lymphoma) Nicole Basset-Seguin, Paris (Skin cancer) Artur Schmidtchen, Lund (Wound healing and Innate immunity) Veronique Bataille, London (Melanoma, Naevi, Photobiology) Matthias Schmuth, Innsbruck (Genodermatoses and Keratinizing disorders, Josip Car, Singapore (Health Services Research and e-Health) Ichthyosis and Retinoids) Brigitte Dréno, Nantes (Acne and Rosacea) Lone Skov, Hellerup (Psoriasis) Regina Fölster-Holst, Kiel (Paediatric dermatology, Atopy and Parasitoses) Enikö Sonkoly, Stockholm (Psoriasis and related disorders) Jürg Hafner, Zürich (Skin cancer, Skin tumours, and Melanoma) Jacek Szepietowski, Wrocław (Psychodermatology) Jürgen Harder, Kiel (Cutaneous innate defense, Skin microbe interactions) Elke Weisshaar, Heidelberg (Itch and Neurodermatology) Roderick Hay, London (Cutaneous Infections) Margitta Worm, Berlin (Atopic dermatitis and Immunology) Kristian Kofoed, Copenhagen (STD and Microbiology) Claus Zachariae, Hellerup (Contact dermatitis, Acute dermatology) Veli-Matti Kähäri, Turku (Skin cancer) Magnus Ågren, Copenhagen (Wound healing & Extracellular matrix) Dennis Linder, Graz/Padua (Psychoderm., Dermato-epidemiology,­ e-Health)

Advisory Board: Masashi Akiyama, Nagoya Rudolf Happle, Freiburg Lisa Naysmith, Edinburgh Mona Ståhle, Stockholm Wilma Bergman, Leiden Lars Iversen, Aarhus Jonathan Rees, Edinburgh Sonja Ständer, Münster Tilo Biedermann, Munich Peter van de Kerkhof, Nijmegen Jean Revuz, Paris Jouni Uitto, Philadelphia Magnus Bruze, Malmö Irene Leigh, Dundee Johannes Ring, Munich Shyam Verma, Vadodara Earl Carstens, Davis John McGrath, London Matthias Ringkamp, Baltimore Gil Yosipovitch, Miami Charlotta Enerbäck, Linköping Maja Mockenhaupt, Freiburg Inger Rosdahl, Linköping Giovanna Zambruno, Rome Kilian Eyerich, Stockholm Dedee Murrell, Sydney Thomas Ruzicka, Munich Christos C. Zouboulis, Dessau

All correspondence concerning manuscripts, editorial matters and subscription should be addressed to: Acta Dermato-Venereologica S:t Johannesgatan 22, SE-753 12 Uppsala, Sweden Editorial Manager, Mrs Agneta Andersson Editorial Assistant: Ms Anna-Maria Andersson Please send an E-mail Please send an E-mail

Information to authors: Acta Dermato-Venereologica publishes papers/reports on scientific investigations in the field of dermatology and venereology, as well as reviews. Case reports and good preliminary clinical trials or experimental investigations are usually published as Short Communications. However, if such papers are of great news value they could still be published as full articles. Special contributions such as extensive feature articles and proceedings may be published as supplements to the journal. For detailed instructions to authors see https://www.medicaljournals.se/acta/instructions-to-author. Publication information: Everything is Open Access and no subscription fee. For publication fees: see https://www.medicaljournals.se/acta/ instructions-to-author.

Indexed in: See https://www.medicaljournals.se/acta/about/adv. Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Psoriasis Itch andpruriticdisorders Previous issues Atopic dermatitis Skin malignancies Forthcoming issues Cutaneous andgenitalinfections Current issue • • • • • • • • • • • • • • • • • • • • • • • • The ChangingSpectrumofSexually Transmitted InfectionsinEurope,A.Stary Skin Diseaseinthe Tropics andtheLessonsthatcanbeLearnedfromLeprosyOtherNeglectedDiseases,R.J.Hay Pustular Psoriasis:theDawnof aNewEra,H.Bachelez Psoriasis andCo-morbidity, M. Amin, E.B.Lee,T-F. Tsai, J.J.Wu Psoriasis and Treatment: Past,PresentandFuture Aspects, C.Reid,C.E.M.Griffiths The Woronoff RinginPsoriasisandtheMechanisms ofPostinflammatoryHypopigmentation,J.Prinz Psoriasis andGenetics,N.Dand,S.Mahil,F. Capon,C.H.Smith,M.A.SimpsonandJ.Barker A.G.S. Zink,S.Ständer Challenges in Clinical Research and Care in Pruritus, A NewGenerationof Treatments forItch,E.Fowler, G.Yosipovitch Itch andPsyche:Bilateral Associations, R.Reszke,J.C.Szepietowski Non-dermatological ChallengesofChronicItch,A.E.Kremer, T. Mettang,E.Weisshaar Mechanisms andManagementofItchinDrySkin,C.SagitaMoniaga,M.Tominaga, K.Takamori The ChallengeofBasicItchResearch,E.Carstens,T. Follansbee,M.I.Carstens Update oftheManagementCutaneousSquamous-cellCarcinoma,E.Maubec It’s NotallSunshine:Non-sun-relatedMelanomaRisk-factors,V. Bataille Cutaneous Melanoma– A ReviewofSystemic Therapies, K. A. Lee,P. Nathan Biomarkers PredictingforResponseandRelapsewithMelanomaSystemic Therapy, S.J.Welsh, P. G.Corrie Melanoma EpidemiologyandSunExposure,S.Raimondi,M.Suppa,Gandini Melanoma RiskandMelanocyteBiology, J.U.Bertrand,E.Steingrimsson,F. Jouenne,B.Bressac-de Paillerets, L.Larue Update intheManagementofBasalCellCarcinoma,N.Basset-Seguin,F. Herms Melanoma Genomics,J. A. Newton-Bishop,D.T. Bishop,M.Harland The ManagementofScabiesinthe21 We Like To Go? Y. Gräser, D.M.L.Saunte AHundred Years Infections: Do Fungal Where Superficial Diagnosing of From, Come WhereWe Are and Now WhereWe Would Skin InfectionsCausedbyStaphylococcusaureus, P. DelGiudice Theme editors:LoneSkovandEniköSonkoly Theme editors:ElkeWeisshaar, Tasuku Akiyama andJacekSzepietowski Content detailsTBA Theme editors:MagnusLindberg andCarl-Fredrik Wahlgren Theme editors:Veronique BatailleandNicoleBassetSeguin Theme editors:RoderickHayandKristianKofoed Centenary theme issuesinVolume 100ofActaDermato-Venereologica Frontiers inDermatologyandVenereology st Century: Past, Advances andPotentials,C.Bernigaud,K.Fischer, O.Chosidow M.P. Pereira, C.Zeidler, M.Storck, K. Agelopoulos, W.D. Philipp-Dormston, An overview

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue:Cutaneous andgenitalinfections Genodermatoses Blistering skindisorders • • • • • • • • • • • • • Ichthyosis: A RoadModelforSkinResearch,A.Vahlquist, H.Törmä Genetics ofInheritedIchthyosesandRelatedDiseases,J.Fischer, E.Bourrat Molecular Genetics of Keratinization Disorders - What’s New About Ichthyosis, Diagnosis andManagementofInheritedPalmoplantarKeratodermas,B.R.Thomas,E. A. O’Toole Legius SyndromeanditsRelationshipwithNeurofibromatosis Type 1,E.Denayer, E.Legius Dental Manifestations of Ehlers-Danlos Syndromes: A Systematic Review, Kambe, G.Kokolakis,K.Krause Symptoms, Cutaneous with Presenting Diseases Genetic Autoinflammatory of Spectrum An EarlyDescriptionofa“HumanMosaic”InvolvingtheSkin: A Storyfrom1945,R.Happle Bullous DrugReactions,M.Mockenhaupt Current ConceptsofDermatitisHerpetiformis,T. Salmi,K.Hervonen Drug DevelopmentinPemphigoidDiseases,K.Bieber, R.J.Ludwig Collagen XVIIProcessingandBlisteringSkinDiseases,W. Nishie Skin Fragility:PerspectivesonEvidence-based Therapies, L.Bruckner-Tuderman Theme editors: Anette BygumandMatthias Schmuth Theme editor:KaisaTasanen I. Kapferer-Seebacher, D. Schnabl, J. Zschocke, F. M. Pope J. Uitto, L. Youssefian, A. H. Saeidian, H. Vahidnezhad H. Bonnekoh,M.Butze,T. Kallinich,N.

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Fischer, O.Chosidow The ChangingSpectrumofSexually Transmitted InfectionsinEurope,A.Stary Diseases, R.J.Hay Skin Disease in the Tropics and the Lessons that can be Learned from Leprosy and Other Neglected The Management of Scabies in the 21 Are We Nowand Where Would We Like To Go?Y. Gräser, D.M.L.Saunte Where From, Come Do We Where Infections: Fungal Superficial Diagnosing YearsHundred Aof Skin InfectionsCausedbyStaphylococcusaureus, P. Del Giudice TABLE OF CONTENTS CUTANEOUSGENITAL AND Roderick J.HayandKristianKofoed INFECTIONS st Century: Past, Advances and Potentials, Theme Editors: C. Bernigaud,Katja 242–247 235–241 225–234 216–224 208–215 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV doi: 10.2340/00015555-3466 infections skin Secondary abscesses. primary and cles, furun folliculitis, impetigo, include infections These lesion. skin minimal a to secondary or lesions evident tion is an infection occurring without preceding clinically secondary. A primary or “spontaneous” cutaneous infec Localized S.aureus skin infections are either primary or LOCALIZED S. AUREUS is mainlyresponsibleforskininfections. red S bert, FR-83600, Fréjus,France. E-mail:[email protected] pitalier Intercommunal Fréjus-Saint-Raphaël, 240 Avenue de Saint Lam Corr: Pascal del Giudice, Service Infectiologie-Dermatologie- Centre Hos- Acta DermVenereol 2020;100:adv00110. Accepted Mar19,2020;Epubaheadofprint24,2020 skin infections;cellulitis;furuncle;abscess. Key words: skin infections; mainlycausingskininfections. MRSA), aureus resistant tomunity-acquired S. methicillin (CA- most important event is worldwide emergence of com can occur in endocarditis, bacteraemia.Currently, the reus. Other manifestationsless frequent cutaneous dermatological manifestationsau associatedwith S. syndrome toxin 1 are the main toxins involved in most leucocidin, exfoliatins, enterotoxins andtoxin shock andvariedclinicalspectrum.Pantonto Valentine arich bythe toxinsa bacteria,whichgiverise produced few The main skin clinical manifestations can be linkedto the climateor geographicalthe patient’sage, of area. gen involved in skin infections worldwide, regardless Centenary theme section:CUTANEOUS ANDGENITALINFECTIONS Staphylococcus aureusisthemostStaphylococcus common patho event is the worldwide emergence of community-acqui considered in this review. Currently, the most important The complex role of bacteraemia. of context the in occur can manifestations associated with manifestations dermatological most in involved toxins syndrome shock toxin and enterotoxins (ETs), exfoliatins (PVL), leucocidin a few toxins produced by the bacteria. Panton Valentine to linked be can manifestations clinical skin main The area. geographical or climate the age, patient’s the of Acta DermVenereol 2020;100: adv00110 Infectiology-Dermatology Unit, Hospital of Fréjus-Saint-Raphaël, Fréjus,France Pascal DEL GIUDICE Skin InfectionsCausedbyStaphylococcus aureus involved in skin infections worldwide, regardless worldwide, infections skin in involved taphylococcus aureus is the most common pathogen S. aureus resistant to methicillin (CA-MRSA), which S. aureus. Other less frequent cutaneous S. aureus in atopic dermatitis is not toxin 1 (TSST-1) are the main the are (TSST-1) 1 toxin staphylococcus aureus SKIN INFECTIONS This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta ; bacterial REVIEW ARTICLE ------neonates. Impetiginization characterizes the secondary the characterizes Impetiginization neonates. in impetigo generalized is neonatorum, pemphigus as known previously neonatorum, Impetigo impetigo. dry and pustules, impetigo, miliary impetigo, giant as such be present. Several classical variants have been reported, is no fever; sometimes a satellite lymphadenopathy may contours. The general physical state is preserved. There tiple lesions can result in polycyclic erosions with circular the occurrence of small family or community outbreaks. is contagious, with the possibility of self-inoculation and It (1–5). communities underprivileged in predominates and children affects mainly Impetigo (1–5). dominant developing countries developing in whereas causes, bacterial the of 90% representing northern countries In both. of combination a or Streptococcus pyogenes, Impetigo is an epidermal infection caused by Impetigo of thephysiopathologyskininfections. understanding an allows it but artificial, or theoretical somewhat appear may and strict not is infection dary secon and primary between distinction This infection. abscesses, lymphangitis, cellulitis and secondary wound secondary impetiginization, include These fections”). cutaneous lesion (usually incorrectly called “superin called incorrectly (usually lesion cutaneous pre-existing a of consequence a as occurring those are any area of the skin can be affected. The grouping of mul typical localization in children is around the mouth, but form an oozing erosion or crust (Fig. 1). A frequent and to ruptures and pustular and inflamed becomes quickly impetigo, the primary lesion is a fragile bullae. The bullae the skin toconsider thisrich and varied clinicalspectrum. further research into do notconsider thiscomplexity. This review shouldhelp tely, most reports of tations associatedwithStaphylococcusaureus. Unfortuna the main toxins involved inmostdermatological manifes liatins, enterotoxins and toxin shocksyndrome toxin 1are clinical manifestations. Panton Valentine leucocidin, exfo specific to giverise which bacteria, the bytoxins produced aureus infections of the skin. Most can be linked to a few This review describesthe characteristics of SIGNIFICANCE The diagnosis of impetigo is clinical. For clinical. is impetigo of diagnosis The Journal Compilation ©2020ActaDermato-Venereologica. S. aureus infections are predominant, Staphylococcus aureus skin infections Staphylococcus aureus infections of S. pyogenes is reported to be pre Staphylococcus S. aureus, S. aureus ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV erosive lesionsonabdomen;d)multipledryerosionsofthehand. on adbomen; b) crusted and oozing erosions on the lower limb;c)bullousand oozing Fig 1.Differentclinicalpresentations ofimpetigo: rare clones of methicillin-resistant of clones rare cross-transmission. handwashing, must be applied to prevent recurrence and to attention strict as such measures, Hygiene 13). (12, antibiotics other most effectiveas as not was Penicillin except in extensive treatment, oral than, effective more or to, effective equally are acid fusidic topical and mupirocin pical of desmoglein1and3(12). proteolytic factor that cleaves the extracellular domains genic exotoxin B (SpeB) has been demonstrated to be a pyro streptococcal the involved; be could mechanism by caused impetigo in reported usually not are bullae Although bullae. a of formation on desmoglein 1 is rupture of keratinocyte cohesion and 9–11). toxin the of action the of consequence main The located in the most superficial layer of the epidermis (1, mainly is it and keratinocytes, between cohesion the is role whose protein desmosomal a 1, desmoglein is B 9–11).(1, B and exfoliatins targetof The protein Aand A toxins exfoliatin of production local the to related lence ofimpetigoinacommunity(6–8). preva the in decrease a in results scabies of treatment in disadvantaged populations (6–8). Mass or individual specifically,more and, worldwide children in impetigo with quently in which deep ulceration forms in the dermis (more fre oozing lesions. A clinical variant of impetigo is ecthyma, etc.) that results in impetigo or impetigo-like crusted and etc.) or secondary to scratching (e.g. pediculosis, scabies, chickenpox, eczema, (e.g. epidermis the affecting ally infection byS.aureus of a pre-existing dermatosis, usu Regarding the risk of antibiotic resistance in impetigo, to with treatment (13) al. et Koning to According is impetigo staphylococcal of pathophysiology The ). Scabies is a major cause of cause major a is Scabies S. pyogenes). impetigo where research is lacking. , a similar a S. pyogenes, (MRSA) (MRSA) S. aureus a), large dry erosive plaque - - - - - microorganisms, such as dermatophytes in kerions, Differential diagnoses include folliculitis caused by lesions.other chronic and extensive by characterized face, the on localized form clinical particular a is shaving, by (stye). Sycosis barbae (Fig. 2), whose spread is favoured eyelid back, arms, perineum, thighs, affected: be can hair high-density with body the of parts All erythema. pustule, centred on a hair a associated with as a peri-follicular manifests it Clinically ostium). (follicular follicle pilosebaceous the of part superficial the to restricted is infection the condition this In folliculitis. Superficial has usually disappeared due to necrosis) ( centred around a pustule on a hair-bearing area (the hair nodule, or papule inflammatory painful a as presents It entirety. its in follicle pilosebaceous the of volvement in with folliculitis of form necrotizing and deep a by characterized are boils, or Furuncles, Furuncle (boil). (including Behcet’s disease) and hidradenitis suppurativa. tis, Gram-negative folliculitis, non-infectious folliculitis dida few days of maturation pus will form, associated with ne albicans in candida folliculitis, Skin infectionscausedbyStaphylococcusaureus baceous follicle). pilose the of (infection folliculitis of cases of majority the for responsible is S. aureus Folliculitis S. aureus (18–20). emergence and spread of fusidic acid resistant of fusidic acid ointment has been linked to the fusB on its chromosome. The high level of use carries the fusidic acid resistance determinant acid resistant Impetigo Clone (EEFIC), which Fusidic European Epidemic the designated resulted from the clonal expansion of a strain have to appears increase This UK. the and of northern Europe, namely Sweden, Norway increased in the early 2000s in some countries with fusidic acid. Resistance to fusidic acid has of resistance in impetigo, the main concern is scribed, mainly from Japan (14–17). In terms producing ETA and/or ETB and have been de Theme issue: Cutaneous and genital infections Fig. 2.Sycosisbarbae. Malassezia folliculi Fig. 3 ). Within a Can 209 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections from abscesses. The majority of primary or spontaneous and drainageofthepusmay occur. and if not drained, spontaneous skin necrosis with rupture evolution, spontaneous of days some after appear may Pus preserved. is state physical associated. general The be may adenopathies satellite and lymphangitis, lulitis, cel rare, is Fever artificial. or difficult is abscess small a and furuncle large a between distinction the abscess, size in the literature for an abscess, therefore in primary can be primary or secondary. There is no clearly defined Abscesses (Fig. 4). pus of collection the of formation the consistency changes and become evolution, soft, indicating the of days few a After plaque. or nodule tous a tender inflammatory and extremely painful erythema An abscess is a collection of pus. The abscess forms from Abscess thrombosis thatcanextendtothecavernoussinus(28). of a peri-nasal furuncle leading to a septic facial venous complication rare exceptionally an is it nowadays but phylococcal infection is a classically described infection, to the high frequency of furuncles. Facial malignant sta­ furuncle are reported, but this appears to be rare relative different partsofthebodyoverseveralmonths(21). characterized by the repeated formation of furuncles on is furunculosis Chronic furuncles. of cluster a as fined confusion, shouldbereservedforS.aureus infection. such as non-tuberculous mycobacteria (27), bacteria, but, to other avoid by caused infection skin for literature also causesuppurativepneumonia. can organisms the recur; to tend and treatment to well the formation of larger skin lesions, which respond less with leucocytes of destruction local to leads leucocidin some areas produce PVL virulence factor (23–26). This that up to 90% of the the necrotic centre (22). In recent years it has been found crosis (21). A circular desquamative flange may surround 210 S. aureus is by far the main infectious bacteria isolated a to secondary infection systemic of reports Many de carbuncle, the is furuncle a of variant clinical A the in used been sometimes has “furuncle” term The P. delGiudice S. aureus, isolated from furuncles in Fig. 3.Furuncle. - - - Emergence ofsuppurativeskin infectionduetocommu at newsites,andinfectionsinhouseholdmembers. subsequent surgical drainage procedure, skin infections SMX was superior to placebo, resulting in lower rates of drainage and were randomly assigned to and receive clinda incision by treated were diameter in less or cm 5 abscess skin a with participants 786 (33), al. et Daum summarized in recent important studies. In the study by on incision and drainage. The role of antibiotics has been often, butnotexclusively, duetoS.aureus (32). most are etc.) injections, septic addiction, drug tion, mec or element, called the staphylococcal cassette chromosome genetic mobile chromosomal a on located gene, mecA the of control the under is PLP2a this of synthesis The ceftobiprole). and ceftaroline cephalosporins new for PLP2a, leading to resistance to all beta-lactams (except betalactams, to affinity less with protein cillin-binding peni modified a of synthesis the to linked is resistance quickly followed by the appearance of MRSA (35). This most of synthetic semi- penicillin resistant first to penicillinase the produced by was it 1961, since available been has nity-acquired methicillin-resistant S.aureus. cipants (73.6%) in the placebo group (p parti 617 of 454 vs. group TMP-SMX the in (80.5%) participants 630 of 507 in occurred abscess the of cure placebo after incision and drainage of abscesses; clinical with TMP-SMX compared (34) al. Talanet group. cin of 263 participants (81.7%), respectively; 215 and (83.1%) participants 266 of (221 group SMX TMP- the in that to similar was group clindamycin the placebo for 10 days; the cure rate among participants in mycin, trimethoprim–sulfamethoxazole (TMP-SMX), or 29–31). Secondary abscesses (accidental direct inocula (23, PVL producing abscesses arecausedbyS.aureus 1-month follow-up were less common in the clindamy at infections new cured, initially were who participants (68.9%), participants 257 of (177 group placebo the in that than higher was group treatment active each in rate cure the The treatment of suppurative skin infections is based is infections skin suppurative of treatment The SCCmec, bordered at both ends by genes called S. aureus at that time (35). Its introduction was p < 0.001 for both comparisons). Among the Among comparisons). both for 0.001 Fig. 4.Primaryabscess. = 0.005). TMP- p = Methicillin Methicillin 0.73), and ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV plays aminimalrole(51). based on surgical excision; antibiotic treatment aureus is the most common one. The treatment is foot. Several bacteria may be implicated, but or hand the of folds nail eponychial the of tion Acute suppurative paronychia is an acute infec Acute suppurativeparonychia isolated communities,families,etc.)(46–50). homosexuals, users, drug teams, sports nel, person (military settings community different of CA-MRSA are regularly described mainly in a low rate, at less than 10% (43–45). Outbreaks strains isolated (most USA 300) (40–42) and others have have a high rate of USA, CA-MRSA, at the approximately 50% as of such countries, some Indeed, infections. those study to is epidemiology its study to way best the infections, skin suppurative from mainly isolated is CA-MRSAcountries. differentAs in varies prevalence relative their and (MSSA) ones methicillin-sensitive PVL from differ infections skin CA-MRSA PVL that suggest to data clinical no MRSAare There infections. purative skin infections as clinical presentations of CA- sup of predominance the explains which toxin, PVL the produce clones, major the including CA-MRSA, of IVSCCmec (mainly CA-MRAS for and V). all Almost (SCCmec I, II and III) are significantly longer than those HA-MRSA for cassettes SCCmec main The USA. the in clone major the being USA 300 (35–39), specificity geographical relative with complexes clonal major few a with different, is CA-MRSA of origin genetic The beta-lactams. from apart antibiotics most to sensitive CA-MRSAremains multi-resistant, generally often are which HA-MRSA, Unlike (35–39). history medical preferentially affect a young population with no previous clearly distinguish them from HA-MRSA (35–39); they that characteristics specific have CA-MRSAinfections (35–39). infections skin suppurative from isolated are rently present worldwide (35–39). Most strains (80–90%) (Australia and New Zealand), these CA-MRSA are cur of healthcare facilities (35–39). First reported in Oceania have emerged in the community setting, namely outside new era the last 25 years. MRSA with new characteristics except for nosocomial operative site infections. infections, skin in involved rarely are clones these However, (1). aminoglycosides or lones fluoroquino macrolides, as such antibiotics, of classes other against genes resistance other they have acquired, in addition to the spread widely throughout the world. Over time, methicillin-resistant (HA-MRSA), clones have exclusively in hospitals, these hospital-acquired almost Described species. within and between or ccRC), which allow horizontal transmission chromosome cassette recombinase (ccRA/ccRB The epidemiology of MRSA has entered a entered has MRSA of epidemiology The gene, mecA gene, S. - - - - - An important feature in the pathophysiology of Superficial septicthrombophlebitis systemic antibiotictherapy. preserved. is state Treatmenthealth general on based is phangitis is sometimes accompanied by fever. Otherwise, Lym(Fig. 5). adenopathy ­ local a namely node, lymph regional draining the towards infection the of origin inflammatory linear band, which usually starts from the erythematous an by characterized clinically is It genes. wound as a result of secondary infection. It is more is It infection. secondary of result a as wound thrombo­ a or abscess an with associated occur may Cellulitis Cellulitis malignant staphylococcalinfection(seeabove). entry. A particular form of such thrombophlebitis is facial is based on antibiotic therapy and treatment of the portal of cord, which begins at the infected site (Fig. 6). Treatment bophlebitis is characterized by an inflammatorythrom indurated Septic catheters. intravenous of infection the to veins. In hospitals, this is most often a complication related superficial venous network, which can spread to the deep cal skin infection can cause septic thrombophlebitis of the Lymphangitis is caused mainly by mainly caused Lymphangitisis Lymphangitis cause septic emboli and secondary locations. Staphylococ a vascular thrombosis allows the infection to develop and of constitution capacity.The thrombotic its is infections Fig. 6.Thrombophlebitisfromcatheter site. Skin infectionscausedbyStaphylococcusaureus phlebitis or complicate an acute or chronic or acute an complicate or phlebitis Fig. 5.Lymphangitis. Theme issue: Cutaneous and genital infections S. aureus or S. aureus S. pyo 211 - - -

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections after weeks (1–2 desquamation erythroderma, macular the following clinical criteria: fever (≥ includes (60) definition CDC 1997 The (56). rotoxins ente other commonly, less and, B enterotoxin cularly parti enterotoxins, staphylococcal TSST-1mainly and tampons fromthemarket(59). and has decreased significantlysince the removal of these 1980 in peaked US the in TSS menstrual of incidence women who used certain types of tampon (57, 58). The failure (56). In 1980 many cases were reported in young erythema, fever, generalized hypotension, diarrhoea a and multi-organhad who children 7 in (1978) Todd by described first was (TSS) syndrome shock toxic The Toxic shocksyndrome DUE TOTOXIN-PRODUCING S. AUREUS SYSTEMIC CUTANEOUSMANIFESTATIONS of bacterialcocci(55). histopathologically, the presence of granules composed slow-growing papulonodules, abscesses and ulcers and, painless by characterized infection granulomatous and chronic rare, a botryomycosis, cause can S. aureus Botryomycosis secondary infectionandcolonizationmaybedifficult. presence of inflammatory signs. The distinction between according to the clinical presentation and, especially, the synonymous with local infection, but must be interpreted of pus (54). The isolation of S. aureus in a wound is not (pain, erythema) or cellulitis, and the possible presence signs inflammatory local show infections secondary Clinically, practice. in situation common a are They Secondary infectionsofacuteorchronic wounds fistulization occurs. cutaneous Sometimes myositis. or aneurysms false ted infec or tenosynovitis bursitis, osteomyelitis, arthritis, simulates an abscess, particularly in the vicinity of septic that mass inflammatory an as manifest They (53). skin These are related to a suppurative focus located near the Contiguous infections of the reports, NF caused by lated cases have been published since. Given the scarcity 14 cases in 2005 caused by CA-MRSA. A few other iso S. aureus have been published. Miller et al. (52) reported A few reports of necrotizing fasciitis (NF) associated with Necrotizing fasciitis systemic antibiotictherapy. with common 212 TSS is due to the production of a toxin by toxin a of production the to due is TSS P. delGiudice . The treatment is based on based is treatment The S. pyogenes. S. aureus seems exceptional. 38.9°C) a diffuse S. aureus, - - - - in Europe(64). name for this disease. Similar cases have been reported the as (NTED) disease exanthematous syndrome-like producing TSST-1. They propose neonatal toxic-shock- MRSA- with associated life of week first the in paenia who developed generalized erythema and thrombocyto therapeutic benefits(62). additional provide could properties anti-toxaemic with inhibitors protein-synthesis as acting antibiotics Some multi-organ failure and the described (61). Treatment is based on the treatment of the and increased sweating on the hands and feet have been after recovery (Fig. 8). Transient alopecia, nail shedding ( generalized erythema (with palm and sole involvement) of cytokines (33). Skin manifestations of TSS include a T lymphocytes resulting in the production of high levels of numbers greater of activation namely aureustoxins, of TSS islinkedtothepropertiesofsuperantigensinS. pathogenesis The identified. not was source the 13% in and focus, post-surgery 18% abortion), or delivery (after 27% in focus genital a cases, of 30% in infection skin a found (57) al. et Reingold TSS, 130 of study a In (57). involvement organ multisystem hypotension, soles), and palms the on particularly illness, of onset Fig. 7). Palmar, sole and finger desquamation may occur In Japan, Takahashi et al. (63) have reported neonates Fig. 8.Distaldesquamationafter toxicshocksyndrome. Fig. 7.Erythemaoftoxicshocksyndrome. S. aureus focus of infection. - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV sied Osler’s nodes gave positive results on culture, and culture, on results positive gave Osler’snodes sied nodes were described at the beginning of the 20 manifestations is confusing; Janeway lesions and Osler’s endocarditis. The description of endocarditis-related skin by caused Endocarditis Skin manifestationsofS.aureusendocarditis BACTERAEMIA SKIN MANIFESTATIONS OFS. AUREUS the eradication of the source of and blisters, large are there where dressings, on based is treatment The sterile. usually is SSSS generalized in fluid blister the site; distant a produced byS.aureusat The diagnosis of SSSS is clinically based. Exfoliatins are (67). diseases underlying to due usually adults, fected af of 60% to up in fatal be may it but 5%, than less of mortality a with good, is treated, appropriately are who for developing SSSS. The prognosis of SSSS in children, adults with impaired renal function is a major by risk factor and neonates by toxins the of clearance renal Poor localized follows disease (68). The desquamation generalized fine a with associated folds body the to limited is SSSS the where described been membranes are usually spared. Mild forms of SSSS have ment of the entire skin surface can occur, but the mucous (with a positive Nikolsky sign) (67). Widespread involve within the next few hours to days, which rupture rapidly by large fragile blisters involving the entire skin surface abruptly with fever and generalized erythema, followed begins disease The diseases. underlying with adults mainly neonates and young children and, exceptionally, (9–11, 67). It is a generalized blistering disease affecting When the ETs spread systemically, they can cause SSSS Staphylococcal scaldedskinsyndrome manifestation of TSS. clinical attenuated or mild a fact, in are, fever scarlet staphylococcal of cases most that possible is It (66). was the predominant toxin involved in a study in Taiwan produced TSST-1,B Enterotoxin both. or enterotoxins, fever scarlet staphylococcal with patients from isolated of strains 17 of out 16 that found (65) al. et erythroderma/rash, was first described in the 1920s. Lina scarlatiniform called also fever, scarlet Staphylococcal “Staphylococcal scarletfever” nodular lesions on the fingers or toes. Only a few biop few a Only toes. or fingers the on lesions nodular painful, small, as described are nodes Osler’s (70–73). positive frequently are specimens skin of culture of results microemboli; septic by caused be to thought are in the dermis and vessel thrombosis (69). These lesions microabscesses neutrophilic show they Histologically, (Fig. 9). feet and hands on occur that lesions purpuric macular, are lesions Janeway reported Classically (1). is classified as acute as classified is S. aureus S. aureus infection focus. S. aureusinfection. S. aureus th century century - - - Fig. 9.Purpuraduringendocarditis. skin infections, and the decolonization of the reservoirs. of of interactions the as such mentioned, not are questions other tic aspectsofS.aureusmany and infections, skin and variedclinicalspectrumofdisease. aureus infections should take into consideration this rich physiopathologies. Further reports and studies on skin tations duetoS.aureus is diverse and related to different contrary,the manifes skin of spectrum clinical the how within the same clinical spectrum. This review shows, on (SSTI)”, giving the illusion that infections all skin structures manifestations are skin and “skin heading the under rature classify skin infections and group of diseases. Unfortunately, complex most reports a in the of lite part are infections skin Staphylococcal CONCLUSION Some oftheseassociationsmaybecoincidental. of course the in mainly culitis or Henoch-Schönlein purpura have been reported, chronic or acute with associated manifestations Immunological S. AUREUS SKIN MANIFESTATIONSIMMUNOLOGICAL OF has alsobeenreported(74). S. aureus bacteraemia. Exceptionally, purpura fulminans tations that have been described as a secondary focus of Such manifestations related to the frequency of endocarditis) Skin manifestationsofS.aureusbacteraemia(without with theskinmanifestationsofS.aureus endocarditis. better corresponds lesions Janeway of description The (73). findings diverse showed examination histological eruptions and abscesses are the main clinical manifes clinical main the are abscesses and eruptions disseminated Purpuric rare. extremely are bacteraemia This review has focused on the clinical and therapeu , the relationships between reservoirs and reservoirs between relationships the S. aureus, with the skin microbiome, the reservoirs the microbiome, skin the with S. aureus Skin infectionscausedbyStaphylococcusaureus S. aureus infections are rare. A few cases of vas INFECTION Theme issue: Cutaneous and genital infections bacteraemia (75–77). S. aureusbacteraemia S. aureus skin infections S. aureus 213 S. S. - - - - -

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Clin Infect Dis 2004; 38:1498–1502. dominant toxin involved in staphylococcal scarlet fever in Skin infectionscausedbyStaphylococcusaureus Theme issue: Cutaneous and genital infections Available from: https://www.cdc. 215 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Humboldt-Universität zuBerlin, and Berlin Instituteof Health, Nationale Reference Laboratory of Dermatophytes, Berlin, Germany, Dermatology andVenerology Task Force for Mycology Co-chair doi: 10.2340/00015555-3467 “ Les published Sabouraud R. mycologist famous the when 1910, until established not was classification cal S jaelland.dk gen, Sygehusvej 5, DK-4000 Roskilde, Denmark. E-mail: disa@regions- sity Hospital, Roskilde, Health Sciences Faculty, University of Copenha Corr: Acta DermVenereol 2020;100:adv00111. Accepted Mar19,2020;Epubaheadofprint24,2020 matomycoses. Key words: diagnostic;microscopy; PCR; dermatophytes; der test systems. tools, mainly focusing on commercially available PCR nomy, andthe reviews available currently diagnostics indermatophyte changes taxo recent paper describes vide detection spectra.This of genus/species different conventional methods. Molecular-based methods pro oradvantages, replace andincreasinglysupplement asPCR,havemany methods,but molecular-based such andhistopathology)copy, culture arestill widely used, geophilic). Traditional diagnostic tests (directmicros the sourceof infection (anthropophilic, zoophilic or priate antifungal agent, and provides an indication of tion guidesclinicianswhenchoosing the most appro identifica species-specific as important, is taxonomy The havingseveralnames(synonyms). in manyfungi several unfortunately,times,changed resulted which, agnostic methods weredeveloped andthe taxonomy 1 Yvonne GRÄSER Like ToGo? We Would Where and Now We Are Where From, Come We Do A Hundred Years of Diagnosing Superficial Fungal Infections: Where Centenary theme section:CUTANEOUS ANDGENITALINFECTIONS Achorion schoenleinii, were introduced. A morphologi dermatophytes the of cultures pure obtaining as such methods, microbiological important Acta DermVenereol 2020;100: adv00111 Superficial fungal infections have been known for known been hundreds of years.During the 20 have infections fungal Superficial of plant parasites (fungi). By the end of the 19 types same the by caused were diseases human some that suggested France from Audouin years the following In (1). fungus a by caused was silkworm the of Bassi in 1835, who showed that the muscardine disease by made was infection of proof scientific first Agostino the before years of hundreds took It children. in thrush of Mycology, Department of Bacteria, Parasites and Fungi, StatensSerum Institut, Copenhagen, Denmark, and of Dermatology,Zealand UniversityHospital,Roskilde, Institute ofMicrobiologyandInfectious Immunology,Charité –UniversityMedicineBerlin,corporatememberof FreieUniversitätBerlin, the 5th century BC, when Hippocrates wrote about wrote Hippocrates when BC, century 5th the since known been have infections fungal uperficial Ditte Marie L. Saunte, Department of Dermatology, Zealand Univer 1 andDitte Marie Lindhardt SAUNTE th century new century di Trichophyton and This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta th REVIEW ARTICLE 3 century Department ofClinical Medicine,UniversityofCopenhagen, 2–5 ------of new diagnostic methods. Unfortunately, this has resul changed several times since then, due to the development and culturecharacteristics. presentation clinical on based suggested, were systems imperfect fungi), imperfect called also cycle, life their in phase sexual no have that (fungi anamorphic 3 included fungi, dermatophyte the of family the that, ratus andG.ceretanicus were used as outgroups. Before nomenclature of the family Fig. 1, based on molecular data, shows the current valid in tree phylogenetic The (2). 2017 of beginning the at The taxonomy of dermatophytes changed most recently TAXONOMY nomy andreviewscurrentlyavailablediagnostictools. paper describes the latest changes in dermatophyte taxo diagnostic methods has contributed to this process. molecular This of development the and initiated, been has attempt to simplify this, by giving “one fungus one name” ted in many fungi having several names (synonyms). An beginning of the 20 the of beginning the At (1). cultures in morphology and infections hair and skin of features clinical on studies and media test of standardization the on based monograph a teignes”, is no standardization as to which fungi they detect. This pa molecular-based methodshave been developed, butthere recent More nails). (hair,skin, specimen the of pathology nally, diagnosis is based on microscopy, culture and histo provide information about the source of infection. Traditio der tochoosethecorrectanti-fungal medication, and to years. It iscrucialtodiagnose the fungus correctly, in or and fungal nailinfections) have been knownfor hundredsof thrush ringworm, (e.g. infections fungal Superficial SIGNIFICANCE the diagnostic toolsavailable. per presents an update on fungal taxonomy and describes The taxonomy of superficial fungal infections has infections fungal superficial of taxonomy The Journal Compilation ©2020ActaDermato-Venereologica. Trichophyton, , encompassing Arthrodermataceae, th century different nomenclatural different century Arthrodermataceae. Microsporum, 5 European Academy of 2 Department Department Epider C. ser 4 Unit ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV affected the medically relevant dermatophytes of the of dermatophytes relevant medically the affected Microsporum, Trichophyton andEpidermophyton(2). genera well-known the in retained were names species were also addressed, i.e. the anthropophilic and zoophilic 1) of the phylogenetic multilocus tree. Medical concerns established at all main clusters (tips of the arrows in Fig. of the botanical code. In principle, a separate genus was crosporum and were introduced to account for the former geophilic ( in dermatophytes was abolished and 4 additional genera phylogenetic data. On this basis, the teleomorphic genus and molecular towards features morphological using mainly because the basis of taxonomy moved away from 2011, this dual nomenclature of fungi was abolished (3), phase in their life cycle) genus ( mophyton, and one teleomorphic (fungi that have a sexual the ribosomalDNA. region of spacer on theinternaltranscribed 1. Phylogenetictreeofthemajority of thefamilyArthrodermataceae,based Fig. of species Nannizzia, At the species level, the nomenclatural changes that changes nomenclatural the level, species the At Lophophyton Trichophyton spp. according to the rules , Paraphyton and Arthroderma) Arthroderma). As early as Mi - genus. genus. Here, corrections were carried out that mainly af teleomorphic the of disappearance the to due 3 further a by reduced were they 2017 in and (4), 19 to reduced anthropophilic and zoophilic was used, because the originally described strains of strains described originally the because used, was name The renamed. be to had enleinii, to related closely phylogenetically was which species previous the change, name ropophilic strains were called own species name, once again, i.e. the zoophilic strains again received their of strains zoophilic and anthropophilic the example, For geophilic). zoophilic, that encompassed their natural sources (anthropophilic, fected the classification of the dermatophytes into groups 21 the of ning these taxonomic changes were proposed at the begin the at proposed were changes taxonomic these aforementioned genera were minor at this time. Most of st Diagnosis ofsuperficialfungalinfections century. For example, the previous 50 previous the example, For century. Theme issue: Cutaneous and genital infections T. mentagrophytes, whereas the anth T. interdigitaleseparated were , Trichophyton species were T. interdigitale T. mentagrophytes, T. quinckeanum . Due to this T. scho 217 T. T. - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections scribed inthefollowingsection. de­ be will methods The worldwide. used still are and years 100 last the over identification fungal of purpose the for used been have culture and microscopy Direct MICROSCOPY, HISTOLOGY ANDCULTURE TRADITIONAL DIAGNOSTICS: DIRECT but canbeequallyapplicabletoantimycotics. resistance, which is well recognized with antibacterials, the human microbiome, and the increasing threat of drug negative impact that unnecessary treatment may have on potentially the is point third Amedications. additional take and diseases underlying other have often who effects and drug interaction, particularly in older patients side- possible the to due and (9), wrong are diagnoses laboratory diagnosis, because up to 40% of the suspected therapy should not be administered without a confirmed performed in the clinical setting (9–11). Oral antifungal tion to genus or species level is important it is not always identifica though Even suspected. also have diagnoses dermatological other when exclusion, of diagnosis a as Finally, a negative fungal laboratory test is also important available. become may resistance and virulence about knowledge new sub-species this studying thoroughly By (8). epidemic dermatophyte relapsing chronic, a of spread countrywide a of agent causative a as isolated uniformly been has VIII genotype T. mentagrophytes specific a where India, in example, for as, outbreaks in useful is typing) (strain identification sub-species Thirdly,disease. of spread further of risk the reduce to order in animal or patient index the treat to possible is it infection, of source the knowing By infection. the of the species name also informs clinicians about the source diffierent antifungal susceptibility patterns (7). Secondly, sometimes also necessary, as different species may have antifungal treatment (5, 6). Species-specific diagnosis is correct the choosing for important is diagnosis curate to reduced was pigs, benhamiae fungus, skin The 1). mentagrophytes 218 practice, but it is important in many ways: first, an ac an first, ways: many in important is it but practice, clinical everyday from remote seem may Taxonomy DIAGNOSTICS CLINICAL SIGNIFICANCE OFFUNGAL dermatophyte namesfamiliartoclinicians(2). genetically robust determinants and to retain well-known purpose of these changes was to base the new system on renamed was gypseum the introduction of new genus names, e.g. also added, which were mostly geophilic species, due to listed as a separate species. New name combinations were removed from the Y. GräserandD.M.L.Saunte , which was isolated mainly from guinea from mainly isolated was which , clustered here (Fig. here var.clustered quinckeanum T. rubrum complex and is now again T. benhamiae. sp. of sp. Trichophyton Nannizzia . The overall The gypsea. T.was soudanense Microsporum Arthroderma - - better for yeasts and non-dermatophyte moulds. media are more dermatophyte-specific, while others are Culture is highly dependent on growth media, e.g. some Genus- andspecies-specificidentification biopsy. 18–20). However, the prerequisite for this is an invasive (11, specimen the in directly fungus the of growth the confirm to able is and contamination out rule may it as nails, in identification fungal for routinely histology use dermatologists Some folliculitis. of causes other out rule to order in suspected, is folliculitis Malassezia when useful is but infections, hair and skin in routinely used not is Histology (15–17). dermatophyte infecting the of genus the of indication preliminary a as used be The growth pattern, combined with the conidial size, can shaft). hair the of surface the surround and follicle hair the of out grow then arthrospores the and mid-follicle at shaft hair the invades fungus the (where ectothrix or endothrix (arthroconidia are present within the hair shaft) favus, either as it classifies dermatophyte the of pattern moulds, butwithoutabsolutecertainty(14). non-dermatophyte and dermatophytes yeasts, specific ans may be able to suggest a differentiation between other pigmented fungal cells. Some very experienced technici possible to distinguish yeasts from hyphae and to detect are neither genus- nor species-specific, even though it is findings microscopic direct that note to important is it ding blastoconidia, but with the exception of this genus bud unipolar characteristic show species Malassezia 13). (12, microscopy after rate detection the enhance can calcoflour, or blankophor as such brighteners, cal skills of the laboratory technicians, whereas molecular whereas technicians, laboratory the of skills All traditional diagnostic methods are dependent on the information. useful clinically more provides and tion detec fungal of chances the enhances it as practiced, area of infection, or due to previous antifungal treatment. either because of insufficient material from the proximal This may be due to the presence of non-viable material, 22). (21, culture-negative are specimens nail positive nail material is challenging, as up to 30% of microscopy- difficult to culture on normal laboratory media. Culture of often is consequence, a as and, lipid-dependent is sezia microscopy after treatment of the specimen with opti with specimen the of treatment after microscopy E or Congo red, are therefore often added. Fluorescence black chlorazol ink, Parker blue, cotton lactophenol as the background, is difficult to interpret, and stains, such light microscopy, without the benefit of any contrast with hydroxide or potassium hydroxide (KOH). Conventional fungal elements in specimens after treating with sodium Direct microscopy is used for the primary identification of clinical specimens Direct “non-specific”detectionoffungalelementsin Direct microscopy of hair is important, as the growth Combination of the different techniques is usually is techniques different the of Combination Malas - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Version 1.0; DG 2.0: DermaGenius Version 2.0;DD: DermaDYN; EADM: Euroarray Dermatomycosis. Nd: no data; DPK: FastDermatophyte PCR Kit; FTD: Track Dermatophytes; MMD: Mentype Mycoderm; MMD LF: Mentype onychomycosis in role a play can that dermatophytes non- few the including species, dermatophyte relevant to differentiate, at the same time, more than 20 clinically able yet not are methods these Nevertheless, detected. be to species of spectrum the extend to used is analysis probes in real-time PCR technology. Thus, melting curve differentlabel to used are which (4–6), labels colour of larger (e.g. 78 in the microarray format) is than the techniques number conventional in hybridizations probe of number the that mind in kept However,be ling. must it tamination. This also eliminates additional bench hand in the same closed reaction tube without the risk of con the amplification and hybridization steps are performed However, the advantages of real-time PCR are that both clers required are less expensive than real-time devices. common pathogen in onychomycosis and tinea pedis tinea and onychomycosis in pathogen common solely detects that PCR real-time a as later and PCR, conventional a (SSI), in Institute Serum Statens the by developed was Kit PCR Dermatophyte The available. been have spectra, cies processed manually. On the other hand, the thermal cy V V X X X V V V V V nd MMD LF nd Copenhagen Denmark in 2 versions; firstly, as T. rubrum at species level, as it is the most Diagnosis ofsuperficialfungalinfections V X X X X X V V V V X DG 1.0 X X X Theme issue: Cutaneous and genital infections V X X X X X V V V V X DG 2.0 V X X X X X V V V V nd DD X nd X X X X V V V V V V V V V V V V V EADM V V V V V V V V V V 219 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV with the 2 changed This detection. pan-dermatophyte included kit Neither Kit. FTD the as spectrum species similar a and gaps identification same the had analysis, curve based on a single multiplex real-time PCR with melting Netherlands, the Maastrict, in produced PathoNostics, Another concurrent test system, DermaGenius 1.0, from a complex together with detect could that kit first the also was was separated from the in combination with combination in violaceum, (T. interdigitale, tonsurans, anthropophilic), the exceptions. same as for Mentype MycoDerm Kit Lateral Flow, with 2 the is detection species The 2018. in available became been enlarged. Now it is possible to detect has detected be to spectrum species the hand, other the On strip. blot a on hybridization probe by replaced was the one hand, the procedure, because fragment analysis on affect, developments Further reactions. PCR 3 with later years 2 available was Flow) Lateral MycoDerm complex. The second version of the test system (Mentype with together complex a in Theme issue: Cutaneous and genital infections the There is no differentiation between the T. tonsuransand and reactions, which can differentiate 2 species (E. floccosum MycoDerm kit in 2013. These utilize 2 conventional PCR den, Germany launched the first version of the Mentype option for the dermatophytes as a group. Biotype in Dres neum anthropophilic). The kit does not have a detection zoophilic, (M. canis complex grophytes, ( 220 (no differentiation between the niches: ecological different other. This includes mainly dermatophytes species with species is detected here, but not differentiated from each are performed at species complex level, i.e. more than 1 T. violaceum, (T. rubrum, species 3 detect to able is analysis, curve melting without but hybridization, probe with PCR real-time 2-tube a system, test This Malta. Sliema, in available made was Diagnostics, Track Fast from test such as sequencing (26). In 2011, the FTD Dermatophyte rubrum species via culture or other molecular non- techniques, of identification species subsequent by followed be may this and dermatophytes, for screening for used be can systems test Both instead. probes hybridization fragments in an agarose gel, DNA whereas real-time amplified PCR uses the of analysis size subsequent with present. The conventional test system is based on a PCR but this will include any non-pathogenic geophilic genera detecting dermatophytes as a group (pan-dermatophyte), ). Otherwise, the kit offers the possibility of possibility the offers kit the Otherwise, Table I). T.complexes. interdigitale ) on the basis of fragment size analyses. size fragment of basis the on N. gypsea) Y. GräserandD.M.L.Saunte nd zoophilic) and the T.and zoophilic) quinckeanum version of the kit (DermaGenius 2.0), which at species level and level species at M. audouinii N. gypsea ). The remaining detections remaining The floccosum). E. T. schoenleinii antropophilic; . The M. ferrugineum. is not included, but T. interdigitale complexes. This T. erinaceiandT. verrucosum. T. equinum, zoophilic and T. violaceum,asisM.canis M. audouinii, T. interdigitale complex is identified is T. rubrum T. tonsuranscomplex T. benhamiaein T. verrucosum T. rubrum, T. tonsurans M. ferrugi T. menta M. canis M. canis T. T. T. T. - - -

is not included (28). In 2018, the last of the kits discus addition In (TableI). dermatophytes FTD to spectrum similar a multiplex 2-tube PCR with a a melting on curve analysis based and detects also is system test This available. by DYN Diagnostics Ltd in Ha’eshel St., Israel became (27). At the same time, the DERMADYN kit developed is. many of the non-dermatophytes involved in the pathoge treat) the sources of infection. Another challenge is that (and find to order in step necessary a is which species, do not discriminate between zoophilic and anthropophilic (Tabledetect importantly,Most tests I). of majority the difference between what the commercial tests are able to separated themcameafterthedevelopmentofkit. from ted from pathogen endemic to the Pacific Islands, is not separated eriothrephon andT.Only bullosum. as such pathogens, rare for detection species is there brevicaulis, (Scopulariopsis level species the at non-dermatophytes species level, including a pan-dermatophyte probe and 6 of all relevant (approximately 20) dermatophytes at the form of a “microarray”. This format enables the detection PCR reaction with subsequent probe hybridization in the multiplex a Germany.is Lübeck, This in launched was sed here, Euroarray Dermatomycosis from Euroimmun, now it has been possible to detect a similar number of number similar a detect to possible been has it now Until species. dermatophyte 19 of identification the allows signatures temperature melting species-specific with beacons molecular sloppy using that report (33) Walseranalysis. melting-curve Bosshard and & probes could differentiate 11 species in a single-tube assay with sequential algorithm, and Bergmans and colleagues (32) a in PCRs 10 to up combining by taxa dermatophyte 9 detect to able were (31) colleagues and Ohst 30). (29, general in dermatophytes and taxa 6 to up identify to able are approaches these of Many PCR. real-time on diagnostics. Of particular interest are the methods based by individual, or a few, laboratories involved in routine dardized, and in the vast majority of cases are used only stan not are they because here, detail in developments these describe not do Wefungi. pathogenic skin other been developed for the diagnosis of dermatophytes and A considerable number of in-house PCR techniques have Non-commercial molecular-based tests and Candidatogenuslevelonly(Mentype)(Table I). maGenius), or they provide detection of dermatophytes (SSI, FTD), apart from the Euroarray. The other test systems do not detect non- kits. The broadest species-specific spectrum is offered by nesis of onychomycosis are not detected in many of the Overall, the clinician should be aware that there is a is there that aware be should clinician the Overall, is clustered together with together clustered T.is benhamiae T. benhamiae,andT. soudanenseisnot differentia N. gypsea is detected, but the because the taxonomic change that change taxonomic T.the because rubrum Fusarium andCandida spp.). Furthermore, T. concentricum,a C. albicans (Der T. simii complex Scopulariopsis T. equinum T. T. - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV for the detection of pathogens in tinea is still wide The use of phenotypic methods (microscopy and culture) CHALLENGES CURRENT ROUTINE DIAGNOSTIC ANDTHEIR grown (22,49–51). are non-dermatophytes when reaction false-positive a tion, detectable at genus level. Some are known to give infec dermatophyte a confirm to able is test, detection immunochromatographic an test, antibody monoclonal anti-dermatophyte The screening. dermatophyte for containing a dermatophyte colour indicator can be used (17, 20,46–48). or onychomycosis from other dermatological conditions be used as add-on tools to differentiate tinea capitis and/ microscopy, all of which are non-invasive methods, can scanning laser confocal and tomography coherence cal non-fluorescent (17). are infections endothrix Wood’sand under light, enish from other dermatophyte infections, as it fluoresces gre Microsporum species ( canis, differentiatefor tool bedside a a by caused capitis tinea as used often is light, ultraviolet Wood’sfiltered light, OTHER DIAGNOSTIC TOOLS has alsobeenusedtodetectantifungalresistance(45). It (44). database in-house an establishing by improved be can Identification 43). (42, complex concentricum mentagrophytes, e.g. species, related closely phylogenetically the differentiate to spectrum databases (41). So far, this method is not able reference Biomerieux and Bruker used widely the in nis, T. mentagrophytes, phytes species (T. tonsurans, specimens (36–40). Protein spectra of 7 and 10 dermato ­ nail hair,or clinical skin to directly applicable not now until but reproducible, and fast is technique This (35). culture material, both yeast, dermatophytes and moulds on directly infection fungal superficial of identification cies matched with a database. It has been applied to the based on the characteristic protein spectrum of each spe try (MALDI-TOF), is used to identify micro-organisms ser desorption/ionization time-of-flight mass spectrome increase the sensitivity of the 2 approach for a commercial test system, if it is possible to (34). array oligonucleotide an promising a be may This as such techniques, post-PCR applying by only species PCR1 (pandermatophytes)waspositive. PCR reaction, which was negative in 76% of cases where Dermatophyte screening test media, an agar medium agar an media, test screening Dermatophyte opti microscopy, confocal reflectance Dermoscopy, Another molecular-based method, matrix-assisted la M. audouinii, T. rubrum/soudanense T. tonsurans/equinum or E. floccosum, T. verrucosum,T. violaceum, audouinii andferrugineum) T. rubrum, nd N. gypsea) are included species-differentiating , T. interdigitale/ T. interdigitale, T. benhamiae/ spread. ­spread. M. ca ------for treatment assessment (11). Microbiological laborato important is which fungus, the of viability the confirm method is still the only diagnostic method that is able to culture The time-consuming. is culture and technicians laboratory the of skills the on dependent are They requires antifungal therapy,antifungal requires car asymptomatic because always PCR, or culture in whether dermatophytes, pathogenic of detection The diagnostics. culture from sufficient quantity. In this respect, there is no difference specimens must be taken from the correct location and in clinical the Therefore, (31). cell fungal one than more is limit detection the diagnostics, culture than sensitive or cannotdetect. can test molecular available locally any fungi what of aware be to important therefore, is, It culture. on based be considered and, if not included, covered by diagnostics then, the detection of potential non-dermatophytes must in order not to miss a possible pathogen. However, even used be should detection pan-dermatophyte a covered, of the test system used. If not all relevant pathogens are pends primarily on the differentiated pathogen spectrum de method identification molecular the of introduction conventional diagnostics will still be used after the wider Whether remunerated. are diagnostics dermatophyte which depends strongly on whether and how molecular microscopy,direct cost-effectiveness,for and culturing number of samples, the availability of trained personnel whether to set up a molecular mycology service are the determining in factors Decisive identification. tophyte derma for used be also can that devices and methods similar established already have often and diagnostics ries appreciate the automation possibilities in molecular ratory is able to detect. Nevertheless, in our experience our in Nevertheless, detect. to able is ratory what the clinician suspects and what the mycology labo It seems logical that there should be coherence between CAN IMPROVE THEDIAGNOSTIC OUTCOME CLINICAL ANDLABORATORY INTERACTION rect identification. must be appropriately validated databases to enable cor PCR, the method has to be validated. Furthermore, there of a sequencing device is expensive and, like an in-house However,diagnostics. fungal purchase for the methods these use routinely already laboratories Some fication. identi species accurate provide then can Sequencing mutations. to susceptible less therefore and conserved more are which primers, dermatophyte-specific only or and false-negativeresultsmaybegenerated. in the primers and probe, so that they can no longer bind, mutations, especially in species-specific sequences used (point) to lead can fungi of evolution the that are neral, ge in tests, molecular available the of Disadvantages riers also spread the fungi and can become symptomatic. Although molecular diagnostics are up to 30% more 30% to up are diagnostics molecular Although This can be remedied by sequencing with broad-range Diagnosis ofsuperficialfungalinfections Theme issue: Cutaneous and genital infections 221 ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections for choosingthemostappropriatediagnosticmethods Table II. Helpful information for the is clinician to needed for fungal pathogens,which the suspected differentiate between laboratory were culture patients’ The (53). 36%) to 100% (from 16 weeks of terbinafine therapy is significantly reduced after load fungal the that demonstrated particular,have in al., et Iwanaga 53). (52, monitoring therapy for used be also can method the far,that so shown have, studies diagnosis of dermatophytosis are beyond question. A few initial the for diagnostics molecular of advantages The FUTURE PERSPECTIVES parallel ifthekithasgapsinitsrepertoire. but also to decide whether a culture should be created in correctly,tests molecular the of results the interpret to order in information this needs microbiologist The sis. with a non-dermatophyte is considered in onychomyco contact is probable animaland whether, an for example, a whether mycosis form referral the on note should pected (Table II). Furthermore, the attending physician sus is genera mould) non-dermatophyte or Malassezia matological disease, and fungal (dermatophyte, (hair, skin or nail) the specimen is obtained, which der laboratory, as a minimum, from which anatomical region mycology the inform to important therefore is It fungi. relevant all detect not do tests molecular-based some have different needs for substrates in order to grow, and fungi different described, As case. the not often it this 222 Non-D: non-dermatophyte. region) Scalp (hair region Anatomical Face Upper body area Groin & pubic Hands Feet Nails Y. GräserandD.M.L.Saunte Disease Help forthecliniciantodifferentiatebetweensuspectedfungalpathogens Tinea capitis Tinea faciei Dandruff Seborrhoeic dermatitis/ Pityriasis versicolor Seborrhoeic dermatitis Malassezia folliculitis Cutaneous candidiasis Tinea manuum Tinea corporis Tinea cruris Cutaneous candidiasis Seborrhoeic dermatitis Tinea pedis Candida onychomycosis infection Cutaneous non-D mould Tinea unguium Non-D onychomycosis Most commonclinicalsigns Scaling Alopecia Favus Kerion Broken hairs red patch Area with raised erythematous border or Greasy skinscales on erythematous skin Hypo- or hyperpigmented maculae primary centro-facial and eyebrows Greasy skinscales on erythematous skin seborrhoeic areas. Nocomedones Monomorphic pustules mainly located at pustules (and skin scales) Erythematous skin folds withsatellite red patches.Skinscales. Hyperkeratosis. Area with raised erythematous border or red patch. Skin scales Area with raised erythematous border or red patch. Skin scales Area with raised erythematous border or Interdigital maceration Greasy skinscales on erythematous skin thickening of the soles erythematous boarder, ’Moccasin foot’, Interdigital maceration, skin scales, raised Nail dystrophy Paronychia Interdigital maceration discoloration, yellow streaks. Hyperkeratosis, superficial white inflammation, nail dystrophy Hyperkeratosis, discoloration, paronychia/ Candida, - - - VIII and VIII genotype with strains resistance inT. mentagrophytes steroids (e.g. clobetasol). Terbinafine resistance or partial containing antimycotics (e.g. terbinafine), antibiotics and hand in hand with the use of goes over-the-counter ointments and years, 6 approximately for lasted has which epidemic, Indian the with changed suddenly has This antimycotics. of use the to dermatophytes in resistance survive in the nail, hair or skin of the human body (55). however, it is not known cells; how long dormant fungal dead cells and live between discriminate to able are continue the therapy. Only very special PCR procedures such a finding is available, in order to decide whether to which in time-span short the mention to not future, the therapy control with PCR procedures may be suitable in (54). Dormant cells are missed in the culture. Therefore, of elderly patients receiving 3-month terbinafine therapy which after 18 months show a complete cure in only studies, 76% follow-up by supported is nail the inside cells continuation of therapy. The survival of dormant fungal present and may potentially germinate again after dis after again germinate potentially may and present still are arthroconidia) of form the in (e.g. cells fungal resting that is this for explanation plausible most The elements could still be detected in the KOH preparation. already negative at this time, but, microscopically, fungal To date, there has been no significant development of Age Children children All ages, but mostly Adults Newborn Young andadults Adults Young andadults All ages All ages All ages Adults All ages Adults All ages All ages Mostly adults increases with age All ages, but prevalence increases with age All ages, but prevalence reach rates of more than 65% and 65% than more of rates T.reach rubrum Suspected pathogen for themicrobiologist Essential information Dermatophyte Dermatophytes Malassezia Malassezia Malassezia Malassezia Candida Dermatophyte Dermatophytes Candida Malassezia Dermatophytes Candida Non-D moulds Dermatophytes Non-D moulds Exposure the microbiologist Information helpful for Earlier treatment Woods light results Endemic contacts Animal exposure Signs of tinea capitis Animal exposure Immunosuppression Immunosuppression Immunosuppression tinea pedis Other signs of tineae.g. Other signs of tinea Animal exposure Immunosuppression Moist exposure Immunosuppression Immunosuppression pedis? Concomitant tinea - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV REFERENCES Euroimmun. from grants and honoraria speaker’s received YG years. 3 last Abbvie, Galderma, Astellas, Novartis and Leo Pharma during the companies: following the from grants received and/or honoraria board meeting by AbbVie, Janssen, Sanofi and received speaker’s Conflicts of interest: DMLS was paid as a consultant for advisory comments andforreviewingthetext. constructive his for acknowledged is Hay Roderick Professor ACKNOWLEDGEMENT is notfarfromthisgoal. evolution of the diagnosis of superficial fungal infections of the involved pathogen by sending a single sample. The possible source of infection and the susceptibility pattern clinician to obtain the correct species identification, the the enable would it tests, these all combine to possible were it If resistance. antifungal causing mutations cific spe of detection as well as possible, is fungi relevant molecular species-specific fungal detectionThe of clinically samples. clinical in directly fungi detect to able only being able to detect fungi in cultures to now being from years, last the during lot a improved already has available. already The is development of molecular-basedequipment methods the and cheap are they as used, methods, such as direct microscopy and culture, are still diagnostic traditional Worldwide techniques. based wide range of clinically relevant fungi using molecular- a detect to able are that techniques current to ago years 100 than more description microscopic first the from The diagnosis of superficial fungal infections has evolved CONCLUSION this problem(8,56–59). overcome could growth fungal the of independent are which resistance), terbinafine to leading mutation gene leading to antifungal resistance (e.g. squalene epoxidase sequencing with detection of specific genetic mutations particular in methods, Molecular routinely. done not therefore and challenging is fungi, the of formation dia coni poor often the and growth filamentous the to due inoculum, the that is disadvantage the defined; be can breakpoints that is latter the of advantage The formed. per be to has test susceptibility a identity,or exact the determine to order in genetics molecular by fine-typed This means that 17%, respectively, in India and are spread globally (56). 2. 1. de Hoog GS,de Hoog K,MonodM,Packeu Dukik A,StubbeD, Kane J, Summerbell R, Sigler L, Krajden S, Land G. 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(7, models animal rimental 17 nature. The mite was first identified and illustrated in the contagious its about write to first the were Romans and disease has been known for over 2,500 years; the Greeks intense itching, associated with typical skin lesions. The tes scabiei var. S France. E-mail:[email protected] Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, FR-94010 Créteil, Corr: Acta DermVenereol 2020;100:adv00112 Accepted Mar19,2020;Epubaheadofprint24,2020 and development; ovicidal. sease; ivermectin; permethrin; moxidectin; acaricide discovery Key words: scabies; Sarcoptes scabiei; neglected tropical di- es, andoutlines prospects forpotential improvements. anupdate advanc onmanagement ofscabies, recent view givesanoverview of limitations thecurrent inthe isurgently leadingto needed.Thisre cure measures and progress in the development of new therapeutic mains largelysuboptimal fromto diagnosis treatment, re Management of scabies sis secondaryto scabies. rheumaticnephritis, fever,or acute fatalinvasivesep with reports aureusbacterialsuperinfections, ofcus zed, including group A Streptococcus and tions. Theburdenof the diseaseisnow well characteri 1 Charlotte BERNIGAUD The Management of Scabies in the 21 years (5, 6), mainly through the development of expe of development the through mainly 6), (5, years host-parasite interactions have been made in the last 30 and physiopathology the in advances Further 4). (3, II Worldduring War1940s the in entomologist, British a Mellanby, Kenneth by provided was transmission and the poor. The earliest understanding of the mite biology and by low interest in an ectoparasite that mainly affects been hampered largely by limited access to the parasite Est University, Créteil, France, Infectious DiseasesProgram,Herston,Brisbane, Australia, the greatest impactinpoor overcrowdedliving condi young affects in Scabies children and particular, has 150–200millionaffecting worldwide, peopleyearly. isone ofScabies themost commonskindiseases – Infections Sexuellement Transmissibles, French Society of Dermatology and Potentials Journal Compilation ©2020ActaDermato-Venereologica. Dermatology Department, AP-HP, Henri Mondor hospital, Paris-Est University, Créteil, France, th century (2). Despite marked advances in parasitology sitic disease caused by the microscopic mite cabies (Latin Charlotte Bernigaud, Department of Dermatology,Henri Hôpital th and 20 and hominis (1). The burrowing mite causes scabere “ to scratch”) is a common para th centuries, research into scabies has scabies into research centuries, 1–5 , Katja FISCHER 4 IACS (International Alliance for the Control of Scabies, and Centenary theme section:CUTANEOUS ANDGENITALINFECTIONS 2,4 andOlivier CHOSIDOW Staphylococ REVIEW ARTICLE Sarcop 3 3Research groupDynamyc,EA7380,FacultédeSanté,EnvA,USCANSES,Paris------(16). Young children in underprivileged populations underprivileged in children Young(16). America Latin and Oceania, Asia, in high particularly is burden scabies the that and year, every world the in mates suggest that 150–200 million people have scabies and has a documented significant burden. The latestregions, esti subtropical and tropical in living populations of the world, with greatest prominence in disadvantaged Scabies is a prevalent disease, which is present in all parts TREATMENT? WHY DOWENEEDTOIMPROVE SCABIES large-scale action to achieve control and eradication (15). for called has and diseases tropical neglected of list the (14). Thus, in 2017, the WHO decided to add scabies to deserves it recognition the scabies given have (IACS), Scabies of Control the for Alliance International the in together brought experts of group a by efforts,made to be a true health target. In the past 10 years, stupendous Scabies was, for a long time, not appropriately considered diagnostic tools or treatments in the near future (10–13). host molecular and biochemical analyses to develop new ques will enable scientists to design large-scale mite and Medicine (9). and Physiology for Prize Nobel discovery,2015 its the after years 35 awarded, recently were researchers the the most important drugs currently used to treat scabies; in the 1970–80s with the discovery of ivermectin, one of scabies, and has opened doorstonew strategies. knowledge of the biology, pathology and management of resulting inhigh-impactpublications, has increased our disease. This additional and increased research activity, of documenting the morbidities and burden caused by the ted tropical diseases after a long and still ongoing process nally, in 2017, scabies was addedtothe WHO listof neglec have worked toimprove the management of scabies. Fi and public health physicians, together with policymakers, dous itch. For more than a century, researchers, clinicians Scabies is more than just a disease that provokes a horren SIGNIFICANCE Currently, the recent expansion of multi-omics techni 1,4,5 st Century: Past, Advances 5 GrIDIST, Groupe Infectiologie Dermatologique 2 QIMR Berghofer Medical Research Institute, Acta DermVenereol 2020;100: adv00112 doi: 10.2340/00015555-3468 - - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections Africa (35) contemporaneously with scabies outbreaks, of acute glomerulonephritis in Trinidad (34) or Southern 1970s, with epidemiological studies showing epidemics (32, 33). This particular link was established early in the be linked with scabies, especially among young children can lesions impetigo of 40% to up that suggesting data areas of the globe and in remote locations (17); with some subtropical or tropical in mainly observed is pathogens This association between scabies parasites and bacterial rheumatic fever (31), both of which can become chronic. acute or (30) glomerulonephritis as such infection, ing some cases, immune-mediated diseases can occur follow­ septicaemia, or more invasive bacterial infections (24). In and soft-tissue infections (including necrotizing fasciitis), impetigo, which can become more severe and cause skin or pyoderma as known also epidermis, the of infection and become invasive, such as group A opportunistic commensal or pathogenic bacteria that can for point entry an creates that barrier skin in breaches life (28). Scratching scabies lesions themselves leads to of quality and (27) performance attendance, on impact negative a to leading school, or work at concentration with interfering (26), sleep of patients depriving i.e. caused by the intense itch can have direct consequences, in any other pruritic skin affections (25). The discomfort to the immense itch is present more often in scabies than been hypothesized that scratching of lesions in response has It 24). (14, infestation parasitic the with appearing to scabies infection, mostly caused by bacterial infections ingly substantial morbidity, and even mortality (23), due increas­ indicate studies epidemiological wever,recent perceived as an ectoparasite that just causes itching. Ho camps (20–22). refugee and populations, homeless schools, prisons, child-care and elderly-care residential facilities (18, 19), communities and institutional settings, such as hospitals, closed in reported often is scabies of endemicity high nations, high-income In outbreaks. and scabies of risk munities or in crowded housing conditions are at higher with each other. Indeed, people living in clustered com interact individuals how and concentration, population and size household load, mite patient’s the on depend transient lifestyles. The risk of transmission is known to develop, and are fuelled by overcrowded households and creased, small epidemics around a single case can easily in dramatically is person per burden mite the which in the case in severe scabies, i.e. profuse or crusted scabies, especially is This affected. be frequently may patients is contagious, persons sharing the same household with scabies below). As see scabies; of forms severe of text con the in (generally environment mite-contaminated contact and, less frequently, via fomites within a patient skin-to-skin via mainly occurs Transmissionscabies of living in crowded conditions are more often at risk (17). 226 For a long time, the scabies mite has been erroneously (29). These bacteria lead to secondary to lead bacteria These (29). S. aureus C. Bernigaudetal. Streptococcus (GAS) - - - - or feet (1). In adult patients, the head is usually not af not usually is head the patients, adult In (1). feet or females, in region periareolar genitals, buttocks, skin, periumbilical wrists, hands, webs, finger as such sites, classical in found are lesions scabies Most epidermis. the through mite the of progress and penetration the by that worsens at night (44) and typical skin lesions caused itch severe are scabies Typically, of symptoms first the WHO DOWENEEDTOTREAT? its management. in improvement global justify to sufficient are but red, economic and psychological ramifications are undersco social, marked Its patients. infested amongst senteeism ab job or school and life of quality affecting impact, social significant a causes still scabies itch, the Beyond (39–43). flourish to bacteria associated allowing mite, the around microenvironment the modulating thereby including complement defence and neutrophil function, immunity host innate the downregulating in proteases) of direct effects of mite gut proteins (serpins and serine and, in part, explained these observations with evidence supported has work experimental fundamental recent More (36–38). campaigns (MDA) administration drug mass during numbers scabies in reduction a paralleling prevalence sores skin or impetigo in reduction or (30), tion in childhood haematuria following scabies treatment aids, which have proved reliable in endemic regions, endemic in reliable proved have which aids, itching in household members (49, 50). These diagnostic diffuse itch, presence of lesions in typical skin areas, and and clinical arguments, such as, for example, a history of bies using a combination of parameters of patient history been created to assist health-workers in recognizing sca and mismanagement. Clinical diagnostic algorithms have misdiagnosis to leading challenging, be can scabies of tion. However, burrows may not be visible and diagnosis lesion of scabies, is observed at a typical site of predilec 1-infested patients)(46–48). including topically-applied medication, HIV-, or HTLV- from any cause (transplant recipients, corticosteroid use elderly or in patients with the underlying in immunodeficiency seen is condition This (1). soles and palms and or diffusely affect multiple skin sites, including the face example, for scalp, the or toe, finger, a to restricted be scabies, hyperkeratotic skin (rather than real crusts) may of forms such In lesions. extensive of development the and patient, per mites of millions even or thousands racterized by a very high parasite burden, with hundreds, profuse and crusted scabies. Both presentations are cha epidermis (Fig. 1A). The severe forms of scabies include the within mite a of presence the indicate which of all pruritic papules are the most common lesions observed, (45). Burrows, vesicles, pustules, nodules, or excoriated fected, although it may be involved in infants, and babies or in interventional studies in the field showing reduc showing field the in studies interventional in or The diagnosis of scabies is easy if a burrow, the specific ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Table I. Comparison of the specificity and sensitivity of the different currently available diagnostic non-invasive methods for scabies. for Adapted fromChosidow&Sbidian(62)andMicalietal.(53) methods non-invasive diagnostic available currently different the of sensitivity and specificity the of Comparison I. Table daily in used tools are microscopy epiluminescence or Dermoscopy necessary. be may scrapings repeated as time-consuming, is and operator-dependent highly is but 1B), (Fig. specificity excellent an has examination specificity are summarized in and sensitivity Their customized. been have nologies microscopic examination of a skin scraping. New tech eggs, eggshell fragments or mite faecal pellets by light visualization of the parasite (adults or immature forms), diagnostic scrapings (53). The gold standard remains the have been developed for directly identifying the methods mite in Non-invasive available. not still is markers other specialties,andnon-experthealth-workers(52). the ease of using it for GPs, experts in dermatology and as well as validated, be to yet have criteria these using diagnosis scabies of reproducibility and accuracy The scabies, and suspected scabies case) and 8 subcategories. includes 3 levels of definition (confirmed scabies, clinical Criteria 2019 IACS The (51). IACS of aegis the under 4-round Delphi process including 34 a international experts using recently developed were scabies of diagnosis prevalence. With this in mind, consensus criteria for the offices to resource-poor field settings, regardless of local range of settings, from the dermatologist’slarger daily a practice across optimized and extrapolated be to have lactophenol (x10, mite cotton bluestaining). scabies adult an showing (A), in the patient end, from scraping the skin at of triangle examination Direct brown (C) a magnification). of (10-fold image jet” an “deltawing and “jet-with-contrail” the showing dermoscopy using (A) in patient from lesion burrow A (B) lesions. scabies papular and vesiclestiny burrows, linear with hand right the of palm the on lesions Scabies (A) 1. Typical lesionsofordinaryscabies. Fig. Prices, USD Duration of the procedure Negative predictive value, % Positive predictive value, % Specificity, % Sensitivity, % References As yet, a simple test for scabies based on molecular on based scabies for test simple a yet, As – entire body 15 min for the 99.4 87.7 98 96.2 algorithm diagnosis Clinical (49) Table I. Light microscopy US$ 500 30 min 90/77 100/100 100/100 90/46 (55)/(63) microscopy and light Skin scraping – 5 min – – 100 36.6 (64) test Burrow ink - US$ 10 10 min 85 100 100 68 (63) tape test Adhesive living mites. These are expensive techniques and the and techniques expensive are These mites. living magnification and can be used to assess the viability of high very allows that computer a to connected camera Videodermatoscopy utilizes a dermoscope with a video (55). 1C) (Fig. mite the of head the representing sign image of a black or an brown triangle, or the burrow,“delta-wing jet” its and mite a representing skin, the in pattern “jet-with-contrail” the of observation the by The diagnosis of scabies using dermoscopy is confirmed taneous disorders, including parasitic infestations (54). while most studies have found a very high specificity,high very a found have studies most while or PCR specifically targeting scabies DNA. With PCR, – time of flight (MALDI-TOF), antigen detection system tools, such as matrix-assisted laser desorption ionization tried to develop diagnostic techniques using molecular this device has been described (57). Some authors have using eggs and mites scabies the of Imaging skin. the into µm 200–300 of depth a to penetrate to resolution optical high provides and laser diode wavelength nm melanoma from benign naevi. The system uses an 830- malignant differentiate to lesions, skin pigmented for confocal microscopy has been developed more recently Reflectance (56). scabies of assessment medical the in use for investigation, entomology or botanical in used refore some authors have adapted low-cost equipment, clinical practice by dermatologists for a variety of cu of variety a for dermatologists by practice clinical US$ 500–700 entire body 5–10 min for the 90/85 88/47 86/46 91/83 (55)/(63) (dermoscopy) microscopy Epiluminescence Management ofscabiesinthe21 Theme issue: Cutaneous and genital infections US$ 25,000 entire body 5–10 min for the 95 97 97 95 (65) Videodermatoscope US$ 150,000 for each lesion 60 s to10 min 92 100 100 92 (65) microscopy confocal Reflectance st century

US$ 200 Half a day –/61.7 –/100 100/100 75.7/37.9 (59)/(66) method PCR-based 227 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections on based different were conclusions the but evaluation, the in included were trials newer no 2017, and 2010 in performed reviews, systematic 2 these Between ments. treat reference the as considered consequently are and safety, and efficacy of level same the at ivermectin and permethrin 5% topical placed (RCTs) trials controlled randomized (77) 15 and (76) 22 respectively from data of reviews systematic Cochrane recent Two 15). day maximum 5–8, day (at fertilized be can that stage adult the of development the and life-cycle) mite the of 2–4 a short window between larval hatching (occurring at day 2-dose regimen still needs to be optimized and should be not eggs (13). The optimal interval between dosing in the only against mobile stages (larva, nymph and adults) and active are they and parasite, the of function muscle and cacy (74, 75). Most scabicides act by affecting the nerve absorption and,accordingly, thismightincreaseitseffi its increase to order in proposed been has meal content high-fat a with drug the Giving 73). (72, model scabies porcine a in trials experimental 2 in shown was which drug (71) and the short half-life of ivermectin in the skin, could be explained by the limited ovicidal activity of the This (68–70). once only given if cure complete of rates dard dose of 0.2 mg/kg and may be associated with lower stan a at given is ivermectin Oral limited. be to appear they but scabies, for medicines topical all with reported are manufacturer.events the Adverse from instructions specific the on depends period application The mouth. surface, from “head-to-toe”, avoiding the eyes, nose, and (67). Topical skin entire the to applied be should agents scabies crusted with patients for or skin, eczematous or recurrent, difficult-to-treat cases, those with superinfected oral ivermectin in 1981, which was, at first, reserved for of arrival the until treatment first-line considered were in summarized are scabies of treatment for available options The contacts. family and household all to given be should and scabies, of cases confirmed all for prescribed be must Treatment Treatment ofsmallclusters(individualandfamilylevel) HOW CANWETREAT SCABIES? further. tools have been developed, but will have to be improved diagnosis of scabies is crucial. Non-invasive diagnostic definitive and accurate the Thus, treated. be to need patients which of identification better from come will dermatological skills. without infection mite identify to method rapid and diagnostic kits have been developed for use as a simple biomarker-based No (61). examination dermoscopic or microscopic by either observation parasite with compared poorer (58–60), 60% to 30% from ranging low, continually was sensitivity 100%, to close often 228 Improvement in scabies management is essential and C. Bernigaudetal. TableTopical II. medicines - - -

Table II. Comparison of treatments in use to treat scabies in humans

Efficacies Use during Use in breastfeeding Drugs Formulations Recommended treatments Cost (Euros) (%)* Main adverse reactions Use in children pregnancy women

Ivermectin 200 µg/kg Repeat after 7 days €19 for 4 tablets at 3 mg=€38 70–100 Nausea, rash, dizziness, itching, Not approved in Only Only recommended in Pills for a complete treatment (weight eosinophilia, abdominal pain, fever, children <15 kg or 5 recommended in France 70 kg) tachycardia years of age France 1% Overnight (8–12 h) – from €20 for 15 g cream=€80 for a 69–85 Pruritus, burning, stinging, eczema Not approved in Not Not recommended Cream/lotion head-to-toe – repeat once after complete treatment children recommended 7–14 days Permethrin 5% Overnight – from head-to-toe – €19 for 30g cream=€38 for a 86–100 Pruritus, burning, stinging, eczema Safe in children ≥2 Approved Not recommended Cream repeat once after 7–14 days complete treatment months of age Benzyl benzoate 10–25% Apply from head-to-toe for 24 €15 for 125 mL emulsion=€30 48–92 Pruritus, burning, stinging, pustules, Safe in children ≥ 1 Authorized if Not recommended Lotion or emulsion h On days 1, 2 and repeat after for a complete treatment skin irritation, eczema month of age necessary 7 days Crotamiton 10% Overnight on days 1 and 2 €7 for 40g cream 63–88 Pruritus, skin irritation, eczema, Safe in children Not Not recommended Cream erythema, anaphylactic reaction recommended Precipitated 6–33% Apply from head-to-toe for 3 – 39–100 Messy application, malodour Safe in children Authorized – sulphur Cream or lotion consecutive nights Malathion 0.5% Repeat after 7 days €12 for 100 ml=€24 for a 47–72 Pruritus, burning, stinging, skin Not approved in Withdrawn from Withdrawn from the Aqueous lotion complete treatment irritation, CNS toxicity, dizziness, children <2 years the European European market seizure of age market Lindane 1% Overnight Repeat after 7 days – 64–96 CNS toxicity, dizziness, seizures, Withdrawn from the Withdrawn from Withdrawn from the Lotion or cream renal and hepatic toxicity reported European market the European European market with overdosage market

*Efficacies according to Strong & Johnstone (76). Updated from Bernigaud C. et al. (13). CNS: central nervous system. Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV two weeks. Itching can persist for up to one month af month one to up for persist can Itching weeks. two Treat­ re-infestation. prevent to and patient the of cure the algorithms, based on high-throughput experimental data order to optimize cure rates. Simplified and generalized in mite-load, high with scabies severe of cases in and scabies of cases non-profuse in (88) treatment the of environment-decontamination procedures on of the success impact the evaluate to needed are Studies common scabies. in least at (3), rare be to thought is fomites by mites of transmission indirect the (87), scabies with environmental dust from floors and furniture of patients of samples in found be can mites living While failure. treatment in factor key a was fomites or furniture of decontamination incorrect that found studies 2 These 86). (85, failure treatment with associated were factors which determine to tried recently authors Some (77)). is observed with permethrin and 68–86% with ivermectin because drugs are not 100% effective (74– 93% clearance warranted. Treatment failure has been observed, mainly are lacking and surveillance for better documentation is Studies debate. of matter a remains importance clinical both permethrin (81, 82) and ivermectin (83, 84), but its for reported been has resistance Parasite (80). contacts close scabies-infested from re-infestation and nails, or skin hyperkeratotic into agent the of penetration poor agent, topical the of application incorrect agent, topical or mite the to secondary dermatitis diagnosis, incorrect include treatment effective an with failure treatment apparent of Causes treatment. successful ter the 21 medication, in June 2019 the WHO added ivermectin to and benzyl benzoate. To widen access to this key effective preparations sulphur as such preferred, are medications other countries. In those countries, available and cheaper mostly used off-label and may not even be accessible in this indication in 10 nations as first-line treatment, and is scabies in 2001, oral ivermectin has been licensed only for since it was first approved in France for the treatment of lability of the drug in the different countries. For example, NCT02407782) (78). Treatment also depends on the avai (SCRATCH,days’efficacious 10 most at the is interval permethrin or 0.2 mg/kg oral ivermectin, both given twice topical 5% treatment, which finally establish to scabies common with patients recruiting currently is protocol, randomized clinical trial, cluster-designed with a robust French evaluate. A to difficult conclusions the making found, was measurements outcome and methods the in the therapeutic trials analysed, a significant heterogeneity ivermectin when 2 doses were given. Overall, among all in 2010, concluded that topical permethrin was equal to as trials same the reviewing (77), 2017 in al. et sumeck Ro scabies. of treatment the for agent efficacious most the was 5% permethrin topical that 2010, in concluded, (76) Johnstone & Strong used. drugs the of regimen the Follow-up is necessary after treatment, to evaluate to treatment, after necessary is Follow-up ment success should be expected in approximately st WHO EssentialMedicinesList(79). - - -

children (aged 1–64 months, body weight 4–14.5 kg) 4–14.5 weight body months, 1–64 (aged children young and infants in off-label ivermectin using reports Recent kg. 15 than less is weight body patient’s the if differ from that in adults. Oral ivermectin cannot be used have been approved. The application time in children can permethrin andkeratolytictherapy. topical repeated with ivermectin oral of doses multiple fested patients are seen (47). They suggest a regimen of in highly where Australia, northern in experience and been performed. Most records come from small studies, have trials controlled randomized no date, to as, sensus The first MDA was performed in a scabies-endemic a in performed was MDA first The has emerged to control scabies in endemic spaces MDA(96). of opportunity the communities, some in high very be can prevalence because and time same the at all treated be to have contacts close their and patients because settings, collectivity these In risk. greater at skin contact, people living in crowded communities are skin-to- by spread disease contagious a is scabies As Treatment oflarge clusters(collectivitylevel) target populationtobetreatedadequately. this enable to work fundamental more as well as sary, neces is surveillance Continued 95). (94, significantly differ not did population reference the in defects birth or stillbirth, miscarriage, of Occurrence in Africa. mes becomes known in onchocerciasis eradication program pregnancy their before inadvertently treated been have cipated foetal toxicity. In practice, thousands of women anti any than rather precaution basic for are treatment ivermectin from women of exclusions Most (93). tion recommenda expert an by supported pregnancy the of trimester any at permethrin, topical 5% after treatment second-line a as ivermectin, of use the allows country one only women, pregnant of treatment the For future. near the in change may infants in ivermectin of use for Recommendations (92). group age this in treatment this of efficacy and safety the on reassuring highly are an anti-pruriticmechanism(91). is their sedative properties that are effective, rather than is no specific treatment. Antihistamines can assist, but it there itch, the For regions. non-tropical in used be may pristinamycin, amoxicillin/clavulanic acid or whereas cephalexin (90), regions endemic tropical in used are G penicillin benzathine intramuscular or (cotrimoxazole) trimethoprim-sulphamethoxazole Oral areas). specific and GAS target to have antibiotics Systemic lesions. profuse with cases in recommended not are acid) fusidic or mupirocin (e.g. secondary bacterial infection. Topical antibiotic creams resource-poor population, were suggested recently (89). including settings, of range large a in used be can that For the treatment of children, only topical treatments For the treatment of crusted scabies, there is no con no is there scabies, crusted of treatment the For Appropriate treatment should also be given for severe Management ofscabiesinthe21 Theme issue: Cutaneous and genital infections (including MRSAin (including S. aureus st century 229 ------

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections 1 to understand factors associated with success, defining mization of these programmes will be required in order largera on Opti populations scale. endemic highly in scabies control MDAto encourage ivermectin to with evidencerobust and results positive provide grammes pro interesting these All (106). Islands Solomon the in malaria of vector the farauti, Anopheles and (105) have been found to be efficient in controlling head lice had additional unintended downstream effects, as they have control scabies for MDAs Remarkably, (104). participants enrolled 26,188 in secure and feasible vince, Solomon Islands, was also found to be effective, for targeting trachoma and scabies in the Choiseul Pro ivermectin and azithromycin of co-administration the effectivebe to found were largera On safe. and scale, (103) strongyloidiasis and scabies or (102), filariasis filariasis and onchocerciasis, or scabies and lymphatic and albendazole administration to treat both lymphatic ivermectin combining scale, smaller a On helminths. schistosomiasis, yaws, or infection with soil-transmitted such as onchocerciasis, lymphatic filariasis, trachoma, (101), programmes eradication diseases tropical ted ported only from Australia (see of oral ivermectin (summarized in use the by followed permethrin, topical lindane, with firstly MDA, by scabies control to world the of parts Successively, multiple programmes have evolved in all region 230 or endemic settings. Controversial results have been re reduction in the prevalence of scabies in highly endemic programmes have resulted in successful and significant MDAmany years, these all During impetigo. in 67% and scabies of prevalence the in baseline from 94% of reduction relative a with effective, most the be to found was ivermectin with treatment mass months, 12 At (36). control as care standard with compared permethrin, topical and ivermectin oral i.e. strategies, intervention2 of 1 to Fiji in islands 3 randomized has (SHIFT) Trial Fiji Intervention Health Skin the trial, to integrate scabies MDA in other schemes for neglec disease, some programmes have looked at the potential impetigo (37). Although, as most MDAs of target prevalence only one the reduce to scabies for MDA during antibiotics add to necessary not is it that indicated has study recent A(30). haematuria in reduction the by signified complications, kidney and (36) impetigo GAS in reduction significant a in result to seems also 5% (100). Interestingly, the treatment of scabies alone than higher prevalence scabies a with communities in this approach seems to be efficient (98, 99), especially sustainability of success of MDA in the longer the term, but on exist data Fewer poor. was regimen treatment because the adherence of the target population with the https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3468 C. Bernigaudetal. of Panama in the 1970s by Taplin et al. (97). al. et Taplin by 1970s the in Panama of Table SI Table SI 1 ), presumably 1 ). Only one - - - - - As mentioned above, treatment either with a topical aca FUTURE? HOW WILLWETREAT SCABIES INTHENEAR seekers (109). asylum in recently, more and, (18), facilities age-care closed institutions, such as schools (107), prisons (108), in outbreaks smaller for extrapolated been has MDAs potential to conduct translational preclinical and phar and preclinical translational conduct to potential real provides model scabies porcine experimental an of development recent The (13). mite the of cycle life eggs, and half-lives too short to cover the whole 14-day against activity limited treatments, repeated with ance compli poor are therapies current of limitations major and/or a combination of topical and systemic drugs. The tervention, but patients often require multiple treatments scabies infection will recover with a suitable medical in standards of care for common scabies. Most patients with current the are ivermectin with treatment oral or ricide found to be poorly effective. Further studies found that found studies effective.Further poorly be to found was weight) body kg per mg (0.2 ivermectin oral of first raised for head lice infestation, as the standard dose was concept This cure. a achieve to ivermectin of dose higher a need may infection parasite the that is thesis hypo emergingarbitrary, decision. An but reasoned, a on based was it studies; dose-ranging high-level after been rushed, and the dose of 0.2 mg/kg was not derived have might parasites other and scabies for ivermectin of development clinical (118).The investigation under currently and option interesting an also is scabies of single-dose treatment for scabies (NCT03905265) (117). France, with the aim of developing moxidectin as a new and in Australia progress in is humans in trial II phase 1-week interval (0.2 mg/kg) (72). A multicentre clinical at ivermectin of doses 2 conventional the than fective ef more be to found was mg/kg, 0.3 of dose single a at for scabies performed in France, moxidectin used orally, model pig experimental the in trial pilot a In mite. bies (72), potentially covering the entire life-cycle of the sca ivermectin than skin importantly,the and, in plasma in absorption, large distribution, and a much longer rapid half-life profile: pharmacological interesting very a has tion (FDA) for treatment of onchocerciasis. Moxidectin ped and approved by the US Food and Drug Administra the same family as ivermectin, and was recently develo pound suitable for oral administration. It is a member of was investigated (72, 73). Moxidectin is a molecule humans com to clinic veterinary the in used drugs existing options for scabies treatment, the concept of translating macokinetic studieswithnewdrugcandidates. numbers ofroundsMDA (24). the determining and use, to regimen appropriate the Similarly, controlling scabies at a larger scale by scale larger a at scabies controlling Similarly, The use of higher doses of ivermectin for treatment for ivermectin of doses higher of use The therapeutic the improve and optimize to order In

------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV REFERENCES authors havenootherpotentialconflictsofinteresttodeclare. tific advisors for Medicines Development for Global Health. The Dermatologie and MSD France. CB and OC act as unpaid scien Dermatologie and lecture fees from Zambon Laboratoire, Codexial ceived drugs, donated free of charge, for research from Codexial Laboratoire Dermatologique and Codexial Dermatologie. OC re Conflicts of interest: CB received research support from Bioderma ACKNOWLEDGEMENTS and theirfamilies. enhance the therapeutic options for will the benefitdiagnostics of patients and drugs new that and scabies, with infested patients for improvement significant a provide body formed in 2012. We hope that the next advocacy 10 global years a will IACS, by driven mainly scabies, of management the concerning completed been has work important of lot century,a 21st the of beginning the at effective to control the disease. During the sufficiently past 20 be years, not may treatments available currently The worldwide prevalence of scabies remains high, and CONCLUSION immediately andshouldbetailoredtoscabiesmites. therapeutic tools. These next-generation drugs are needed new design to help will technologies biochemical and molecular advanced of use The (123). fungus genic entomopatho even and 122) (121, compounds herbal and D7(GALECRUSTED,NCT02841215)(120). D0 on permethrin 5% topical and therapy emollient of D14), supplemented in both arms with daily application of 0.2 mg/kg, given 3 times 7 days apart (on D0, D7 and dose of 0.4 mg/kg with the conventional treatment dose efficacy of ivermectin given orally as the higher double zed controlled clinical trial is in process, comparing the France, a French Ministry of Health-approved randomi In infestation. scabies controlling at effective more are ongoing to determine whether higher doses of ivermectin Dose-ranging experimental studies in the pig model are results were reported for other parasitic infections (118). Similar (119). effective 95–100% approximately was dose) double (a ivermectin mg/kg 0.4 with treatment 5. 4. 3. 2. 1. Other novel treatments are also in development, using present andfuture.Parasit Vectors 2017; 10: 297. Arlian LG, Morgan MS. 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PLoS Negl Trop Dis - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV This isan open access article under the CC BY-NC license.www.medicaljournals.se/acta verruciformis (2). Likewise, the prevalence of scabies of prevalence the Likewise, (2). verruciformis epidermodysplasia resembling warts plane extensive spikes in the prevalence of molluscum contagiosum and local with associated be can community the in HIV of level high underlying an of presence the and regularly less common although warts and herpes simplex are seen generally is infection Viralskin infections. Malassezia and Candida as well as dermatophytosis including ses skin infections such as pyodermas and cellulitis, myco bacterial including infections, by dominated is picture this climates, Generally,hot (1). in disease skin of tion distribu and pattern normal the in variations local of underlying prevalence of skin disease and the existence by skin problems, although this varies, depending on the of new consultations at primary care level are motivated most countries with a tropical climate between 20–40% In (1). regions all in level care health line front at seen fore unsurprising that it is one of the common disorders S ifd.org House, 4 Fitzroy sqaure, London W1T 5HQ, UK. E-mail: roderick.hay@ Corr: Roderick Hay, The International Foundation for Dermatology, Willan Acta DermVenereol 2020;100:adv00113. Accepted Mar19,2020;Epubaheadofprint24,2020 toma; leprosy. Key words: skindisease; tropics; NTDs; scabies; tinea; myce- at regional and national levels. commitment lasting and firm by backed is programme way, it is critically important that time invested in this training andmonitoring andasthework getsunder is both logical andwelcome.However,thisrequires as a route to diagnosis by front line health workers initiative to useskinpresentations of tropical diseases leprosyless frequent andmycetoma. including The to thosefrom ascabies, that the are common, such in healthseen care facilities. Thesediseasesrange targets forworldwide control or elimination arealso cal diseases of the skin or Skin NTDs, which are the conditions knowncollectively asthe neglected tropi as pyodermas and such fungal infections, a group of dominated by infections. Along with common diseases gions is wherethepatternofclinical,presentations Skin disease is a common illness in mostSkin diseaseisacommon tropical illness re Journal Compilation ©2020ActaDermato-Venereologica. Kings College London and the International Foundation for Dermatology,London UK Roderick J. HAY from Leprosy andOtherNeglectedDiseases Skin DiseaseintheTropicsandLessonsthatcanbeLearned 900,000,000 persons globally each year.there each is globally It persons 900,000,000 than more affect to estimated is disease kin Centenary theme section:CUTANEOUS ANDGENITALINFECTIONS REVIEW ARTICLE - - - - - skin disease may also be associated with severe mental severe with associated be also may disease skin incapacity physical Beyond 9). (8, areas rural remote in even package, care integrated of form effective an as diabetic foot or podoconiosis, is increasingly used as such needs, similar with conditions other with patients of that to management their Yetlinking (7). resources ling in lymphatic filariasis are major challenges to local swel scrotal and limb massive the or leprosy in ulcers neuropathic the as such conditions ulcerated tropical disability and preventing further damage in patients with pain and debility, as well as loss of work (6). Alleviating lopment of recurrent episodes of cellulitis which lead to for lymphatic filariasis, is a major risk factor for the deve endemic areas in living lymphoedema, with patients in circumstances. For instance, the presence of tinea pedis individual and region with both vary can which bidly associated with significant levels of disability and mor and disability of levels significant with associated also are tropics the in infections Skin (5). region one in centres) health (primary posts aid individual of budget skin disease, accounted for more than 30% of the health Papua New Guinea managing tropical ulcer, or just one In food. additional as such needs other for destined given was ineffective (4). This used up all cash reserves household to treat scabies – and generally the treatment period, households in 3-month rural areasa were over using over that, 24$ per estimated Mexico in study One resources. overstretched on impact significant a have these infections in poor communities, although they may initiatives designedtocontroltheinfection(3). health public major driven have and Pacific West the and Ethiopia from reported been have rates prevalence these 10%; than more of levels higher even reach can affectsit more than 5% of the population in the tropics, it often while and, time over changes and variable is feasible. the skin, their treatment and control becomes much more that by detectingthem, because of their appearances in and skin the in appear first blindness, river and leprosy as that many of the serious diseases seen in the tropics, such WHO programme has been to take advantage of the fact de illnesses like ringworm, impetigo and scabies. A recent Skin diseases are very common in the tropics. They inclu SIGNIFICANCE There is less data on the social and economic costs of Acta DermVenereol 2020;100: adv00113 doi: 10.2340/00015555-3469 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections health inequalities, it has been important to recognise and addressing and control their implementing on focus to as Skin NTDs (16) (see yaws and scabies constitute a group of disorders known leprosy,filariasis, such lymphatic diseases cluster such one in clusters; into diseases neglected these group to health strategy. A key element of this initiative has been whose elimination or control forms a core part of global tive and supportive care, as well as research, for NTDs, cura preventative, integrating of strategy a on focused has journals, scientific and agencies other by ported sup Organisation, Health World the Recently NTDs. or Diseases Tropical Neglected as collectively known are leishmaniasis, and onchocerciasis as such tropics, the in care health dominate that infections disabling important the of differentMany a context. in important Skin disease or diseases that present in the skin are also NEGLECTED TROPICALDISEASESOFTHESKIN cupation isagriculture. oc main whose populations rural in manage to ficult dif is This (15). dermatoses sensitive light debilitating persistent and itching severe cause may which prurigo actinic to predisposed genetically are groups American other specific skin conditions. For instance, some native to susceptible also are populations Certain carcinoma. cell squamous fatal of risk high a is there treatment, as well as advice sun-protection without left patients and ignored is it if as, systems health resource-limited on strain a poses This 14). (13, Region Pacific the and countries from Central America, to Sub-Saharan Africa in living those affecting north, colder the than regions non-melanoma skin cancer, is more common in tropical Oculocutaneous albinism, with its attendant risk of early groups. population particular in encountered problems (12). specific areas also tropical are some There in sing evidence that the prevalence of is atopic eczema is increa there and services clinical in frequently more seen hot climates eczema, particularly atopic eczema, is now in distributed sparsely previously Although health. on impact important an have may diseases skin other that fection in tropical countries, it is important to recognise for divorcearemakingadifference (11). sing to use the word “leper” or listing leprosy as grounds and even simple but important interventions such as cea in various activities that had previously been prohibited has been repealed thereby allowing patients to participate legislation, which was often introduced many years ago, cluding leprosy. This is now changing. In most areas such in diseases, skin some with patients against legislation both community discrimination as well as discriminatory been has there countries some In (10). stigma and tion household and societal relationships through discrimina affects it addition in and depression particularly illness 236 While the pattern of skin disease is dominated by in by dominated is disease skin of pattern the While R. J.Hay Table I for the full list). In order ------recognition of skin diseases and Skin NTDs has been pro and providinghealtheducation. discrimination and stigma and in sensitising communities combatting in problems, these by caused disability of management the combining from derived be to benefit scarce resources (17–19). There is also a further practical ges of an economy of scale and to rationalise the use of with these complications - LF and Podoconiosis. *Integrated strategy for morbidity management of two tropical endemic diseases Table I.Theneglectedtropicaldiseasesoftheskin(skinNTDs) in school children and prevalence rates in schools can schools in rates prevalence and children school in sub-Saharan Africa, for instance, tinea capitis is endemic ner. This is also subject to variation in different areas. In tropics, tinea capitis and tinea corporis are much commo frequent presentations in colder climates whereas, in the matophyte infections, onychomycosis and tinea pedis are the clinical patterns of infection. For instance, with der from those encountered in temperate climates, different including are that encountered changes other are there overcrowding, particularly household overcrowding. But that favour spread and pathogenesis, such as climate and cal countries is thought to reflect the prevalence of factors The reason for the dominance of skin infections in tropi Fungal disease INFECTIONS SPECIFIC ANDCOMMONTROPICAL SKIN and Whats-App technologies(22,23). electronic messaging and communication e.g. Telederm rithms and the use of long range expert support through on handheld devices, to the provision of diagnostic algo field the in usable (21) apps diagnostic of development well as to provide as specialist support, detection, that range from case the improve to designed and work this There have been a number of new initiatives arising from drugs used for mass administration are in development. of co-distribution and pathways management common as improving access to training programmes, developing such NTDs Skin address to strategies Other (20). ages duced by the WHO and is available in 5 different langu mapping, it will be possible to maximise the advanta the maximise to possible be will it mapping, integrated schemes for case detection, management and developing strategy.By skin-centred overall an of part leprosy,as as such diseases neglected serious more the with together infections, fungal and impetigo as such conditions, skin treatable readily common the include • • • • • • • • • In furtherance of this initiative a new handbook on the Yaws Scabies Onchocerciasis Mycetoma, chromoblastomycosis andother deep fungal infections Lymphatic filariasis(LF) (lymphoedema and hydrocoele)* Leprosy Post-kala-azar dermalleishmaniasis Cutaneous leishmaniasis Buruli ulcer ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV to have mutations in the squalene epoxidase gene, mea corporis and some strains of mentagrophytes (27, 28). This results in extensive tinea phagocytosis. As a result, scabies infestation and has a activation direct complement with interfere may which (33) SMIPPs or Paralogues Protease Inactivated Mite as the mites produce different substances, such as Scabies between streptococci and scabies mites is a complex one, seen in association with scabies (31, 32). The relationship these regions. Streptococcal skin infection is particularly matic fever (32) are a potential public health problem in climates and the complications of nephritis (31) and rheu northern in than tropics the in commoner are infections streptococcal A Group But infections. skin of cause colder environments ces in the pattern of skin infection seen in the tropics. In Amongst the bacterial infections, there are also differen Bacterial infections people ofMalaysia(30). Batek the amongst and Islands Solomon the in being latest the – (29) reported be to continue imbricata tinea widespread scaling and itching. New endemic areas for by caused imbricata tinea endemic of persistence is there tropical countries, particularly in isolated communities, or an initial response followed by early relapse. In other treatment adequate despite persistence its and infection Middle East and Europe, are the widespread nature of the some adjacent countries and migrant populations in the and affectingIndia is which epidemic, new this in seen differences main The Europe. in seen been have cases lity generic antifungals. Over the past few years similar topical potent corticosteroid combinations and low-qua of this infection include the ready availability and use of effective. Other factors which may have affected spread less is enzyme, this targets which terbinafine, that ning by caused infection dermatophyte recalcitrant of epidemic in the tropics. In India, for instance, there is a widespread infection fungal superficial of features distinctive other are There achievable. not currently is which strategy a community,the within capitis tinea of control requires cluding kerion, pose a dilemma as effective management inflammatory symptomatic forms of scalp ringworm, in tinea capitis does not persist into teenage years the more normally, that, recognise communities local Although oral antifungal therapy is costly and inaccessible to most. through treatment effective and countries these in tion (24–26). There is little to no surveillance for scalp infec although still common, dominated the pattern of disease previously, whereas, East WestAfrica, both and in prevalent more with tion recent years have emphasised a changing in pattern of studies infec several Furthermore (24–26). 20% exceed T. concentricum which can result in chronic and very and increasingly a strain of strain a Trichophytonincreasingly and rubrum Trichophytonbecome to beginning tonsurans T. violaceumandMicrosporum audouinii , Staphylococcus aureus is the main T. mentagrophytes appears T. T. ------Tropical skindiseaseandneglectedtropicaldiseases(NTDs) can proceed to cause severe limb deformities and os and deformities limb severe cause to proceed can unchecked, if that, disease the by caused disability of risk the reduces which diagnosis early achieving and based on the lack of progress in controlling this largely infection was decision The designation. this given be to infection fungal first the becoming WHO, by disease tropical neglected a be to declared formally was toma and epidemiology. The call for change was taken up in up taken was change epidemiology.for and call The diagnostics new development, drug new on research of lack corresponding a been has There (36). teomyelitis prevalence are Mexico and Sudan (35). In 2016, myce 2016, In (35). Sudan and Mexico are prevalence Mexico to Thailand (35). The countries with the highest (Fig. 1) or fungi (eumycetoma) in tropical regions from actinomycetes or by filamentous bacteriaeither (actinomycetoma) caused is It surface. skin the on tracts sinus and papules of development the and swelling localised are signs first whose infection, chronic a is Mycetoma Mycetoma NEGLECTED TROPICAL DISEASES mites inpredisposingtobacterialinfection(34). declines as well which supports a direct role for scabies infection bacterial also but mites, scabies the combat only not will this that shown has scabies of treatment drug mass as used ivermectin drug oral the with work current infestation, scabies the then and first infection bacterial secondary treat to need the emphasized often As a result although traditional dermatological teaching infection. streptococcal of development the on impact Fig. 1.Actinomycetomadueto Theme issue: Cutaneous and genital infections Nocardia brasiliensis. 237 - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections remains thedominantorganism. anmar and Singapore (47). In other countries My Brazil, in detected been also has M. lepromatosis where there can be vasculitic ulceration of lesions (46). leprosy known of as diffuse form lepromatous leprosy the or Lucio’sof leprosy cases for responsible is it and disease, human of cause a as two the of commoner the parts of the world. In Mexico for instance it is probably clonal variants (46). The latter causes leprosy in certain two, confirming that they are distinct species rather than There is a difference of 9.1% in nucleotides between the second species,M.lepromatosis, is now recognised (45). leprosy are caused by human of cases Most damage. nerve further as well as disease eye and arthritis rash, swelling, tissue by nied (44). These severe symptomatic reactions are accompa fatal potentially are which reactions systemic and local Type 1 and Type 2 leprosy reactions, lead to aggressive infection, the to responses immunological in Changes progressive sensory loss and destructive to trophic changes. leads damage nerve destructive, and extensive be es. While it causes skin lesions, which, if untreated, can Leprosy has long been a scourge in many tropical countri Leprosy selecting thebesttreatmentforpatients(43). identification of the causative organisms is a key step in as diagnosis, laboratory to access improving and (42) disease such as in detection of cases at community level formidable problems in some of the simplest aspects of remain Yetthere (41). cotrimoxazole and dapsone nal traditio more the to addition in linezolid, and floxacin moxi imipenem, including antibiotics of range wide a to respond to found been have which Nocardiaspecies proaches to the treatment of actinomycetoma caused by this group of antifungals (40). There are also newer ap of effectiveness potential the supporting data vitro in to due mycetoma fungal of now a new clinical is trial Thereof fosravuconazole itraconazole. for treatment to sensitive not is instance, for options. treatment of choice the and agnosis recognise now we instance, For identified. species new several with changed been also taxonomy of the genera of fungal mycetoma agents has hedges around corrals used to pen the thorn livestock (38). the The to close identified been has M. mycetomatis where cattle are grazed close communities to houses in and the infection organism of increase associated an is there Sudan In infection. this about findings interesting gramme for WHO (37). pro NTD the of Director the by attended and Sudan in February 2019 in a large conference on mycetoma held 238 This may have implications for accurate laboratory di laboratory accurate for implications have may This tropicana, However, despite slow progress there are several new R. J.Hay M. pseudomycetomatis and Mycobacterium leprae, although a M. mycetomatis,basedon M. mycetomatis, (39). M. fahalii M. fahalii, M. leprae M. M. ------leprosy was still endemic in the 19 Norway,in studies planned methodically where his out carried Hansen Amauer Gerhard that ago long so not our region now only see imported cases, although it was levels (50). A key aspect of leprosy has been the recog as well as heightened awareness at national and regional combinations, drug effective suitable of pioneering the drugs with potent antileprosy activity. This also involved detection and the evolution and deployment of a series of the end of the twentieth century followed intensive case the redsquirrel(49). and armadillo 9-banded the – naturally infected be can these have yielded results, although two animal species of none yet environment, the in sources ofM.leprae natural potential identify to attempts many been have although it is still seen in most parts of the tropics. There years, the over shrunk has areas endemic in leprosy of burden the Elsewhere (48). years recent in Italy, from Europe, in reported been has case autochthonous one infectious and transmissible nature of the infection. Only paucibacillary forms known as lepromatous and tuber and lepromatous as known forms paucibacillary sparse or undetectable. These are the multibacillary and in others the skin lesions are different and bacteria very whereas organisms, of numbers large by accompanied having distinctive changes on the skin and in the nerves forms some with spectrum, a in presents it that nition Fig. 2. Leprosy – borderline tuberculoid leprosy Fig. 2.Leprosy–borderlinetuberculoid on thechestwall. freed from active infection as a result of treatment. Early as trophic change and disfigurement even if the patient is limbs. These are prone to trauma and ulceration as well anaesthetic in resulting areas denervated with left are patients completed, been has process destructive this possible to repair the damaged and defunct nerves, once (51). The other key feature of leprosy is that, as it is not ( regularly seen are form, indeterminate an as well as forms, tuberculoid and lepromatous borderline as such spectrum the of poles two these between diate interme variants respectively,although leprosy culoid Although once endemic in Europe dermatologists in dermatologists Europe in endemic once Although Atowards leprosy of cases of numbers the in decline th century, to prove the Fig. 2) - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV was often drawn away from implementation of rigo of implementation from away drawn often was attention Ironically,target. suitable a as promoted was leprosy of elimination millennium, the with coincide such as using a combination of different laboratory different of combination a using as such is also worth considering the adoption of other options, numbers of organisms, is potentially a difficult target. It low very and immunity of level high a is there where this may be due to bacterial load – tuberculoid leprosy, part In (54). disease active no have who contacts and patients between distinguish or forms paucibacillary identify patients with leprosy of both multibacillary and PCR probe has been identified that will unequivocally or antigen single no evolving, still is and out carried been has work of deal great (53). a test Although tion detec antigen card a or tool molecular simplified a as such resource minimal with implemented be can that techniquesusing – test care of point a – environments laboratory based test deliverable in front line health care work force. So one priority has been to devise a simple staining facilities and depend on an of adequately trained availability the or skills observer in variations to susceptible are both as limitations have useful, while biopsies, skin of histopathology and smear skin slit the methods testing laboratory-based traditional two include both laboratory-based and clinical actions. The and simplify the process of making the diagnosis. These different initiatives designed to improve detection rates of improved case finding there have been a number of importance the Given infection. the of transmission presumably,cases, Such PB. onwardof risk a provide bacilli (AFB) have been detected in cases classified as acid-fast instance, for scheme; this in flaws some are There (52). leprosy of forms (MB) multibacillary as 5 than more with those and (PB) paucibacillary as classified are lesions 5 than less with patients sions; le skin of number the of assessment on based is for thedetectionofnewpatients. reporting leprosy depends on implementing programmes as picture, actual the of underestimate significant a are regions other from figures official current the that kely li is it and numbers case substantial reporting still are Brazil and India as such countries Several increase. to the numbers of new cases to stabilise and, in some areas, allowed subsequently disease, the of period incubation long the given which countries, some in programmes a result, there was a reduction in planned case detection target,this deliver softened. were criteria diagnostic As to order in and, decline, the on be to appeared numbers case as disease, of detection the for programmes rous of leprosycare,eveninthe21 disability and stigma remain other important components tion to purely clinical features of the disease, combatting to prevent this disabling consequence of leprosy. In addi recognition and treatment of individual cases is the way In the course of identifying major health goals to goals health major identifying of course the In The current classification of leprosy used by WHO by used leprosy of classification current The st century. - - - - - Tropical skindiseaseandneglectedtropicaldiseases(NTDs) NTDs, arenowunderway(17,57). endemic of range a detecting at aimed programmes, such approaches in the field as part of broader Skin NTD The detection of both requires training. Attempts to use nerves. peripheral of enlargement or sensation of loss through e.g. damage nerve detectable of presence the as such signs other two or one least at by supported be lies a realisation that direct clinical observation needs to training manual (20). Behind most of these WHO programmes new the of premise basic the forms this – team expert more a to cases suspected refer to worker health primary a allow would that disease the of features lest its many different forms or the identification of the simp training programmes for clinical recognition of leprosy in and surveillance novel strategy,differenton a focusing for successfuldiagnosis(56). route another be may smears in organisms of detection molecular methods with a different test system including Combining 55). (51, 15% as low as from starting wide, is results of range the although sensitivity, 80% to up with bacilli of presence the detect to studies perimental world freeofleprosy. attention from delivering a potentially achievable goal – a about elimination has served to confuse as well as divert messages mixed sending and societies many in feared already beenadoptedaspolicyinmanyareas. has scheme PEP existing the as assess, and activate to and inclusivity of PEP, although this may prove difficult scope the widen to dosages, different or combinations drug as such methods, ancillary seek to taken being are though this is even essential for detection, identifying case contacts. Measures new i.e. control deliver can that strategy the from resource and attention diverting risks social ostracisation. A further practical problem is that it support, there is a consequent risk of discrimination and small communities, unless there is adequate local patient in drawing attention to the presence of cases of leprosy in leprosy patients (60). There is also a social downside as effectiveonly is and treatment post of contacts some in sources of spread; also it only protects for up to 2 years patients with multibacillary ofleprosy who are the greater contacts protect to appear not does it that notably strategy, this of deployment widescale the in inherent idea behind this has merits, there are potential problems as post exposure prophylaxis or PEP (58, 59). While the leprosy patients with single dose rifampicin. It is known delivered that centres around the treatment of contacts of being is strategy new a recognition, case for grammes rRNA which are the most frequent markers used in ex in used markers frequent most rRNAthe are which 16S and RLEP element repetitive M. leprae-specific algorithm basedonclinicalfindings. an with combined be might that some including tests, In order to rationalise the need for extensive pro extensive for need the rationalise to order In Other methods, that have been attempted, have adopted Leprosy is a complex disease which has long been long has which disease complex a is Leprosy The most recent molecular results have focused on focused have results molecular recent most The Theme issue: Cutaneous and genital infections 239 - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections REFERENCES veillance –andforthesakeofwhat? sur and work hard of years undo to possible is it ball” the off eye ones “taking metaphor,by soccer Toa coin scabies. or leprosy is this whether burden, overall its in improvement an be to appears there as soon as control to aim they that disease the forget to not workers, line front to officials Ministry from care, health in involved those all re-reminding and reminding in unrelenting be other tropical diseases in the past, that it is important to to important remember a key message learned from experience with is it this all in But mission. this to key also is services media national or regional through and level, community at advocacy through support, Public improvement, well beyond the confines of the skin itself. of diseases that are seen on the skin as a means of health the importance of proper identification and management in Ministries of Health and regional health offices about care health national for responsible those sensitise to is strategies, health of rethink radical a for point entry the as skin, the using of potential the maximise to step first port, such as diabetes and cardiovascular disease. 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DNA detection in asymptomatic household contacts. BMC Manta FS, de Oliveira LBP, et al. High frequency of M. leprae Trop Dis 2018; 12: e0006403. it leastandisnotacost-effective intervention. PLoSNegl dose rifampicin chemoprophylaxis protects those who need bacteriol 2017; 6:1–8. Dis 2018;3.pii:E107. leprosy diagnosis – a systematic review. Tropfor Med Infect test laboratory care of point potential a as (PCR) tion feasibility study in Indonesia. BMC Infect Dis 2018; 18: 324. prevention in isolated communities: a three year follow-up tion-wide administration ofsingledoserifampicinforleprosy 2016; 6:e013633. rates ofcontacttracing BMJOpen doserifampicin. andsingle for evaluating thefeasibility andimpact oncasedetection protocol study programme: (LPEP) Prophylaxis Exposure Post- Leprosy group). study LPEP ( al et A, Tiwari JH, dus Theme issue: Cutaneous and genital infections 241 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV can be divided into subtypes with differing clinical ma pathogens is permanently increasing and many of them transmissible or transmitted sexually of number The nature. in ectoparasitic or protozoal viral, bacterial, be may They manifestations. clinical and aetiology their with the availability of antibiotic therapy after the Se diseases wasdiscovered.Theinfection ratedropped doi: 10.2340/00015555-3470 relevant the when transmitted sexually exclusively as recognized were and inguinale, granuloma and (LGV), venereum lymphogranuloma chancroid, gonorrhoea, nifestations, e.g.Chlamydiatrachomatis (Table I)(1). A Austria. E-mail:[email protected] Venerodermatological Diseases, Franz Jonasplatz 8-2-3, AT-1210 Vienna, Corr: Acta DermVenereol 2020;100:adv00114. Accepted Mar19,2020;Epubaheadofprint24,2020 syphilis; gonococcalresistance. Key words: nital cancer. asapreventivestrategyforge for young adolescents ce of humanpapilloma programmes virusvaccination of thecountries. Thereisgeneralawareness importan programmes havebeenestablishedinmanyEuropean healthrus infections,sexual serviceswith screening connection betweengenital cancerandpapillomavi ledge of theof long-term STIsandthe consequences pecially forprevention of STIs.Dueto betterknow infections have become a therapeutic es challenge, nitalium, causestherapeutic problems. Viral genital 21 cond World War.However,sincethebeginningof 20 This situation continueduntil the beginningof the haddevastatingoutcomes.many of which diseases, therapeutic optionsof ledto venereal ahighincidence efficient of lack and poverty, War, intercourse. sexual wereobserved inconnection discharge withcoccal Centenary theme section:CUTANEOUS ANDGENITALINFECTIONS As longAs as400yearsago, syphilitic ulcersandgono Acta DermVenereol 2020;100: adv00114 such asNeisseriagonorrhoeae andMycoplasmage such Antibiotic resistanceinseveralgenital pathogens, Europe, especiallyinmenhavingsexwith men(MSM). number of reportedcasesof syphilis is increasingin infections hasbeenrecognizedThe worldwide. (STIs) Outpatients Centrefor the Diagnosis of Infectious Venerodermatological Diseases, Vienna, Austria Angelika STARY The Changing Spectrum of Sexually Transmitted Infections in Europe The so-called venereal diseases (VD) include syphilis, st th century, a steady century, increase in sexually transmitted century, whenthemicrobial century, aetiology of venereal Angelika Stary, Outpatients Centre for the Diagnosis of Infectious transmission, the diseases vary enormously in enormously vary diseases the transmission, of mode common a by defined are STIs lthough sexually transmitted infection; venereal disease; This isan open access article under the CC BY-NC license. www.medicaljournals.se/acta REVIEW ARTICLE ------herpes), mucosal inflammation or discharge (gonorr discharge or inflammation mucosal herpes), genital chancroid, syphilis, (GUD): disease” ulcer nital of entry of the microorganism and appear as ulcers (“ge tes oftransmissionmayevenpredominate(2). (e.g. hepatitis B virus, HIV, yeasts), and non-sexual rou intercourse, others may qualify as sexually transmissible transmitted predominantly, or even exclusively, by sexual sexually transmitted pathogens. While some of them are matic infections or conditions due to the high number of asympto or symptomatic of number increasing the of recognition the reflects STIs or (STDs) diseases mitted Evolution from the term the from Evolution trans sexually term the to VD countries. many in written were regulations and laws Table I.Venerealdiseasesandsexuallytransmitted infections (STIs) Granuloma inguinale Lymphogranuloma venereum Chancroid Gonorrhoea Syphilis Venereal diseases treat STIs, they remain amajor problem. pattern of STIs. Despite efforts to prevent, diagnose, and human papilloma virus and HIV/AIDs, have changed the emergence of new viral infections, suchasgenital herpes, development of antibiotic resistance in gonococci,and the reported numbers of infections worldwide. However, the ward in the control of STIs, leading to a decrease in the the agent, and to describe it tookseveral centuries todetectTreponema pallidum as contact. While syphilis was recognized aslongago1496, that share a common mode of transmission throughsexual broad a to spectrum of bacterial, fungal, viral and protozoal infections refer (STIs) infections transmitted Sexually SIGNIFICANCE biological diagnostic advances, were enormous steps for cause of gonorrhoea. Discovery of penicillin, and molecular In most STIs clinical symptoms first occur at the point Journal Compilation ©2020ActaDermato-Venereologica. Neisseria gonorrhoeae STIs Zika virus Ebola virus Hepatitis B virus (HBV) Human papillomavirus(HPV) Herpes simplexvirus (HSV) Human immunodeficiencyvirus(HIV) Scabies Pediculosis pubis Candidiasis Trichomonas vaginalis (TV) Anaerobic bacteria Ureoplasma urealyticum Mycoplasma hominis Mycoplasma genitalium Chlamydia trachomatis as the ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV mercury, organic arsenicals, bismuth, and fever cycles, fever and mercury,bismuth, arsenicals, organic diagnostic procedure. Treatment of syphilis ranged from philis, which, in modified form, is still the recommended was the first step to aThis reliablemedicine. serological diagnosisinternal offor sy­ congress a during 1908 in and the results were presented at a conference in Vienna “Wassermannlater,developed, the years was reaction” an enormous increase in publications on syphilis. A few ponema pallidum (6). This observation was followed by classification genus new croscopy,the created and mi dark-field by specimens in microbe the of presence the validate to able was Landsteiner Karl until diverse, into syphilis,alittleover100yearsago. pillomas”. This was the beginning of intensive research presence of Spirochaetes in syphilitic lesions and in Pa the on report “Preliminary paper the in discovery their published and pallida Spirochaeta microorganism the from a woman with papule secondary syphilis (5). vulval They named erosive an of secretion the examine to rotating spiral organisms when using a Zeiss microscope Schaudinn and Eric Hoffmann, in 1905, recognized pale syphilis had been detected and described in Europe. Fritz This situation continued for 400 years, until the cause of “venereal disease”, stigmatizing the infected individual. cognized as sexually transmitted, and was identified as a microorganism causingsymptoms(4). transmissible sexually a but commensal, harmless a be Trico-monas vaginale), suggesting that it might not only discoveries about important some made who Donne, by 1836, in Paris in tract might be caused by microorganisms was discussed in research on STIs. The vision that diseases in the genital More than 100 years ago, Europe was the leading region INFECTIONS INEUROPE HISTORY OFSEXUALLY TRANSMITTED tion ofthefoetus/infantandavarietyotherdiseases. infec postnatal and perinatal congenital, puerperium, the and pregnancy of complications (SARA), arthritis reactive sexually-acquired symptoms, neurological lae, cer, pelvic inflammatory disease (PID) and related seque mainly affect extragenitalsites. region (3). Hepatitis B (HBV), scabies and HIV-disease, in invasive carcinoma of the vulva, cervix, penis or anal sionally bear the risk of malignancy and possibly result occa may genotypes high-risk with infections (HPV) virus papilloma human warts), (genital benign usually While neurosyphilis). syphilis, secondary septicaemia, salpingitis/epididymitis) and distant organs (gonococcal (gonococcal neighbouring to spread may infection the tion, trichomoniasis), or even neoplasia. In certain STIs and chlamydial hoea, At that time, opinions on the cause of syphilis were syphilis of cause the on opinions time, that At 16 the as ago long As The major complications of STIs include AIDS, can Trichomonas vaginalis (former name: Mycoplasma genitaliuminfec th century, re been had syphilis Tre ------from the symptomatic men, finally silencing doubters (9). picture of gonorrhoea. He also re-cultivated the bacteria of cultures pure with men of urethra the inoculated theim WerPrague, In bacteria. other from indistinguishable cultivation of the microbes was difficult, and they were the and doubts, were there However, (8). discharge urethral with men from smears in gonococci detecting microbiology.in person leading the was Neisser Albert in advantage scientific important another was pathogen genital different a of recognition The population. ted the International Union against Venereal Diseases and VenerealDiseases against Union International the individuals became mandatory. After the First World War regulated in several countries, and notification of infected and Wassermann tests was recognized. Prostitutes were examinations medical of army.importance US The the become a problem for the soldiers and, in particular, for had VD syphilis. and gonorrhoea with those especially washing units were established for infected individuals, and rooms ablution Venerealtreatment. for facilities inadequate with infections genital of kinds different of genital areasandtheskin. between papilloma viruses on the mucous lesions in the differences were there that realise to sites anatomical differentfrom extracted virus with compare and nomes ge viral cloned prepare to ability the needed it plates, agar on or viruses, culture-like cell in either cultured be not could papillomaviruses Since 1960s. late the in to skin warts was finally proven by electron microscopy anogenital condylomas were caused by a virus identical that hypothesis (12).The warts”) (“gonorrhoeal hoea the severe syphilitic epidemic that threatened the infec by Alexander Fleming in St Mary’s Hospital in London. tortuous treatments ended with the discovery of penicillin leading cause of death in the USA in 1923–25 (7). These a serious cause of disability or even death, and the 10th penicillin era, infections with pre- the In death. including side-effects, severe to mild by followed often was This combination. their even or different authors, along with an association with gonorr condylomata acuminatum, and these were described by to konylos from changed was designation clinical their finally bymolecularbiology(11). and, furthermore, by modern immunological assays and discover the organism to by cultivationtime in took embryo egg it cells but infections; ocular and (trachoma) genital between connection a postulated Lindner (10). 1907 in orangutans of eyes infected the of scrapings in bodies inclusion described Prowazek & Halberstaetder caused byChlamydiatrachomatis was still not defined. be to known now infections urethral of identity the but syphilis, chancroid and gonorrhoea had been discovered, By the beginning of the 20 the of beginning the By During the First the During World Warnumbers high were there For a long time gonorrhoea was overshadowed by overshadowed was gonorrhoea time long a For Penile and anal warts were well known for many years, Neisseria gonorrhoeae and induced the typical clinical Sexually transmittedinfectionsinEurope Theme issue: Cutaneous and genital infections Treponema pallidum were th century the aetiology of aetiology the century 243 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections European countries, and laws have been changed during all, not but most, in controlled and regulated legally is STIs of treatment and tracing, contact Reporting, (17). (Euro-GASP) programme surveillance antimicrobial gonococcal European the includes and countries, EEA EU/ in surveillance STI and situation epidemiological the into insight better a offers (TESSy).This reporting online and collection data annual through (ECDC) trol were collected by the European Centre for Disease Con the numbers of genital infections in European countries are acquired every day (15, 16). During the last decade, 1 than more Organization(WHO), Health World the from data to according and, years, 15–49 aged women and men in year each occur chomoniasis) EUROPE INTHE21 SEXUALLY TRANSMITTED INFECTIONS IN in developing,aswelldeveloped,countries. tion, resistant microbes became a problem for gonorrhoea reduced use of condoms to prevent transmission. In addi the and revolution, sexual so-called the contraception, oral movements, population to due was STIs and VD of resurgence The uraemia. developed even or sterile, emerged, and many men developed epididymitis, became treatment and better diagnosis, the symptoms of STIs re- diminished. However, despite the availability of effective European countries and in the USA the importance of VD USA, and this was followed by mass treatment. In many policy of mass testing for syphilis was established The in the world. the throughout infections early of number the in decline dramatic a with infections, gonococcal Second World War changed the pattern of syphilitic and development of penicillin and other antibiotics after the added to a high and uncontrolled incidence of STIs. The and in the Far and Middle East of Asia, and war poverty Africa in also but Europe, in only not sex, for looking were Soldiers VD. of situation epidemiological the mandatory inpartsoftheUSA. services began to improve and VD reporting also became pregnancy, and established contact tracing (14). Clinical with compulsory blood tests before marriage and during tention. He established programmes for syphilis control, Parran (13) who brought the VD problem to national at STIs had almost disappeared in the USA. It was Thomas in interest the development, diagnostic and clinical and opened in Europe with improvement in health education were clinics VD While contacts. their and individuals infected of surveillance post-treatment and treatment, diagnosis, in network European a for need the on ment agree­ was There VD. of control and prevention the in collaborate to nations member encouraging of aim the with 1923, in formed was (IUVDT) Treponematoses 244 major STIs (chlamydia, gonorrhoea, syphilis and tri and syphilis gonorrhoea, (chlamydia, STIs major 4 the of 1 of cases new million 357 over Worldwide, The Second World War had an enormous impact on impact enormous an WorldWarSecond had The A. Stary ST CENTURY million STIs million - - - - the status of HIV infection was changed to that of a ch this century, a steady increase has occurred again, when of beginning the HIV,since acquiring but of threat the with decreased STIs reported of number the Europe In benefit. public with STIs, of recognition the increased has health reproductive on STIs/HIV of impact the of Knowledge STIs. of pattern clinical and epidemiology the influenced has HIV of emergence The prevention. and treatment for options more as well HIV,as and STIs with concerned services of number the and lities, faci diagnostic science, of quality the in improvement Dermatology associationsintheUSA. and Venereology (EADV), STIs are not part of remit of Dermatology of Academy European the to contrast In population. general the in “venereology” term the with cine (GUM) in order to minimize the stigma associated medi genitourinary to changed name the 1970s, the In diseases. venereal of management the for specifically cialty, called “venereal diseases” with clinics and services European countries, reporting of many In reported. be should information on much how and what regarding differs procedure the but fections, and PEP). In 2016, 28 EU/EEA(PREP Member States prophylaxis reported retroviral post- and pre- with and with, the availability of efficient antiretroviral treatment This was especially recognized after, and in connection HIV-infected(Fig. 1) of individuals. proportion high a re-emerging and affects two-thirds (66%) of MSM, with blem. Since the beginning of this century the infection is penicillin, long-acting of dose single a with effectiveness atment tre and tests diagnostic sensitive and simple Despite SYPHILIS nuloma venereum(LGV)andgonorrhoea. lymphogra syphilis, of cases of proportion significant Europe, data suggest that HIV-positive men contribute a (18, 19). Although the surveillance methods vary across detect asymptomatic infections in both, men and women diagnostics. Improved molecular biological methods sensitive can more with associated been has increase the have sex with men (MSM), except for chlamydia where who men between transmission to due predominantly EU/EEAthe in increased have STIs of 1990s, the since diagnoses new of rates and number The disease. ronic chancroid, and syphilis are mandatory reportable in reportable mandatory are syphilis and chancroid, gonorrhoea, countries, the of most In decade. last the Ireland, municipal authorities in established a and separate UK spe the in 1948, In regions. anglophone the in not but America, Latin and Asia, Europe, in specialty recognized the is Dermato-venereology Europe. across mandatory. infection is recommended, and, in a few countries, even In the past 50 years there has been an extraordinary an been has there years 50 past the In The organization of medical services for STIs varies STIs for services medical of organization The syphilis remains a global public health pro health public global a remains Chlamydia trachomatis ------

Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV needed to ensure that ensure to needed are involvement community and advocacy strong Therefore, nations. developing in year thousand stillbirths and neonatal deaths every neurosyphilis, notably ophthalmic notably neurosyphilis, of forms However,early recognized. been has penicillin it can easily be treated, since, so far, no resistance against remained stablein2015and2016(Fig.2). cases gonococcal the UK the in while 2016, until region, European the in years 15 last the over increased cases reported of number The (ECDC). MSM in were (46%) cases reported the of half almost 2016 In Europe. Europe, with higher rates reported in northern STIs. Infection rates vary considerably across bacterial worldwide and European prevalent most second the are infections Gonococcal NEISSERIA GONORRHOEA high priorityonnationalhealthagendas. recommend dual therapy with ceftriaxone with therapy dual recommend currently Europe, IUSTI and ECDC, CDC, as such WHO, institutions, Most treatments. all antimicrobials previously used as first-line seria gonorrhoeae has developed resistance to men thaninwomen. in higher times 8 being population, 100,000 per 6.1 of approximately 30,000 syphilis cases to the ECDC, a rate is given by Gianfranco Spiteri,[email protected]. figure this publish to Permission Kingdom. United the and Sweden Slovenia,Slovakia, Iceland, Ireland, Latvia, Lithuania, Malta, the Netherlands, Norway, Portugal, Romania, Country reports from the Czech Republic, Denmark, Finland, France, Germany, Hungary, and year, EU/EEA countries reporting category transmission consistently, gender, by cases EU/EEA, syphilis confirmed . 2010−2016 Source: of Number 1. Fig. under-diagnosed. S under-diagnosed. In contrasttoTreponema pallidum, The clinical presentation of yphilis syphilis still causes several hundred hundred several causes still syphilis is still given a a given still is syphilis, has not changed and Neis often remain remain often - Permission to publish this figure is given by Gianfranco Spiteri, ECDC. Gianfranco. Spiteri, byGianfranco [email protected]. given is figure this publish to Permission Malta, the Netherlands, Norway, Romania, Slovenia, Sweden and the United Kingdom. Country reports from the Cyprus, the Czech Republic, Denmark, France, Latvia, Lithuania, and year, EU/EEA countries reporting consistently, EU/EEA, 2008−2016. Fig. 2. Number of confirmed gonorrhoea cases by gender, transmission category in thetreatmentofpharyngealinfections(27). urogenital and rectal infections, but was less efficacious for results successful with performed, was zoliflodacin harbouring other genes (26). A new treatment study with from them discriminate to and A-alleles pen mosaic harbouring assay was designed to detect the genomic DNA of strains PCR-based real-time a strains, resistant on information with azithromycin as first-line drugs (20). Al together volumes), variable in (injectable, necessary. In order to obtain better diagnostic still is culture gonococcal of performance ever-present concern (24, 25). In this regard, an is gonorrhoea multidrug-resistant of danger realistic a and Europe in gonorrhoea drugs. Progression of resistance of Neisseria coccal strain with resistance to both first-line gono a of diagnosis the by influenced g, 1 therapy with ceftriaxone, at a high dosage of mendation from dual therapy to a single-shot recom the changed already has (BASHH) HIV and Health Sexual for Association British The macrolides. and cephalosporins third-generation with treatment gonococcal dual of mainstays the affects strains, sistant re or MICs azithromycin in increase The 23). (22, worldwide decreasing is (ESCs) cephalosporins extended-spectrum both to susceptibility the However, (21). regimen acceptance by patients as an oral single-dose its to due countries, many in preferred been ternatively, cefixime (400 mg once orally) has spp. strains spp. N. gonorrhoeae andNeisseria Sexually transmittedinfectionsinEurope Theme issue: Cutaneous and genital infections Source: Source: 245 - - - - Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV Theme issue: Cutaneous and genital infections this figureisgiven by Gianfranco Spiteri,[email protected]. States reporting the largest of number cases in2016, 2007–2016 Member EU/EEA five the among cases venereum lymphogranuloma Confirmed 3. Fig. significantly more effective, withis cure ratesazithromycin approaching whereas 30%, only of rate cure a has Doxycycline treatment. effective universally a of lack the is concerns main the of One patients. symptomatic in recommended is treatment and Diagnosis Europe. in use diagnostic for approved are tests CE-marked new and available, method diagnostic only the is tests tion disease (PID) (33). Detection by nucleic acid amplifica proximately 10% of women having pelvic inflammatory ap probably and urethritis non-gonococcal with men symptomatic of 15–25% in agent aetiological the is It with a clinical pattern similar to women, and men in infections genital of cause portant im an as recently described been has M. genitalium MYCOPLASMA GENITALIUM in theguidelinesofIUSTIEuropeandEADV (32). summarized are recommendations Treatment (29–31). HIV-positiveindividuals infected in especially strains, buboes, rectal ulcerations are caused by these chlamydia the classical clinical symptoms, with ulcers and inguinal to addition In (28). (Fig. 3) HIV-positivityrate 70% a cases. notified Almost all 2,043 cases were the reported among MSM of with 86% for accounted UK the and ropean countries, out of which France, the Netherlands, reum (LGV). In 2016, LGV data were reported by 22 Eu population. and at the country level, with 150–250 cases per 100,000 European the at both stable, appeared trend overall the young adult women and heterosexuals. Over recent years, among highest be to continue and Europe, across ably Notification rates of chlamydia infections vary consider CHLAMYDIA TRACHOMATIS 246 genotypes LGV1-3, causing the Lymphogranuloma vene A special subgroup of A. Stary Chlamydia trachomatis are the Chlamydia trachomatis. ­ - - - - - . Permission topublish drugs are effective against HSV infections, and are re are and infections, HSV against effective are drugs (HIV-disease).retroviruses Antiviral and B), (hepatitis intraepithelial neoplasia, genital cancer), hepadnaviruses (HPV,warts, genital causing groups low-risk and high- viruses papilloma human herpes), genital (e.g. viruses causing STIs belong to various families, such as herpes Viruses challenge. therapeutic major a represent still amenable to curative treatment, whereas most viral STIs usually are latter the because mainly is infections. This bacterial than rather viral from derives predominantly today health public on STIs of impact major The STIs. bacterial with comparison in STIs, viral in rise steep a high risk of contracting HIV.indi contracting such of infected, risk Once high gonorrhoea or chlamydial infections are at a particularly and/or GUD with patients promiscuous Sexually STIs. course and frequency of HIV infection and that of other delivery.of time the Abetween exists association close at newborn the to infections, brain including problems, serious cause annually.can observed HSV are relapses commended prophylactically if a high number of genital also helptocontrolthespreadofHIV infection. will not only reduce the incidence of these infections, but STIs for programmes treatment and screening of tation HIV transcription. These facts imply that the upregulate implemen viruses different that observation the from accelerate the course of HIV-disease; this can be deduced may Conversely,STIs lesions. genital without persons viduals shed considerably more virus than HIV-infected The 21 The VIRAL SEXUALLY TRANSMITTED INFECTIONS (34–36). and has to be considered in treatment recommendations Europe, in reported is resistance macrolide in increase an However, infections. macrolide-susceptible in 90% For viral STIs, vaccination against Hepatitis B and B Hepatitis against vaccination STIs, viral For st century, in general, has been characterized by characterized been has general, century,in disease (37). Vaccination programmes and modulate the progression of HPV worldwide available are infections against high- and low-risk genital HPV protect Vaccinesmen. to and women in tract genital the in warts genital or cancers other inducing also are pes HPVgenoty low-risk and High- ces. potentially life-threatening consequen most common cervical carcinoma with the cause and cancers, cell squamous central role in the pathogenesis of most several high-risk strains of HPV play a pear to be subclinical or asymptomatic, acquired genital HPV infections ap infections HPV genital acquired of majority the Although 2–16%. is prevalence of high-risk HPV in Europe in the West and Centre of Europe. The HPV has become common, especially ------Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV 14. 13. 12. 11. 10. 18. 17. 16. 15. 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