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PROPIONIBACTERIUM ACNES AND ANTIBIOTIC RESISTANCE – IMPACT ON PUBLIC HEALTH Victor Gabriel Clătici, Ana Maria Veronica Draganita, Dragomir-Ananie Emiliana Teodora, Simona Fica

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Review

Propionibacterium acnes and antibiotic resistance – impact on public health

PROPIONIBACTERIUM ACNES AND ANTIBIOTIC RESISTANCE – IMPACT ON PUBLIC HEALTH PROPIONIBACTERIUM ACNES ȘI REZISTENȚA LA ANTIBIOTICE – IMPACT ASUPRA SĂNĂTĂȚII PUBLICE Victor Gabriel Clătici (1), Ana Maria Veronica Draganita (2), Dragomir-Ananie Emiliana Teodora (3), Simona Fica (4,5) Dermatology Department, ELIAS Emergency Universitary Hospital, Bucharest, Romania; (2) Medical Practice Zimnicea, Romania (3) Endocrinology, diabetes and metabolic disorders, „Dunarea de Jos” University of Galati, Romania (4) Professor, University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania (5) Endocrinology Department, ELIAS Emergency Universitary Hospital, Bucharest, Romania (1)

Corresponding author: Victor Gabriel Clatici, 17 Bd Marasti Street, Sector 1, Bucharest, Phone 021 / 3161600 – 190 / 224, fax 021 / 3173052, E-mail victor.clatici@rojced.com

Open Access Article

Abstract Keywords: acne, Propionibacterium acnes, antibiotic resistance, public health, P acnes resistance to antibiotics

Acne represents a chronic inflammatory disease, very frequent in adult persons and with a big impact on the patient’s quality of life.

Propionibacterium acnes (P acnes) is involved in acne pathogenesis and its eradication requires treatment with antibacterial substances, especially antibiotics.

The use of antibiotics in acne was associated with the development of P acnes resistance to antibiotics and the possibility to transfer the resistance factors to other bacterial species. In this paper we present the main causes responsible for the development of antibiotic resistance and the measures to preventit.

Rezumat Cuvinte-cheie: acnee, Propinibacterium acnes, rezistență la antibiotice, sănătate Cite this article: publică, rezistența la Victor Gabriel Clătici, antibiotice a P acnes, Ana Maria Veronica Draganita, DragomirAnanie Emiliana Teodora , Simona Fica.

Propionibacterium acnes and antibiotic resistance – impact on public health RoJCED 2015; 2(4):242-247

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Acneea reprezintă o afecțiune inflamatorie cronică, frecventă la persoana adultă și asociată cu un important impact negativ asupra calității vieții pacienților. Propionibacterium acnes (P acnes) este implicat în patogenia acneei și necesită un tratament antibacterian, în special cu preparate antibiotice. Utilizarea preparatelor antibiotice în acnee a fost asociată cu posibilitatea dezvoltării rezistenței lui P acnes la antibiotice și cu transferul factorilor de rezistență la alte specii bacteriene. În acest articol prezentăm principalele cauze care au condeus la dezvoltarea rezistenței lui P acnes la antibiotice precum și măsurile care se impun pentru prevenirea instalării rezistenței la antibiotice.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Victor Gabriel Clătici, Ana Maria Veronica Draganita, Dragomir-Ananie Emiliana Teodora , Simona Fica

Introduction Acne is a chronic disease, which requires adherence to the treatment in the long-time management(1,2). Antibiotics represent an important option in acne treatment for many clinicians(3, 4), and because acne has the caracteristics of a ,,chronic disease,,(5,6), the treatment strategy must comprise on a combination of atack treatment and maintenance therapy (7).

Propionibacterium acnes (P. acnes) plays an important role in the pathogenesis of acne vulgaris (8, 9, 10) . P acnes, previously classified as Corynebacterium parvum, has been implicated in the pathogenesis of acne for more than 100 years, starting with Unna (11) in 1896.

Antimicrobial resistance is a major problem and is an important issue to consider in acne treatment (12) and is a significant public health issue (13). The main contributors in the development of antibiotic resistance are the pharmaceutical industry, the agriculture and animal husbandry industry, patients, and healthcare providers (14).

The importance of antibiotic resistance is highlighted by Financial Times (15), respectively ,,With increasing urgency, national and international health authorities are calling for physicians to limit antibiotic use,,.

History of P acnes resistance to antibiotics The development of resistance to antibiotics is a direct results of use and abuse of antibiotics (16), and unfortunately the antibiotics use in acne treatment lacks bacterial specificity and has an important risk to generate resistance to antibiotics bacteria (17).

In the last few decades Propionibacterium acnes (P. acnes) has become resistant to many different antibiotics, making them less efficacious in treating acne (18,19). A paper from 1976 (20) showed that in more than 1000 patients with acne there was no evidence of antibiotic resistant P acnes, and it was believed that P acnes is incapable of developping antibiotic resistance.

But, shortly after the introduction on the market of topical formulations of erythromycin and clindamycin, P. Acnes's resistance to antibiotics was firs noted (21). In 1979, Crawford (22) reported the first indication of resistance to topical antibiotics in acne, and in the eighties P. Acnes was reported to be resistant to tetracycline (23).

Impact of P acnes resistance to antibiotics The most important issues regarding P. Acnes’s resistance to antibiotics are represented by the mechanism of resistance, the prevalence of resistance induction,, the role of topical and systemic antibiotics, and the persistence of resistance after the antibiotics are stopped. In respect of the topical antibiotics, the resistance induced is limited on the treated area but with oral antibiotics, the resistance can develop in all body area (24). The effects of antibiotic resistance of P acnes in patients with acne are represented by a reduction of clinical response to antibiotic therapy, a potential increase

of P acnes pathogenicity and, a multidisciplinary implication, the possibility of resistance transfer to other pathogenic organisms (25).

The presence of P acnes resistant to antibiotics will have an important effect and impact on treatment outcome (26, 27), respectively reduced response or no response or relapse shortly after the treatment (23, 26, 27) Presence of P acnes resistant to clindamycin, erythromycin and cyclines is strong connected with no clinical response or frequently relapses after the treatment (23, 28, 29) According to (30), respectively a systematic review of 50 clinical trials with topical antibiotics, there is a gradual decrease of efficacy of topical erythromycin in acne ( both on inflammatory and non-inflammatory lesions), probably connected with the development of antibiotic resistance of P acnes.

Another problem(31) with P acnes resistance to antibiotics is represented by the implications for other infections, respectively the possibility of transmission of factors conferring resistance to other bacteria(26, 32). Topical or oral antibiotics for acne treatment used for a long period can select or transfer resistant genes to staphylococci and / or streptococci (22, 33) One neglected problem in treating acne patients with antibiotics is represented by the patients’ contacts, respectively Miller et al (34) showed that contacts of acne patients being treated with antibiotics demonstrate significant increased prevalence and density of resistant strains of coagulase-negative Staphylococcus (CNS) compared to those with no contact with acne patients.

This problem can be the direct result of development of resistant coagulase-negative staphylococci (CNS) on both local and distant anatomical sites in patients with acne treated with topical erythromycin (26, 35, 36), and CNS has been shown to transfer resistance to the more pathogenic S. aureus (37).

The modalities of dissemination are represented by person-to-person contact and the spreadding of resistant strains can be carried out by the treatting physician, family or friends(38, 39, 40). An important issue is related with the persistence of antibiotic resistance of P acnes after the antibiotic treatment is stopped, and the data are divergent, respectively some authors suggest that resistant isolates disappear after antibiotic treatment is stopped (41) other data suggest that resistance persists and can be reactivated rapidly (42).

An alarming fact is represented by an increasing number of reports of systemic infections (43) caused by resistant P. acnes in non-acne patients (e.g. post-surgery) and this is another side effects of P acnes resistance to antibiotics.

Factors associated with P acnes resistance to antibiotics The percentage of acne patients carrying P. acnes strains resistant to these antibiotics is increasing worldwide and vary from one region to another (31, 40, 44, 45, 46, 47, 48, 49), and probably the main reasons regarding the differences among different November 2015

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Propionibacterium acnes and antibiotic resistance – impact on public health

countries are connected with the prescription of different antibiotic habits and â „ or different ethnicity of the patients (31).

Countries with higher rates of oral antibiotic use (,,prescribing practice,,) for acne had significantly higher rates of resistance of P acnes (40) and resistance to commonly used antimicrobial drugs is remarkably higher in countries where antibiotics are not restricted (50). Severity of acne and sales of antibiotics are other factors involved in development of P acnes resisteance to antibiotics, respectively resistance is more frequent in patients with moderate-to-severe acne and in countries with high outpatient antibiotic sales (43). About the possibilities of acquiring of antibiotic resistance, the authors describes two modalities: for long time and / or contact with people which already have resistant strains (51, 52) The fact that a lot of patients are are already colonized with resistant P. Acnes before starting any acne therapy, is a valuable proof that resistant strains can be transmissible via humanto-human contact (40), possibly among family and friends. An alarming fact is represented by the existence of resistant strains of P acnes in younger siblings and children of patients with acne (38) and the implication to have resistant strains of P acnes colonizing the face (25 of 39 tested) (40).

Topical erythromycin and topical clindamycin (the most commonly antibiotics used in acne) are the main ,,culprits,, for antibiotic resistance of P acnes (23, 53, 54, 55, 56). Monotherapy with topical antibiotic should be prohibited because resistant P. acnes strains have been shown to emerge after only 8 weeks with the number of resistant strains increasing progressively if the treatment is continued(57). Other factors which can be connected with the possibility of developing the antibiotic resistance are previous treatment (41, 40, 29), the amount of a given antibiotic used (58, 59) and prescribing practices (39, 60). The probability of P acnes resistance increases with the patient’s age, duration of acne, and duration of treatment with topical or systemic antibiotics (31). Ross et al (39) showed that the mechanism involved in erythromycin and clindamycin resistance is connected with four phenotypes with cross-sensitivity to macrolide, lincosamide and streptogramin B (MLS) antibiotics. Genetic mutations occur mainly in 23S rRNA, and strains that possess the erm (X) resistance gene are highly resistant to MLS antibiotics. Mutations in genes encoding 23S and 16S represent the molecular basis of resistance, and are widely distributed(39). In contrast, additional resistant strains without these mutations have also been identified and the mechanisms underlying their reduced antibiotic susceptibility remain to be elucidated (39, 61). Resistance to clindamycin develop in other ways, with the most common being the bacterium changing the binding site (62, 63).

On the other hand, tetracycline resistance is associated with a single G-C transition in the 16 S rRNA of the small ribosomal subunit (64) and there is

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an association between resistance to tetracycline, doxycycline and minocycline(39).

How can we prevent the antibiotic resistance?

The strategies and guidelines for the limitation of antibiotic resistance (38) will change the prescribing practice ( the levels of resistance is strongly correlated with the levels of antibiotic use) and will prevent transfer of resistance factors to other bacteria.

According to 2012 European guidelines, oral antibiotics should be used for inflammatory acne only during the induction phase and then discontinued during a maintenance phase with topical therapy(21). The main objectives of the guidelines are improvement in the care of acne patients, reduction of serious conditions and scarring, promotion of adherence and reduction of antibiotic resistance. Pathogenesis of acne is complex and multifactorial and a combination of different classes of drugs is the best practical approach. The most useful combination, targeting the growth of P acnes inflammation and comedogenesis, is represented by antibiotics WITH retinoids (65-67).

Because the antimicrobials and topical retinoid have complementary mechanisms of action, the combination will have a greater efficacy in reducing number of inflammatory and non-inflammatory lesions compared to monotherapy (68, 69, 70, 71). Another advantage is the fact that patients on combination therapy show faster signs of improvement (72, 73, 74), and the quicker onset of action is connected with better adherence and will reduce the amount of antibiotic exposure and risk of P. Acnes resistance.

We must not forget that poor outcome of treatment may be caused by poor adherence (75, 76).

Rates of adherence with acne treatment are higher in adult females, compared with both males and adolescents (77) and the main factors involved in adherence are patient education, use of combination therapies, patient satisfaction, response to treatment and side-effects. In order to have a better adherence we must simplify treatment regimens, decrease doses per day and number of medications used, use medication reminders, following up by phone, encourage patients to join support groups and educate patients during the consultations (78, 79). Benzoyl peroxide (BPO) has been used since the 1930s due to its antibacterial, keratolytic, and comedolytic properties (80, 14) and is a broadspectrum antibacterial agent that comes in many formulations and works through the interaction of oxidized intermediates with various constituents of microbial cells (81). Very important, until now (despite its widespread use) bacterial resistance has not been reported. Topical benzoyl peroxide or azelaic acid may be added to antibiotic therapy to reduce the potential for developing P. acnes resistance (55). The combination benzoyl peroxide plus a topical retinoid is often used in conjunction with antibiotics to prevent or eliminate the development of antibiotic-resistant P. acnes (82). The combination of BPO with clindamycin or erythromycin

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Victor Gabriel Clătici, Ana Maria Veronica Draganita, Dragomir-Ananie Emiliana Teodora , Simona Fica

is more effective than monotherapy at reducing P. Acnes growth (83, 84) and decreases the risk of resistance (85, 57), and the washing with products containing BPO effectively reduces P. acnes, (55, 86) including resistant populations (87). BPO and systemic antibiotics should be used in combination with a topical retinoid, since retinoids target acne precursor lesions (microcomedones) and have a significant effect on comedones (55).

Retinoids do not contribute to antibiotic resistance and are a part of eco-responsible acne treatment (55, 38, 88). Combination therapy involving a topical retinoid plus an antimicrobial is the recommended first-line approach and numerous clinical studies showing improved efficacy of this approach (38, 55). By tailoring the choice of antimicrobial and duration of antibiotic use, the combination topical retinoid plus an antimicrobial can be used for almost all patients with acne, providing results that are faster and superior to antibiotic therapy alone(4, 55). Combination therapy is likely to have a more significant effect because it targets 3 major areas of acne pathophysiology: P. acnes proliferation, inflammation, and hyperkeratinization (55), and topical retinoids are also first-line agents for maintenance therapy (38). Combination therapy aimed at eradicating P. acnes, normalizing the abnormal desquamation of the follicular epithelium, thereby eliminating the environment that supports bacterial proliferation, and controlling the formation of the microcomedo which in turn will prevent formation of new inflammatory acne lesions and comedones(89). Current recommendations also include limiting the duration of systemic antibiotic use, avoiding the use of topical and systemic antibiotics together, adding BPO to retard emergence of resistant bacteria, including a topical retinoid to improve outcomes and using topical retinoids for maintenance therapy adding BPO if needed (38). ,,The Global Alliance to Improve Outcome in Acne Group recommended the following strategies to limit the development of resistance of P. acnes which included: (1) combine a topical retinoid plus an antimicrobial; (2) limit the use of antibiotics to short periods and discontinue when there is no further improvement or the improvement is only slight; (3) co-prescribe a benzoyl peroxide-containing product or use as washout; (4) oral and topical antibiotics should not be used as monotherapy; (5) concurrent use of oral and topical antibiotics should be avoided, particularly if chemically different; (6) do not switch antibiotics without adequate justification; (7) use topical retinoids for maintenance therapy, with benzoyl peroxide added for an antimicrobial effect if needed; (8) avoid use of antibiotics for maintenance therapy.,,(38).

The current consensus is that topical antibiotics alone should not be used as monotherapy in acne

because of their relatively slow onset of action and their potential for causing bacterial resistance (55).

The duration of antibiotic therapy and its effects have not been widely studied (27, 90, 91, 92, 93), and a consensus group suggested limiting the duration of oral antibiotics (55) (oral antibiotics will be used for 3 months and then discontinued when there is good clinical improvement) and that this ‘‘acute’’ treatment must be sustained by topical maintenance therapy (38) . Other recommendations of recently published guidelines suggest that the duration of antibiotic therapy can be limited to 3 to 6 months (21, 82, 94, 95).

Other recommendations in order to prevent development of antibiotic resistance include stricter crossinfection control measures when assessing acne in the clinic and combining any topical ⁄ systemic antibiotic therapy with broad-spectrum antibacterial agents, such as BPO (38, 40, 96).

Conclusions Success against antimicrobial resistance requires an interdisciplinary approach, with increased microbial surveillance, judicious use of antimicrobials not only in human medicine but in agriculture and animal husbandry also, increased research on the biology of microbes and mechanisms of resistance; development of novel antibiotics and vaccines as well as rapid, point-of-care diagnostics; and, most importantly alteration of old prescribing habits (14, 97). Acne lesions typically recur for years, and so acne is nowadays considered to be a chronic disease(1), and the correct approach is atack therapy followed by maintenance therapy.

Maintenance therapy can be defined as the regular use of appropriate therapeutic agents to ensure that acne remains in remission (21). For a successful long-term treatment, any acne maintenance therapy must be tolerable, appropriate for the patient’s lifestyle and convenient. The natural history of acne suggests that maintenance therapy should continue over a period of months to years depending upon the patient’s age (21). Therapy is therefore tailored to the individual patient depending on the nature and severity of their acne (98, 99). In the present era of increasing antibiotic-resistance, it is essential that dermatologists and family physicians treating acne patients be vigilant in prescribing antibiotics (31) and all patients should be informed about the specific risks associated with any given topical and ⁄ or systemic therapy(21).

Aknowledgement This paper is supported by the Sectorial Operational Programme Human Resources Development (SOP HRD), financed from the European Social Fund and by Romanian Government under the contract number POSDRU/159/1.5/S/137390.

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27 Ozolins M, Eady EA, Avery AJ, Cunliffe WJ, Po AI, O’Neill C, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomized controlled trial. Lancet 2004; 364:2188-95.

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51. Eady AE, Cove JH, Layton AM. Is antibiotic resistance in cutaneous propionibacteria clinically relevant?: implications of resistance for acne patients and prescribers. Am J Clin Dermatol 2003; 4: 813–831.

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54. Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol. 1989 Jul;121(1):51–7.

55. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003 Jul;49(1 Suppl):S1–37.

56. Leyden JJ, Preston N, Osborn C, et al. In-vivo effectiveness of adapalene 0.1%/benzoyl peroxide 2.5% gel on antibiotic-sensitive and resistant Propionibacterium acnes. J Clin Aesthet Dermatol. 2011 May;4(5):22–6.

57. Cunliffe WJ, Holland KT, Bojar R, et al. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther. 2002 Jul;24(7):1117–33.

58.Wolff MJ. Use and misuse of antibiotics in Latin America. Clin Infec Dis. 1993;17(2):5346–5351.

59. Lee HY, Liu G, Thiboutot D, Leslie DL, Kirby JS, A retrospective analysis of the duration of oral antibiotic therapy for the treatment of acne among adolescents: Investigating practice gaps and potential cost-savings. J Am Acad Dermatol 2014;71:70-6 60. Cars O, Molstad S, Melander A. Variation in antibiotic use in the European Union. Lancet 2001;357:1851-3.

61. Leydenn JJ Current issues in antimicrobial therapy for the treatment of acne .

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63. Gasbarre Christopher C, Schmitt Steven K, Tomecki Kenneth J. “Chapter 231.

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64. Ross JI, Eady EA, Cove JH et al. 16S rRNA mutation associated with tetracycline resistance in a gram-positive bacterium. Antimicrob Agents Chemother 1998; 42: 1702–1705.

65. Bergfeld WF. Topical retinoids in the management of acne vulgaris. J Drug Dev Clin Pract 1996;8:151-60.

66. Weiss JS. Current options for the topical treatment of acne vulgaris. Pediatr Dermatol 1997;14:480-8.

67. Webster GF.Topical tretinoin in acne therapy. J Am Acad Dermatol 1998;39 (2 Pt 3):S38-44.

68. Leyden, J.J., L. Krochmal, and A. Yaroshinsky, Two randomized, double-blind, controlled trials of 2219 subjects to compare the combination clindamycin/tretinoin hydrogel with each agentaloneandvehicleforthetreatmentof acnevulgaris.JAmAcadDermatol,2006.54(1):p.73–81.

69. Mills, O.H., Jr. and A.M. Kligman, Treatment of acne vulgaris with topically applied erythromycin and tretinoin. Acta Derm Venereol, 1978. 58(6): p. 555–7.

70. Tanghetti, E., et al., Tazarotene versus tazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris: a multicenter, double-blind, randomized parallel-group trial.

J Drugs Dermatol, 2006. 5(3): p. 256–61.

71. Eichenfield, L.F. and M. Wortzman, A novel gel formulation of 0.25% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years. Pediatr Dermatol, 2009. 26(3): p. 257–61.

72. Thiboutot, D.M., et al., Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol, 2007. 57(5): p. 791–9.

73. Wolf, J.E., Jr., et al., Efficacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin: a multicenter, randomized, investigator-blinded study. J Am Acad Dermatol, 2003. 49(3 Suppl): p. S211–7.

74. Gold, L.S., et al., A North American study of adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis, 2009. 84(2): p. 110–6.

75. Yentzer BA, Alikhan A, Teuschler H, et al. An exploratory study of adherence to topical benzoyl peroxide in patients with acne vulgaris. J Am Acad Dermatol. 2009;60:879-880.

76. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: Scientific review. JAMA. 2002;288:2868-2879.

77.Thomas B,Tan JKL.Adherence optimization in acne management. Skin Ther Lett 2011; 7: 1–3.

78. Lucero M, Bendeck S, Ramos-Ceballos F, et al. Language disparities between patients and dermatologists in describing acne lesions. J Am Acad Dermatol. 2007;56:268-273.

79. Koo J. How do you foster medication adherence for better acne vulgaris management?

Skinmed. 2003;2:229-233.

80. Mareledwane NG. A randomized, open-label, comparative study of oral doxycycline 100 mg vs. 5% topical benzoyl peroxide in the treatment of mild to moderate acne vulgaris. Int J Dermatol. 2006 Dec;45(12):1438–9.

81. Eady EA, Farmery MR, Ross JI, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and -resistant skin bacteria from acne patients. Br J Dermatol. 1994 Sep;131(3):331–6.

82. Zaenglein AL, Thiboutot DM. Expert committee recommen- dations for acne management.

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84. Leyden, J., K. Kaidbey, and S.F. Levy, The combination formulation of clindamycin 1% plus benzoyl peroxide 5% versus 3 different formulations of topical clindamycin alone in the reduction of Propionibacterium acnes. An in vivo comparative study. Am J Clin Dermatol, 2001. 2(4): p. 263–6.

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92. Poulin Y, Sanchez NP, Bucko A, Fowler J, Jarratt M, Kempers S, et al. A 6-month maintenance therapy with adapalene- benzoyl peroxide gel prevents relapse and continuously improves efficacy among patients with severe acne vulgaris: results of a randomized controlled trial. Br J Dermatol 2011; 164:1376-82.

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SKIN AND SOFT TISSUE INFECTIONS: MICROBIOLOGY AND EVIDENCE BASED ANTIBIOTIC THERAPY INFECŢII CUTANATE ŞI ALE ŢESUTULUI SUBCUTANAT: MICROBIOLOGIE ŞI TERAPIE ANTIBIOTICĂ BAZATĂ PE DOVEZI Laura Maria Lucia Papagheorghe1, Mihai Lupu1, Andra Georgiana Pehoiu1, Vlad Mihai Voiculescu1, Raluca Papagheorghe2 2.

1.

Department of Dermatology, Elias University Emergency Hospital, Bucharest, Romania Microbiology Department, Central Laboratory, Colţea Clinical Hospital, Bucharest, Romania

Corresponding author: Laura Papagheorghe, 17 Mărăşti street, sector 1, Bucharest Phone 021/316 1600 - 190/224, fax: 021/317 3052 E-mail: laura.papagheorghe@gmail.com

Open Access Article

Abstract Keywords: SSTIs, microorganisms, virulence factors, antibiotic therapy

Skin and soft tissue infections are a frequent reason to address the dermatologist’s office. Their evolution depends both on the patients’ comorbidities and on the pathogenicity of the infecting microorganism. The antibiotic therapy is the core of the treatment.

Its success is the result of the co-operation between clinician and microbiologist. Well tailored initial therapy, guided by local flora and the Gram smear data may enhance success and reduce complications.

Rezumat Cuvinte-cheie:

Cite this article: Laura Maria Lucia Papagheorghe, Mihai Lupu, Andra Georgiana Pehoiu, Vlad Mihai Voiculescu, Raluca Papagheorghe.

Skin and soft tissue infections: microbiology and evidence based antibiotic therapy RoJCED 2015; 2(4):248-253

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Infecţii cutanate şi ale ţesutului subcutanat, microorganisme, factori de virulenţă, terapie antibiotică

Infecţiile cutanate şi cele ale ţesutului subcutanat sunt un motiv frecvent de adresare a pacienţilor la cabinetul medicului dermatolog.

Evoluţia acestor infecţii depinde atât de comorbidităţile pacienţilor cât şi de patogenicitatea agentului infecţios. Terapia antibiotică este esenţa tratamentului. Succesul acesteia este rezultatul cooperării dintre clinician şi microbiolog. O terapie iniţială adaptată corect, ghidată de flora locală şi coloraţia Gram, poate creşte şansele de succes terapeutic şi poate reduce complicaţiile.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Laura Maria Lucia Papagheorghe, Mihai Lupu, Andra Georgiana Pehoiu,Vlad Mihai Voiculescu, Raluca Papagheorghe

Epidemiology Skin and soft tissue infections (SSTIs) are a border pathology. Their management may yield medical co-operation among several specialties. In USA 14 million patients address for SSTIs yearly and their number is increasing, both in inpatient (29% from 2000 to 2004) and outpatient settings, as well as in the emergency room (ER). [1] SSTIs are a burden to the healthcare systems; they are incompletely studied and necessary care resources are yet unknown. Rare epidemiological studies [2-5] show the increasing prevalence and augmented interest of the scientific medical community towards this pathology.

Etiology and pathogenicity SSTIs have different degrees of severity, ranging from mild to life-threatening; they present with or without complications, but the common feature is the need to diagnose the infecting microorganism(s). The most common are staphylococci, with Staphylococcus aureus being the main infective agent. Pseudomonas aeruginosa is the second most frequent pathogen. Gram negative bacilli belonging to the genus Enterobactericeae are third most common, together with enterococci and other streptococci. Coagulase negative staphylococci (CoNSs) are controversial as pathogens.

Figure 1. Staphylococcus spp (Photo library of Dr. Raluca Papagheorghe)

[6, 7]

Pathogenicity of S. aureus and CoNS Staphylococcus spp. (Figure 1) colonize the anterior nose of mammals and may be a contaminant as well as a pathogen in SSTIs. However, when obtained in a culture from a SSTI, it is usually a pathogen. Moreover, patients tend to develop infections with own flora, outside epidemiologically confirmed nosocomial infections.[8, 9] 20-30% of normal people shelter MRSA - meticillin resistant S. aureus strains. [10] Six categories of factors contribute to infection and to evasion of host defense mechanisms; each is encoded by specific genetic elements. The pathogencity of different strains varies according to the clonal type or to the genetic expression of virulence factors; little is known of their expression during infection.[11] 1. Adhesion factors: Surface proteins adhere to various cellular structures, thus enabling the microorganism to enter the endothelial cell. It initiates endovascular infections and may persist in the endothelial cell. Thus it may account for chronic or recurrent infections with the same strain. Adherence molecules (MSCRAMMmicrobial surface components recognizing adhesive matrix molecules) enable staphylococci to bind to vascular devices. Protein A (Spa) belongs to the MSCRAMM family because it binds to the von Willebrand factor, a large glycoprotein that mediates platelet adhesion to the damaged endothelial cell. Spa displays several additional properties: it interferes with immunoglobulin-mediated opsonization, it mimics a B-cell superantigen and it binds to TNF-R1. These proteins also adhere to

Figure 2. Pseudomonas aeruginosa (Photo

library of Dr. Raluca Papagheorghe)

vascular catheters and prosthetic valves. The binding to the endothelial cell enables a phagocytosislike internalization process that favors the intracellular persistence of the staphylococci [12, 13] 2. Persistence factors: Polysaccharide production, intercellular adhesion, small-colony variants, and intracellular persistence contribute to biofilm formation. Cells belonging to the biofilm community have a different metabolism and a different antibiotic susceptibility from the planktonic cells recovered from cultures.

Therefore, antibiotic therapy (ATB) schemes remain ineffective in patients having intracorporeal devices with biofilm.[14, 15] 3. Evading/destroying host defenses: Leukocidins (e.g., Panton- Valentine (PVL) and gtoxin), capsular polysaccharides (e.g. protein A) Invasive skin infections and necrotizing pneumonia produced by community acquired methicillin resistant S. aureus (CA-MRSA) strains are often associated with PVL, abscesses are associated with capsular polysaccharides.

4. Tissue invasion/penetration enzymes: proteases, lipases, nucleases, hyaluronate lyase, phosNovember 2015

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Table 1. Examples of broad spectrum ATBs and the possible permissive effect Broad spectrum ATB

Microorganisms able to survive by permissive effect

Comments

Cephalosporin’s and carbapenems

Enterococci

Enterococci are naturally resistant to cephalosporins

Second and third generation cephalosporins

Extended Spectrum betalactamases (ESBL) producing Gram (-) bacilli

Resistant to all betalactams, except carbapenems and betalactamase inhibitors (clavulanic acid, sulbactam, tazobactam )

Third generation fluoroquinolones All anti Pseudomonas antibiotics (Ex: anti pseudomonas carbapenems, piperacillin, ticarcillin, colistin)

Multidrug resistant P. aeruginosa (MDR-PA) and Acinetobacter spp.

Currently, many species are MDR, susceptible only to colistin. This is the last resource antibiotic against Gram (-) bacilli. [30]

Glicopeptides and oxazolidinones

Vancomycine resistant enterococci (VRE) Resistant S. aureus (Vancomycine inhibitory S. aureus) and CoNS [31]

Although ATB options are available against

All ATBs

Clostridium difficile

Clinical manifestations of C. difficile infection require infectious diseases specialist’s opinion.

pholipase C, and metalloproteases (elastase) are encoded by separate genetic determinants (V8, hysA, hla, plc, sepA) causing tissue destruction and metastatic infections. [16] 5. Toxin-mediated disease and/or sepsis: Enterotoxins, toxic shock syndrome toxin-1, exfoliative toxins A and B, a-toxin, peptidoglycan, and lipoteichoic acid, food poisoning, toxic shock syndrome, scalded skin syndrome, bullous impetigo, and sepsis syndrome.

6. With poorly defined role in virulence: coagulase and bacteriocin [16] The pathogenicity of the S. epidermidis (CoNS) strains is related to the resistance to antimicrobial agents, to the production of invasins and the formation of biofilm. The resistance to oxacillin is high, almost 80% in some studies. Lipase activity has contributed to the ability of invading the dermal-epidermal tissue; the proteolytic activity plays a proven role in tissue destruction and the inflammatory response of the host. Adhesins which facilitate the formation of biofilms have also been related to the proliferation of S. epidermidis on the surface of the intravascular catheters and implants and have been involved in tissue invasion.

Methicillin resistance in Staphylococci strains renders supplemental difficulty to therapeutic ATB schemes. MRSA are more virulent than MSSA. Methicillin resistant CoNS act as reservoir of resistance determinants.[17, 18]

Pathogenicity of Gram negative bacilli (Enterobactericeae and P. aeruginosa) The common pathogenicity factor is the endotoxin, from the bacterial cell wall. It is a deadly structure because it triggers septic shock. Its pathogenic activity is identical, regardless of the bacterial origin. It consists essentially of the injury of the vascular endothelium and the activation of cellular and humoral immune factors, of which the by-passing complement activation plays a key role. The lipopolysaccharide (LPS) in the endo-

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toxin structure attaches to the circulating proteins (LPS-binding protein), and the formed complex is bound to a specific receptor (CD14) on monocytes, macrophages and neutrophils. A lipid component (Lipid A) and a common polysaccharide complex (core) represent the toxic part of the endotoxin macromolecule which together with the specific polysaccharides determines the structure of O antigen (somatic), a basic constituent of the wall of the Gram-negative bacteria (both bacilli and cocci). The stimulation of CD14 lymphocytes (even with low doses of 10 pg/mL) generates intracellular signals via a related receptor, “Toll-like receptor”, protein 4 (TLR-4), leading to the activation of the mononuclears and the production of a strong cytokine: IL-1 and tumor necrosis factor (TNF). They act on the endothelial cell and cause various effects, including decreasing synthesis of anticoagulant factors. The effects of cytokines are amplified by the activity of TLR-4 on the endothelial cells. The activity of TLR triggers actions of the complement system by means of by-pass activation. [19, 20] In addition to the endotoxinic factor, the exotoxins, capsular polysaccharides, cilia can add to the virulence activation in some species, the latter playing a role in the attachment to and colonization of the host cell. P. aeruginosa (Figure 2) is a nosocomial pathogen, unlike the other agents discussed.

The first step in the P. aeruginosa infection is the colonization. Normally, 3-6% of the people can be P. aeruginosa carriers; in hospitalized patients the carrying ratio increases to 50%. In P. aeruginosa the virulence usually occurs after a substantial break of the first-line defense barriers (trauma, surgery, burns, intracorporeal systems implanting), imbalances of the normal flora of the mucous membranes as a result of the broad-spectrum antibiotic treatment or of the impairment of immunological mechanisms (in neutropenia). [21] The exotoxic factors secreted by P. aeruginosa can add to the aggressive virulence equipment.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Laura Maria Lucia Papagheorghe, Mihai Lupu, Andra Georgiana Pehoiu,Vlad Mihai Voiculescu, Raluca Papagheorghe

Figure 3. Enterobacteriaceae (Photo library of Dr. Raluca Papagheorghe)

mExotoxin A is produced by most clinical isolates; it determines the inhibition of protein synthesis. It causes local tissue damage, invasiveness and could cause even immunosuppression (inhibits the response of the macrophages). mProteases play a major role in producing infections. The proteolytic capacity of P. aeruginosa is a major determinant of virulence in acute infections.

Elastin, a major compound of blood vessels, is destroyed. mLPS (has the same role as in other Gram-negative bacilli) causes sepsis mLeukocidin inhibits the lymphocytes and neutrophils function. mPyocyanins inhibit other bacteria, cause oxidative damage to the tissues, particularly the oxygenated tissues, such as the skin and lung.

Capsule production: high molecular weight polysaccharides, recovered in strains isolated from clinical samples. This is one of the major virulence factors meant to evade clearance from an infectious site.

The capsule provides bacteria with protection from the host immune response as well as antibiotics, by not allowing opsonizing antibodies to be recognized by phagocytic host defense cells. This enhances inflammatory response in their effort to clear the microorganism.[22] Although multi-drug resistance (MDR) is not a virulence factor per se, it “protects� bacterial colonization, indirectly contributing to the activation of the pathogenesis of Gram-negative bacilli. P. aeruginosa acts as reservoir of resistance determinants for other Gram negative bacilli. The association with an immunosuppressant background often creates catastrophic circumstances. [23]

Pathogenesis of enterococci spp infections Enterococci (Figure 3) are a group with reduced or incompletely understood intrinsic virulence.

Several virulence factors have been reported: - The AS substance (aggregation substance) responsible for the adherence, internalization and intracellular survival,

Figure 4. Streptococcus spp (Photo library of Dr. Raluca Papagheorghe)

- The biofilm-producing ESP substance, especially in the strains of the urinary tract infections.

- The pili are responsible for the adhesion and biofilm production. mGelatinase (GelE) is a zinc-dependent extracellular metalloendopeptidase secreted by E. faecalis which has characteristics similar to those of elastase in P. aeruginosa; GelE can hydrolyze gelatin, casein, hemoglobin and other bioactive peptides, which makes it a potential virulence factor in enterococci. mCytolysin has hemolytic activity on the human red blood cells and bactericidal activity on other Gram-positive bacteria.

The pathogenicity of the enterococci is especially connected to the multi-drug resistance expression. The resistance to vancomycin is the hardest situation to overcome during treatment.[24]

Pathogenicity of β-hemolytic streptococci The most important pathogen in this group is Streptococcus pyogenes or Group A streptococcus (SHA) (Figure 4).

It produces necrotizing fasciitis, abscesses as well as immune diseases (glomerulonephritis, cardiac and neurologic long term complications).

Group B, C, G, and F are less virulent; they accompany S. aureus in most lesions. Pathogenic factors of SHA are better described, as a result of the severe evolution of infections.

It produces an extracellular invasion by braking down the barriers of a tissue and disseminates within the host while remaining outside of host cells. SHA produces enzymes with citolytic effect that cleaves proteoglycans in connective tissue, breaks down fibrin clots, degrades accumulated host oils, and digests released RNA and DNA. Haemolysins (which punch holes in host cells) expressed by these species destroys erythrocytes and other cell types as well and may also contribute to their spread in host tissues.

Extracellular invasion allows these pathogens access to niches in tissues where they are able to November 2015

251

Review

Skin and soft tissue infections: microbiology and evidence based antibiotic therapy

proliferate, disseminate to other sites in the body, express toxins, and initiate inflammatory responses. [25]

Microbiology findings Sample collection Clinical manifestations of infection such as local redness, lymphangitic spread, swelling rapid progression of lesions and bullae, crepitus, are signs of increased severity. Systemic inflammatory response (SIRS): temperature >38°C or 24 breaths per minute, tachycardia >90 beats per minute, or white blood cell count >12 000 associated with C reactive protein >5 ng/dl and positive procalcitonin test may yield for an invasive infection. In these cases, blood cultures (BC) and biochemical evaluation are needed. BC are necessary when there are manifestations of lymphedema, immune deficiency, fever, pain out of proportion to the findings on examination, tachycardia, or hypotension, especially in patients with infections involving specific anatomic sites, such as the mouth and eyes.

Whenever lesions require incision and drainage or with spontaneously draining purulent fluid, carbuncles, furuncles, boils, cellulitis with purulent drainage, chronic ulcer, and deep wounds, the preferred method is puss aspiration.

The main difficulty in the microbiology of SSTIs is the ability to differentiate a contaminant from an infective agent. Communication with the laboratory regarding the most appropriate sampling mode, a smear from aspirated puss and/or clinical data are of great use.

Gram Stain and cultures Easy to perform and cost effective, these investigations are recommended for impetigo and ecthyma. They are intended to help identify SHA, to estimate the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score [26] and evaluate glomerulonephritis risk.

Furthermore, cultures assess the presence of Staphylococcus and aim to determine MRSA. Blood cultures (BC) are recommended (strong, moderate), and cultures and microscopic examination of cutaneous aspirates, biopsies, or swabs should be considered in patients with malignancy on chemotherapy, neutropenia, severe cell-mediated immunodeficiency, immersion injuries, and animal bites (weak, moderate).

In pyomyositis BC are recommended (strong, moderate), along with abscess cultures. [27] In erysipelas and cellulites cultures are not recommended. Microbiological report of a gram smear should be able to communicate the presumable infective agent, staphylococcus spp, streptococci Gram (-) bacilli (with differentiation of Enterobacteriaceae from other species), or fungi. It should describe the presence of leukocytes and their report with the microorganisms (intra or extracellular). In figure 1 we show one aspect of staphylococcal infection.

252

Antibiotic treatment Antibiotic therapy is dictated by the patient’s clinical appearance. The empiric therapy may be guided by international guidelines.[28] The initial therapy is based on local data of antibiotic susceptibility of circulating microorganisms (annual cumulative reports of SSTI pathogens and their susceptibility). Both these therapeutic approaches are life-saving in many situations. However, the latter spares last resource ATBs, by addressing the local pathology. The more appropriate the ATB therapy, the best therapeutic success.

After the complete microbiological report is received, de-escalation therapy is applicable. Thus, the patients will receive a more appropriate agent, with the narrowest activity specter.

The nature of ATB treatment prior to the sample collection is useful information. It enables the rationale of the permissive effect. [29] Treatment with a broad spectrum ATB (i.e. following the guidelines), kills all susceptible microorganisms. This will enable the survival and multiplication of naturally resistant species. Pathogenic or not, will be able to colonize necrotic tissue and/ or produce infections in immunocompromised patients. In table 1 we show some examples of broad spectrum ATBs and the possible permissive effect.

The need of ATB therapy is the dermatologist’s option.

However, many specialists tend to give too much credit to this therapy. Sometimes it is overused unnecessarily in SSTIs contributing to MDR pathogens. Low resource settings, scarce microbiological availability, high prevalence of SSTIs and insufficient study and communication among specialists are only some reasons to overuse ATBs.

Conclusions The algorithm of diagnosis and treatment of SSTIs differs very little from that of other infections.

This paper enhances three important aspects of dermatology in the era of multidrug resistant microorganisms: - the patient outcome may be improved as a result of effective communication between the microbiology laboratory and the dermatologist; - local studies of SSTIs pathogens and their annual susceptibility contributes both to the therapeutic success and to the practice of sparing last resource ATBs. Preservation of skin microbiome is an important factor of local homeostasis.

- molecular biology findings explain the gravity of persistent and recurrent infections.

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Laura Maria Lucia Papagheorghe, Mihai Lupu, Andra Georgiana Pehoiu,Vlad Mihai Voiculescu, Raluca Papagheorghe

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7.Ray GT, S.J., Baxter R, Trends and characteristics of culture-confirmed staphylococcus aureus infections in a large U.S. Integrated health care organization. J Clin Microbiol 2012. 50: p.

1950–1957.

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10.Wertheim HF, M.D., Vos MC, et al. , The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis, 2005. 5: p. 751–62.

11.Peacock SJ, M.C., Justice A, et al., Virulent combinations of adhesin and toxin genes in natural populations of Staphylococcus aureus. Infect Immun, 2002. 70: p. 4987–96.

12.Chifiriuc, M.C., Lixandru, M., Iordache, C,. Bleotu, C., Larion, C., Israil, A.M. , Internalization of Staphylococcus aureus and Pseudomonas aeruginosa bacterial cells by non-phagocytic, epithelial human cells Romanian biotechnological letters, 2008. 13, number 2.

13.Krut, O., Sommer, H., and Krönke, M., Antibiotic-induced persistence of cytotoxic Staphylococcus aureus in non-phagocytic cells. Journal of Antimicrobial Chemotherapy, 2004. 53: p. 167–173.

14.Costerton J W, G.G.G.C.K.-J., How bacteria stick. Sci. Amer, 1978. 238(1): p. 86-95.

15.Mihai, A., Balotescu-Chifiriuc, C., Lazăr, V., Stănescu, R., Burlibașa, M., Ispas, D. C., Microbial biofilms in dental medicine in reference to implanto-prostethic rehabilitation. Rev. chir. oromaxilo-fac. implantol, 2012. 1(1).

16.Gordon, R., Lowy, D, Pathogenesis of Methicillin-Resistant Staphylococcus aureus Infection Clinical Infectious Diseases, 2008. 46: p. 350–9.

17.Michelim, L., Lahude, M et all, Pathogenicity Factors And Antimicrobial Resistance Of Staphylococcus Epidermidis Associated With Nosocomial Infections Occurring In Intensive Care Units. Brazilian Journal of Microbiology, 2005. 36: p. 17-23.

18.Yu, F., Yunling Liu, Y et all, Antimicrobial susceptibility, virulence determinant carriage and molecular characteristics of Staphylococcus aureus isolates associated with skin and soft tissue infections. Brazilian Journal of Infectious Diseases, 2015.

19.Winn, W.J., Allen, S. et all, Koneman’s Color Atlas And Textbook of Diagnostic Microbiology.

Sixth Edition, ed. E.W. Koneman. 2006: Lippincott Williams&Wilkins.

20.Buiuc, D., Negut, M., Tratat de microbiologie clinica. Editia a II-a. 2008, Editura medicală Bucureşti 21.Peleg, Y.A.a.H., C.D, Hospital-Acquired Infections Due to Gram negative Bacteria N Engl J Med 2010. 362: p. 1804-1813.

22.J W Wilson, M.J.S., C L LeBlanc, R Ramamurthy, K L Buchanan, C A Nickerson, Mechanisms of bacterial pathogenicity. Postgrad Med J, 2002. 78: p. 216-224.

23.Aloush, V., Navon-Venezia, S., Seigman-Igra, Y., Cabili, S., Carmeli, Y., Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob. Agents Chemother, 2006. 50: p. 43-48.

24.Jett, B.e.a., Virulence of Enterococci Clinical Microbiology Reviews, 1994. 7(4): p. 462-478.

25.Cleary P, C.D., High frequency invasion of mammalian cells by b hemolytic streptococci.

Subcell Biochem, 2000. 33: p. 137–66.

26.Wong CH, K.L., Heng KS, Tan KC, Low CO, The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med, 2004. 32: p. 1535–1541.

27.Stevens, D., Bisno, L et all Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America IDSA Practice Guidelines for SSTIs, 2014. 59: p. 149-150.

28.IDSA. Infectious Diseases Society of America. Practice Guidelines 2015.

29.Karam, G., Understanding trends in antibiotic resistance: focus on the hospital environment. Proceedings, 2004. 4(4A): p. 262-268.

30.Papagheorghe, R., Angelescu, N., Sparing anti pseudomonas antibiotics in intraabdominal infections. Surgery, 2012. 107(4).

31.Ma XX, W.E., Liu Y, Luo EJ, Antibiotic susceptibility of coagulase-negative staphylococci (CoNS): emergence of teicoplanin-non-susceptible CoNS strains with inducible resistance to vancomycin. J Med Microbiol, 2011. 60(11): p. 1661-8.

November 2015

253

Case Presentation

Psoriasis and vitiligo: four clinical cases.

PSORIASIS AND VITILIGO: FOUR CLINICAL CASES PSORIAZIS ȘI VITILIGO: PATRU CAZURI CLINICE Virgil Pătrașcu1, Raluca Ciurea2, Florentina Delcea3 Dermatology Department, University of Medicine and Pharmacy Craiova 2.

Pathology Department, University of Medicine and Pharmacy Craiova 3.

Emergency County Hospital, Craiova, Dermatology Department

1.

Corresponding author: Virgil Pătrașcu, Professor, MD, PhD, University of Medicine and Pharmacy from Craiova, Petru Rares Street, No 2-4, 200345; phone 004-0724273676; e-mail: vm.patrascu@gmail.com.

Open Access Article

Abstract Keywords: psoriasis, vitiligo, etiopathogenic interferences.

Psoriasis and vitiligo are two diseases frequently encountered in dermatological practice. The first case of psoriasis associated with vitiligo was described in 1955 by Selenyi.

We studied four patients (two males, two females), aged between 34 and 72 years old, who were diagnosed with vitiligo and psoriasis.

The diagnosis of vitiligo was made based on the clinical aspects.

Psoriasis was diagnosed using clinical and histopathological exams.

We calculated PASI, DLQI, VASI scores for each patient, in order to assess the seriousness for both conditions. For each patient we performed biological investigations to analyse the comorbidities and, in one of the cases, we used them so that we could monitor the biological therapy. We encountered the following clinical cases of psoriasis: plaque psoriasis (three cases) and guttate psoriasis (one case). All of the four cases that we studied presented non-segmental vitiligo. Considering the four cases we underline the etiopathogenic interferences, aspects which suggest that the association of the two diseases does not seem coincidental.

Rezumat Cuvinte-cheie: psoriazis, vitiligo, interferențe etipatogenice.

Cite this article: Virgil Pătrașcu, Raluca Ciurea, Florentina Delcea.

Psoriasis and vitiligo: four clinical cases.

RoJCED 2015; 2(4):254-258

254

Psoriazisul și vitiligo sunt două afecțiuni frecvent întâlnite în practica dermatologică. Primul caz de psoriazis asociat cu vitiligo a fost descris în anul 1955 de către Selenyi.

Am studiat patru bolnavi (2 femei, 2 bărbați), cu vârste cuprinse între 34 și 72 ani, care prezentau vitiligo și psoriazis. Diagnosticul de vitiligo a fost stabilit pe baza aspectului clinic. Psoriazisul a fost diagnosticat prin examen clinic și histopatologic. Am calculat scorurile PASI, DLQI, VASI la fiecare pacient pentru aprecierea severității celor două afecțiuni. La fiecare bolnav am efectuat investigațiile biologice în vederea precizării comorbidităților și la un singur caz pentru monitorizarea terapiei biologice. Am întâlnit următoarele forme clinice de psoriazis: psoriazis în plăci și placarde (trei cazuri) și psoriazis gutat (un caz). Toate cele patru cazuri studiate de noi au prezentat vitiligo non-segmental.

Pornind de la cele patru cazuri scoatem în evidență interferențele etiopatogenice, aspecte care sugerează că asocierea celor două boli nu pare întâmplătoare.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Virgil Pătrașcu, Raluca Ciurea, Florentina Delcea

Introduction Psoriasis and vitiligo are two frequently encountered conditions in the dermatological practice.

The worldwide psoriasis incidence in the general population is 1-3% and the one for vitiligo is situated between 0,5-1%. The first case of vitiligo associated with psoriasis has been described in 1955

by Selenyi(1). In 1989, Menter et al. (2) described the first case of guttate psoriasis associated with vitiligo, and Dahar and Malak described in 1998 the association of these two conditions for a boy aged 9 years old (3). Within this article, we present the observations made on four patients, where the two skin conditions coexist. On this occasion we bring into discussion common etiopathogenic factors for the two diseases.

Clinical cases The epidemiological data for each patient are described within table I, followed by the clinical forms of psoriasis and vitiligo (fig. 1, 2, 3), comorbidities and therapeutic means that we applied.

The diagnosis of vitiligo was made based on the clinical aspect. Psoriasis was diagnosed using clinical and histopathological exams. We calculated PASI (Psoriasis Area and Severity Index), DLQI (Dermatology Life Quality Index) and VASI scores (Vitiligo Area Severity Index) for each patient, in order to assess the seriousness for both conditions.

For each patient we performed biological investigations to specify comorbidities and, only in one case, we used them so that we could monitor the biological therapy.

Discussions Psoriasis is a chronic inflammatory dermatosis characterised by the hyperproliferation of the evolving whimsical keratinocytes, sometimes disabling. Psoriasis vulgaris represents more than two thirds of the cases, and comprises several aspects: dotted, follicular, guttate, nummular, circinate, plaque psoriasis, universal. In the case of our patients we met the following clinical forms: plaque psoriasis (three cases) and guttate psoriasis (one case).

The etiopathogenesis of psoriasis is multifactorial. Thus, when speaking about the etiopathogenesis of psoriasis, the literature mentions(4): psychological disorders, certain medications, infections, traumas, the endocrine factor, the alcohol excess consumption, smoking, the immunological and metabolic disorders, but also the involvement of genetic factors is nowadays well substantiated.

When referring to the infectious factor, things are clearer regarding the relationship between the guttate psoriasis at young people and the infectious episode, particularly the nasopharyngeal one. The role of the HPV infection in the psoriasis etiopathogenesis is not clear. The idea that some types of HPV can act as superantigenes has been postulated, as well as the fact that it may be encountered in latent form and activated by some proinflammatory cytokines5). For the cases presented,

Figure 1.

Psoriasis (guttate and nummular lesions) and vitiligo (case 1)

we consider the chronic alcohol consumption (two cases) and the beta-antagonistss medication (for one case, managed for portal hypertension) factors that can be incriminated. Psoriasis is often preceded by the excessive alcohol consumption.

The chronic alcohol consumption can interfere in the pathogenesis of psoriasis through the following links: the occurrence of stressful events in the life of the patient, induction of hepatic pathology, immunosuppression induction, increased frequency and severity of infections with the release of proinflammatory cytokines. Vitiligo is a kind of hypomelanosis characterized by the progressive appearance of the hypopigmented macules, related to the rarefaction until the disappearance of the melanocytes within the epidermis(6). The following etiopathogenic theories were invocated: autoimmune, autocytotoxic, neural, enzymatic, the one of the oxidative stress, transepidermal melanocitoragy, the apoptosis . The genetic susceptibility was encountered in 24-38% of the patients diagnosed with vitiligo. The disease occurs more frequently in people with HLA - B12, HLA - B 13, HLA - BQ4. The familial cases are increasing by 4,5 times the risk of disease for descendents. Vitiligo has been associated with several autoimmune diseases, more commonly type I diabetes mellitus, Addison’s disease, pernicious anemia, thyroid diseases and alopecia areata. Thyroid disorders are encountered at approximately 12% of the adults diagnosed with vitiligo, more commonly than for the general population, where the prevalence ranks between 1-2%. Also, the Addison’s disease occurs in 2% of the cases, and the Biermer anemia is 30 times more frequent in the case of the patients with vitiligo. Diabetes mellitus is met in 1-7 % of the cases, and, more particularly, in the case of the insulinoNovember 2015

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Case Presentation

Psoriasis and vitiligo: four clinical cases.

Table 1. Psoriasis and vitiligo diagnosed patients - epidemiological, clinical and terapeutical data Crt. No.

1.

2.

3.

4.

Sex

Age

F

66 years old

M

F

M

34 years

72 years

47 years

Family Family history of history of psoriasis vitiligo

neg.

neg.

neg.

neg.

neg.

neg.

neg.

pos.

Vitiligo onset age

40 years

13 years

52 years

22 years

Psoriasis onset age

60 years

34 years

62 years

47 years

Vitiligo Type

Non-segmental vitiligo; VASI 79,8

Non-segmental vitiligo; VASI 10,8

Non-segmental vitiligo; VASI 67,5

Non-segmental vitiligo; VASI 29

dependent diabetes. In what comes next, we describe two clinical types of vitiligo: Non-segmental or symmetrically vitiligo, defined by Vitiligo European Task Force as a �chronic acquired disease characterized by hypopigmented macules, often symmetrical, which are growing in size, across the time, and correspond to a significant loss of the melanocytes functionality, located upon the epidermis and also upon the hair follicle�(6) and segmental, with unilateral distribution, that affects one or more dermatomes. All of the four cases that we studied had manifested non-segmental vitiligo.

A retrospective, cross-sectional and comparative study(7), made on 740 patients with chronic dermatoses, that were undergoing phototherapy, observed that 35,27 % of the cases manifested vitiligo (segmental 15,3%) and 44,72 % had psoria-

256

Psoriasis clinical form

Disseminated plaques PASI 16,2 DLQI 21

Disseminated plaques PASI 18,9 DLQI 24

Other comorbidities

Treatment

-Obesity gr. II -HTA stage. II

-Enbrel -Etanerceptum -Calcipotriol 50 microg/betame tasone dipropionate 0,5 mg/g gel

-Epilepsy (grand mal) -Chronic ethanol hepatitis

-Mometasone furoate 0.1%/ 5%Salicylic acid -Calcipotriol 50 microg / bethametasone dipropionate 0.5 mg / g gel

-Von RecklinghausenNeuroDisseminated fibroma plaques tosis PASI 8 -DecompenDLQI 14 sated cirrhosis, portal and parenchymal

Guttate psoriasis PASI 7,5 DLQI 15

No

- Betame tasone dipropionate 0,05%/ Salicylic acid, 3% ointment

-Tinefcon 2x2 capsules/ daily -Calcipotriole 50 microg/betame tasone dipropionate 0,5 mg/g gel - Betame tasone dipropionate 0,05%/ salicylic ointment 3%

sis. Vitiligo associated with psoriasis was observed only on 9 patients (3,44 %). The latter were analyzed having in mind the following parameters: sex (6M and 3F), mean age (32 years, between the interval 14-75 years), phototype ( phototype III prevailed, for four patients).

The family history of vitiligo was encountered only in a single case, the same as allergic rhinitis and asthma. The Koebner phenomenon and the poliosis were encountered in three or four cases.

The commonly affected areas were the head (four cases), face (two cases) and in one case, several areas were affected: forearms, shoulders or a generalized vitiligo form was encountered. In the cases of 5 patients, from a chronological aspect, vitiligo debuted firstly, and the strictly developed psoriasis on vitiligo areas was found in two cases.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Virgil Pătrașcu, Raluca Ciurea, Florentina Delcea

Figure 3.

Figure 2.

Plaque psoriasis and vitiligo in a female patient with von Recklinghausen Neurofibromatosis (case 3)

If we report our conclusions on the four cases that we presented, we can emphasize the equal gender distribution. The onset of vitiligo (mean age 31,75 years) preceded with 20 years the onset of psoriasis mean age of (51,75 years). The family history was psoriasis-negative for all the patients and vitiligo-positive in one of the patients.

Psoriasis/vitiligo: etiopathogenic interferences The explanation for the psoriasis - vitiligo coexistence is not clear. In 1982, Koransky and Roenig(7) conducted a literature review and presented 25 cases of vitiligo associated with psoriasis, concluding that the association of these two conditions is relatively rare. Chronologically, in all our cases vitiligo preceded psoriasis. It was suggested that the melanin decrease or absence may be a predisposing factor for the psoriasis plaques development(8).

It is known that both dermatoses have an autoimmune component concerning the pathogenesis. The level of TNF-α is increased within the psoriasis lesions, as well as in perilesional skin of the patients with vitiligo, fact that can lead to the conclusion that TNF-α may be a link between psoriasis and vitiligo. In vitro studies(8) have shown the increased production of TNF-α at the level of the melanocytes in vitiligo. The favorable results obtained for both diseases after the treatment with cyclosporine and tacrolimus support this hypothesis(9).

Anothers factors described as being responsible for this coexistence are the Koebner phenomenon, commonly met to both diseases, but also NALP1 gene association, and an activation of the Th1 and Th17 cellular immune system pathways(10). AIS 1 locus, susceptible for vitiligo, is located on the level of the chromosome 1p31.3 - p32.2 which is closely situated to the locus PSORS7 of psoriasis. Howev-

Guttate psoriasis and vitiligo (case 4)

er, the possibility that these two loci are identical, is minimized by the low encountered prevalence of psoriasis in vitiligo patients(11). AIS 1 was found only in the case of patients with generalized vitiligo and it is possible that it may not be present in other vitiligo forms.

Recently, Prignano et al.(12) suggested that both diseases are immune-mediated, with a genetic connection, and Zhu et al.(13) found that both psoriasis and vitiligo have an ordinary common locus, within the major histocompatibility complex (MHC).

We did not find data in the literature regarding the triple combination, including psoriasis, vitiligo and neurofibromatosis type I, pathology seen in one of our cases. The association between psoriasis and neurofibromatosis type I is rare and the authors could not determine whether the existence is purely coincidental or is determined by common genetic defects(14). Within table II we summarized psoriasis, vitiligo and type I neurofibromatosis data (the type I neurofibromatosis was found in one of our cases), facilitating the separation of certain commonly points related to the pathogenesis of the three diseases. Based upon data from the speciality literature related on the two diseases, we can say that T lymphocytes, keratinocytes, melanocytes and cytokines have an essential role for the psoriasis and vitiligo coexistence. Satisfactory results may be obtained in these patients by using the following therapies: PUVA therapy, treatment with UVB – narrow band (twice weekly) associated with tacrolimus ointment 0,1% (twice weekly), xenon laser 308 nm chloride excimer, potent topical corticosteriods, vitamin D3 derivatives, calcineurin inhibitors (tacrolimus, pimecrolimus), calcipotriol 50 microg/betamethasone dipropionate 0,5mg, overall corticosteroids therapy. The therapeutic results in the four cases were satisfactory, if we are judging them from the perspective of controlling psoriasis flares, but without beneficial effects on the depigmented areas. For the female patient who received biologic therapy with Etanercept, after four months from the treatment initiation, November 2015

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Case Presentation

Psoriasis and vitiligo: four clinical cases.

Table 2. Psoriasis, Vitiligo and von Recklinghausen Neurofibromatosis: comparative data Vitiligo

Genetic predisposition

Psoriasis

Polygenic AD Transmission; Polygenic transmission can multiple susceptible loci involve multiple genes situaand candidate genes have ted on different locus. been involved

Involved genes from the following chromosomes 1, 2, 3, 6, 7, 8, 10, 11, 12, 14, 17, 21, 22, 28

PSORS2 Genes on 17q, PSORS1 6p21.3, PSORS3 pe 4q, PSORS4 pe 1q21.3, PSORS5 pe 3q21, PSORS6 pe 19p, PSORS7 pe 1p, PSORS8 pe 16q, PSORS9 pe 4q28-Q32 și PSORS10 pe 18p11.26, 27

Genetic Markers – antigens

HLA-B12, HLA-B13 and HLA-BQ4

HLA-B13, B17 and HLA-CW6, BW57, psoriasis vulgaris, HLA-B27 highly emphasized to the patients diagnosed with artropathy psoriasis; HLA-DQB1alpha for generalized pustular psoriasis

Antibodies

AC antimelanocytes

AC corneous antistrat

The stress contribution is significative

The environment factors contribution is a significative one: infections (streptococical, HIV, etc.), medicines, traumatisms, smoking, stress, etc.

„candidates” genes involved

Environment factors

en confetti pigmentation occurred, on the upper limbs and trunk, without any improvement of the aesthetics.

Conclusions The psoriasis/vitiligo coexistence is rarely encountered in medical practice. Extensive epidemiological studies are needed in order to know the real rate of these two diseases association.Future pathogenesis research for each of the two conditions may bring new data in order to confirm that there is not a coincidental coexistence or even to contradict this hypothesis.

von Recklinghausen Neurofibromatosis AD monogenic transmission.

Variable expresivity.

100% penetrance.

NF1 gene located on the long arm of cromosome no. 17 and codates the neurofibromin-proteine, which is linked to RAS gene

Conflicts of interest: none declared E-mail adress of the others authors: delcea_florentina@yahoo.com; raluca1ciurea@gmail.com

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

Bibliography 1. Selenyi A. Vitiligo and psoriasis on the same side with syringomyelia. Borgyogy Venerol Sz. 1955; 9:94-96.

2. Menter A, Boyd AS, Silverman AK. Gutate psoriasis and vitiligo: anatomic cohabitation. J Am Acad Dermatol.1989; 20:698-700.

3. Dhar S, Malakar S: Colocalisation of vitiligo and psoriasis in a 9-year-old boy. Pediatr Dermatol. 1998;15:242-3.

4. Griffiths CE, Barker JN.Pathogenesis and clinical features of psoriasis. Lancet.2007; 370:263-271.

5. Simeone P, Teson M, Latini A, Carducci M, Venuti A. Human papillomavirus type 5 in primary keratinocytes from psoriatic skin. Exp Dermatol. 2005 Nov;14(11):824-9.

6. Ali Alikhan, Lesley M. Felsten, and Vesna Petronic-Rosic. Vitiligo: A comprehensive overview.

J Am Acad Dermatol, 2011; 65:473-91.

7. Caio César, Silva de Castro. Prevalence of psoriasis in a study of 261 patients with vitiligo. An Bras Dermatol. 2005;80(5):489-92.

8. Percivalle S, Piccinno R and Caccialanza M. Concurrence of vitiligo and psoriasis: a simple coincidence? Clin and Exp Dermatol. 2009;34:90-1.

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9. Madan V, Griffiths CE. Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther.

2007 Jul-Aug;20(4):239-50.

10. M. Arunachalam, F. Dragoni, R. Colluci, S. Berti, E. Crocetti, M. Galeone, R. Conti, S. Moretti.

Non-segmental vitiligo and psoriasis comorbidity – a case-control study in Italian patients.

JEADV 2014, 28, 433-437.

11. Fain PR, Gowan K, LaBerge GS, Alkhateeb A, Stetler GL,Talbert J, et al. A genomewide screen for generalized vitiligo confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. Am J Hum Genet. 2003; 72:1560-4.

12. Prignano F, Pescitelli L, Ricceri F, Lotti T. The importance of genetical link in immunomediated dermatoses: psoriasis and vitiligo. Int J Dermatol 2008; 47:1060-1062.

13. Zhu KJ, Lv YM, Yin XY, Wang ZX, Sun LD, He SM, Cheng H, Hu DY, Zhang Z, Li Y, Zuo XB, Zhou YW, Yang S, Fan X, Zhang XJ, Zhang FY. Psoriasis regression analysis of MHC loci identifies shared genetic variants with vitiligo. PLoS One 2011; 6: e23089.

14. Neurofibromatosis Associated With Plaque-Type Psoriasis: Coincidental Occurrence or Casual Association? Vasili E, Saraceno R, Vargu M, Hysi K, Kellici S, Fida M. Cutis. 2012; 90:147-148

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

MODIFICAREA MICROBIOMULUI CUTANAT: O NOUĂ ABORDARE ÎN MANAGEMENTUL DERMATITEI ATOPICE Prof. Thomas Bieber, MD, PhD, MDRA Departamentul de Dermatologie și Alergologie, Universitatea din Bonn, Germania

Cunoștințele acumulate în înțelegerea cât mai profundă a afecțiunilor cronice și inflamatorii ale pielii au fost posibile datorită progresului în domeniile epidemiologiei, geneticii și imunologiei. În acest context, rolul organismelor microbiene a fost întotdeauna luat în considerare din punctul de vedere al caracteristicilor patogene. În ultima vreme, datorită analizelor metagenomice moderne s-a dovedit că, la fel ca și în cazul altor organe, pielea fără leziuni este colonizată de o comunitate bogată de microorganisme comensale , iar diversitatea acestora este un factor cheie pentru o piele sănătoasă. Pe de altă parte, multe afecțiuni sunt caracterizate de o colonizare microbiană anormală (așa numita «disbioză»), al cărei rol patologico-fiziologic rămâne un subiect de dezbatere. În aceast caz, o modificare directă a microbiomului cutanat, ce are ca scop diversificarea acestuia, reprezintă o abordare terapeutică interesantă pentru multe afecțiuni.

O astfel de strategie a fost explorată pentru tratarea dermatitei atopice înca de acum câțiva ani. Având la bază observațiile realizate în Centrul Termal Terapeutic din orășelul francez La Roche-Posay, s-a presupus că un emolient îmbogățit cu o biomasă de Vitreoscilla Filiformis (VF) crescută în apă termală, ar putea avea un efect clinic asupra acestei afecțiuni. Într-adevăr, într-un articol publicat în 2008 în British Journal of Dermatology, Gueniche et al. au raportat o îmbunătățire semnificativă la pacienții cu dermatită atopică, folosind această strategie.

Aceste rezultate încurajatoare i-au determinat pe cercetători să analizeze în detaliu mecanismele implicate. Într-o lucrare mai recentă publicată în Clinical, Cosmetic and Investigational Dermatology, Mahe et al. au arătat că un lizat Aqua Posae Filiformis (APF), obținut din VF crescută în APĂ TERMALĂ LA ROCHE-POSAY, a fost capabil să activeze celule prin intermediul receptorilor Toll-like 2 și să exercite un impact asupra expresiei superoxid dismutazei 2 și expresiei peptidelor anti-microbiene, cât și asupra proteinei S100A7. Aceste experimente sugerează că un extract de VF este capabil să stimuleze componente importante ale sistemului imunitar cutanat.

Prin urmare, sunt martorii unei noi și fascinante ere în domeniul dermatologiei, în care rolul «musafirilor microbieni permanenți» din organismul nostru, abia începe să fie înțeleasă.

N oEADV v e m b e 2014. r 2015 Extras din Editorial Prof. T. Bieber. Rezumat publicații,

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Case Presentation

Cutaneous metastases in squamous cell carcinoma of the larynx Case report

CUTANEOUS METASTASES IN SQUAMOUS CELL CARCINOMA OF THE LARYNX - CASE REPORT METASTAZE CUTANATE CU PUNCT DE PLECARE DE LA UN CARCINOM SCUAMOS LARINGIAN – PREZENTARE DE CAZ Loredana Elena Stoica1), Rucsandra Cristina Dascălu1), Claudia Cîrstea1), Raluca Niculina Ciurea2), Otilia Constantina Rogoveanu3), Andreea-Oana Enache1) Dermatology Department, University of Medicine and Pharmacy of Craiova, Romania 2) Pathology Department, University of Medicine And Pharmacy of Craiova, Romania 3) Department of Physical Medicine and Rehabilitation, University of Medicine and Pharmacy of Craiova, Romania 1)

Corresponding author: Loredana Elena Stoica, MD, PhD, University of Medicine and Pharmacy from Craiova, Petru Rareș Street, No2-4, 200345, Craiova, Romania, phone: 004-0722857395, e-mail: tanaseloredanaelena@yahoo.com E-mail addresses of the others authors: Andreea-Oana Enache – oana.popescu86@yahoo.com Raluca Ciurea - raluca1ciurea@gmail.com Rucsandra Cristina Dascălu – rucsandrag@yahoo.com Claudia Cîrstea – claudia_cirstea22@yahoo.com Otilia Constantina Rogoveanu – otilia.rogoveanu@gmail.com Acknowledgement This paper was published under the frame of European Social Fund, Human Resources Development Operational Programme 2007-2013, Project No. /159/1.5/S/136893.

Open Access Article

Abstract Keywords: cutaneous metastasis, squamous cell carcinoma, larynx, histopathology

Cite this article: Loredana Elena Stoica, Rucsandra Cristina Dascălu, Claudia Cîrstea, Raluca Niculina Ciurea, Otilia Constantina Rogoveanu, AndreeaOana Enache.

Cutaneous metastases in squamous cell carcinoma of the larynx Case report.

RoJCED 2015; 2(4):260-264

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Cutaneous metastasis from head and neck cancers are rare but, when are present, they are usually considered a poor prognostic sign. We report a patient who showed multiple skin metastases 28 months after the diagnosis and treatment of a laryngeal carcinoma.

A 57-year-old male with past history of smoking, was referred to our department in 2015 for the presence of 21 skin tumors, varying in size between 0.5 and 2 cm, red-pink in color, depressed center, located on the scalp, face, trunk and limbs.

In 2012, the patient underwent total laryngectomy followed by chemoradiotherapy for a squamous cell carcinoma of the subglottic larynx stage IV (T4N2MX).

The histopathological exam (double biopsy one from the scalp and the other from the right thigh) shows proliferation of malignant tumor cells arranged in islands in deep dermis, cells with marked atypia, multiple atypical mitoses and unicellular keratinization.

Based on clinical and paraclinical examinations we established the diagnosis of cutaneous metastases with laryngeal neoplasm starting point, excluding other conditions that might be confused from clinical point of view. After confirmation of the cutaneous metastasis, the patient was directed the Oncology Department for adequate treatment.

The clinical polymorphism of cutaneous metastasis raises numerous problems of clinical diagnosis, leading to significant delays in diagnosis and initiation of treatment.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Loredana Elena Stoica, Rucsandra Cristina Dascălu, Claudia Cîrstea, Raluca Niculina Ciurea, Otilia Constantina Rogoveanu, Andreea-Oana Enache

Rezumat Cuvinte-cheie: metastaze cutanate, carcinom spinocelular, laringe, histopatologie

Metastazele cutanate cu punct de plecare de la un cancer cu localizare la nivelul extremității cefalice sunt rare, dar atunci când apar, reprezintă un factor de prognostic nefavorabil.

Prezentăm un bolnav cu multiple metastaze cutanate apărute la 28 de luni de la diagnosticul și tratamentul unui carcinom laringian.

Pacient în vârstă de 57 ani, fost fumător, se prezintă în clinica noastră în 2015 pentru 21 de formațiuni tumorale, cu dimensiuni cuprinse între 0,5 și 2 cm, culoare roz-roșietică, cu centrul deprimat, localizate la nivelul scalpului, faciesului, trunchiului și membrelor. În 2012 pacientul a suferit laringectomie totală urmată de chimioradioterapie pentru un carcinom spinocelular laringian subglotic stadiul IV (T4N2MX).

Examenul histopatologic (dublă biopsie de la nivelul scalpului și coapsei drepte) a relevat proliferare de celule tumorale maligne, dispuse în insule situate în dermul profund, celule cu atipii marcate și prezența de mitoze atipice și keratinizare unicelulară.

Pe baza aspectelor clinice și paraclinice am precizat diagnosticul de metastaze cutanate cu punct de plecare de la un carcinom laringian, excluzând multiple afecțiuni confundabile din punct de vedere clinic.

După confirmarea metastazelor cutanate, bolnavul a fost îndrumat către Departamentul de Oncologie pentru stabilirea schemei optime de tratament. Polimorfismul clinic al metastazelor cutanate ridică numeroase probleme de diagnostic diferențial determinând astfel întârzierea diagnosticului și inițierea terapiei.

Introduction Cutaneous metastases are encountered in 0.79% of all skin tumors [1].

Cutaneous metastasis from head and neck cancers are rare but, when present, they are usually considered a poor prognostic sign. The incidence of cutaneous metastasis from head and neck squamous cell carcinoma (SCC) is less than 1% [2].

Clinical case A 57-year-old male, with past history of smoking, presented in 2015 in our department with 21 skin tumors, varying in size between 0.5 and 2 cm, red-pink in color, depressed center, some of them covered by purulent deposits and hematic crusts, other with keratotic surface. The tumors were located on the scalp (13), face (1), trunk (2) and limbs (5) (Figure 1-3).

The patient affirms that the tumors appeared about six months ago, initially on the left hand (index), with rapid extension at the regions previously described.

In 2012 our patient underwent total laryngectomy extended to the first tracheal ring with jugular and carotid lymph node dissection followed by chemoradiotherapy for a squamous cell carcinoma of the subglottic larynx stage IV (T4N2MX). The

pathological examination confirmed the diagnosis of moderately differentiated squamous carcinoma.

There were no other known environmental and family risk factors.

At clinical examination the patient was afebrile and appeared pale and debilitated with marked asthenia. He had a palpable, mobile and painful left retromandibular lymphadenopathy and right supraclavicular lymphadenopathy. We also retained the presence of a tracheostomy tube. The patient is Fitzpatrick skin type III. The patient had undergone severe weight loss.

Dermoscopic examination of skin tumors revealed the pink homogeneous structureless areas, serpentine and linear irregular vessels asymmetrically distributed, polymorphic vessels (dotted vessels, comma-like vessels, hairpin vessels) (Figure 4).

The histopathological exam (double biopsy one from the scalp and the other from the right thigh) shows proliferation of malignant tumor cells arranged in islands in deep dermis, cells with marked atypia, multiple atypical mitoses and unicellular keratinization (Figure 5,6). This aspects confirm the metastases of squamous cell carcinoma.

Routine hematological investigations did not reveal any pathology other than severe anemia (Hb November 2015

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Cutaneous metastases in squamous cell carcinoma of the larynx Case report

1

2

Figure 1-3. Multiple skin tumors varying in size

between 0.5 and 2 cm, red-pink in color, depressed center, some of them covered by purulent deposits and hematic crusts, other with keratotic surface, located on the face, scalp, trunk

7.5 mg/dl). Biochemical parameters and routine urine examination were normal.

HIV and VDRL tests were negative.

Ultrasonography of superficial lymph nodes: retromandibular lymphadenopathy 13/5 mm in diameter and right supraclavicular lymphadenopathy of 10/5 mm diameter. CT scan found tissue nodules on both lung fields, multiple supratentorial brain metastases with maximum axial diameter of 14 mm and perilesional edema. Based on clinical and paraclinical examinations we established the diagnosis of cutaneous metastases with laryngeal neoplasm starting point, secondary severe anemia and also brain and lung metastases.

After confirmation of the cutaneous metastasis, the patient was directed to Oncology Department for adequate treatment.

Discussions SCC is the most common tumor in upper respiratory tract being also the primary cause of carcinoma of the larynx in adults [3]. Distant metastases in SCC of the larynx occur with an incidence of 6.57.2% and the most frequently involved organs are the lungs, the liver and the bones [1,4]. Cutaneous metastases, when they occur, are usually located on the neck, chest, scalp, face, arms and fingers [5].

The mechanism of skin metastasis in squamous cell carcinoma of subglottic larynx is not fully understood. There are three possible mechanisms: direct spreading, lymphatic and hematologic spreading. Direct spreading is made by direct invasion of the surrounding tissues. Spread through dermal lymphatics can result in the development

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3 of cutaneous metastases. The hematogenous spread is made by pulmonary circulation or by azygos and vertebral venous plexus [6].

The clinical picture of cutaneous metastasis varies from macules, infiltrated or indurated plaques, discoid lesions, nodular tumors with telangiectasias, bullous or papulosquamous lesions, to scarred plaques or pigmented tumors [7].

Cutaneous metastases are mostly multiple and rarely solitary, as was seen in our case [8].

In all cases, a high index of clinical suspicion is mandatory for diagnosis of skin metastases. As a rule, biopsy is mandatory in patients with a history of cancer, especially if there are associated symptoms like weight loss, fatigue or severe anemia [9].

Based on clinical exam and paraclinical explorations we excluded the following diagnosis: skin cancers (basal cell carcinoma, sarcoma, etc.), eruptive keratoacanthoma, cutaneous pseudolymphoma, cutaneous manifestation of leukemia.

Cutaneous metastases are early indicators for invasive metastatic cancers and usually are associated with limited survival period [10]. Rarely they can

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Loredana Elena Stoica, Rucsandra Cristina Dascălu, Claudia CĂŽrstea, Raluca Niculina Ciurea, Otilia Constantina Rogoveanu, Andreea-Oana Enache

Figure 4.

Dermoscopic aspect - pink homogeneous structureless areas, serpentine and linear irregular vessels asymmetrically distributed, polymorphic vessels (dotted vessels, comma-like vessels, hairpin vessels)

be the first sign of an unknown malignancy [11]. In our case, the primitive tumor was already known.

In 80-85 % of cases, the laryngeal cancer diagnosis is established in advanced stages (stage III, IV), situation encountered also in our case.

In stage III and IV of subglottic larynx cancer the 5-year relative survival, is 32-47 % [12]. In our case, the prognosis is poor, given the large number of cutaneous metastasis and due to the presence of visceral metastases.

In patients with laryngeal cancer the risk of developing the second tumor is estimated at 10-24% of cases [13].

There is no agreed consensus in the management and treatment of cutaneous metastasis with laryngeal neoplasm starting point. Treatment and prognosis depend mainly on the type and stage of the primary tumor, cutaneous metastases usually being associated with poor prognosis.

In case of multiple cutaneous metastases the aim of the treatment is to provide symptomatic relief and to improve the quality of life.

In the case of disseminated disease with multiple skin metastases, the treatment is mainly palliative including surgery, hypofractionated radiation therapy, chemotherapy, and their combinations [14,15].

The median overall survival is significantly improved (by 2,7 months) after the administration of cetuximab with platinum/5FU versus chemotherapy alone. [16,17]. Photodynamic therapy and carbon dioxide laser therapy also can be useful for palliation of skin metastases [18,19].

An early diagnosis and a good follow-up can help greatly in reducing morbidity and mortality.

Figure 5.

Figure 6.

Proliferation of malignant tumor cells arranged in islands in deep dermis, HE stain X 40

Cells with marked atypia, multiple atypical mitoses and unicellular keratinization. HE stain X 200

Conclusions The clinical polymorphism of cutaneous metastasis raises numerous problems of clinical diagnosis, leading to significant delays in diagnosis and initiation of treatment.

Although the disease depends on the underlying malignancy and its therapeutic response, cutaneous metastases are usually associated with poor prognosis.

The authors have declared no conflict of interest.

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

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Cutaneous metastases in squamous cell carcinoma of the larynx Case report

Bibliography 1. Jain A, Chauhan M, Pandit A, Kumar R, Sharma A, Dubey I. FDG PET/CT in a rare case of multiple cutaneous metastases in carcinoma larynx. Indian Journal of Nuclear Medicine : IJNM : The Official Journal of the Society of Nuclear Medicine, India. 2012;27(4):259-261.

2. Rahman, Tashnin et al. “Cutaneous Metastasis from Squamous Carcinoma of the Base of Tongue.” North AmericanJournal of Medical Sciences 7.1 (2015): 24–26.PMC.Web.17 Oct. 2015.

3. Adams GL, Maisel RH. Malignant tumors of the larynx and hypopharynx. In: Cummings CW, Fredrickson J, Harker LA, editors. Otolaryngology head and neck surgery. 3rd ed. St. Louis: Three Mosby Company; 1998. p. 2130 4. Krunic AL, Cockerell CJ, Truelson J, Taylor RS. Laryngeal squamous cell carcinoma with infradiaphragmatic presentation of skin metastases. Clin Exp Dermatol. 2006Mar;31(2):242-4.

5. Kumar N, Bera A, Kumar R, Ghoshal S, Angurana SL, Srinivasan R. Squamous Cell Carcinoma Of Supraglottic Larynx With Metastasis To All Five Distal Phalanges Of Left Hand. Indian Journal of Dermatology. 2011;56(5):578-580.

6. Bottoni U, Inocenzi D, Mannooranparampic TJ, Richetta A, Del Guidice M, Calvieri S. Inflammatory cutaneous metastases from laryngeal carcinoma. Eur J Dermatol.

2001;11:124–6.

7. Nashan D, Müller ML, Braun-Falco M, Reichenberger S, Szeimies RM, Bruckner-Tuderman L. Cutaneous metastases of visceral tumours: a review.J Cancer Res Clin Oncol.2009 Jan; 135(1):1-14.

8. Dey A, Sinha RT. Cutaneous metastasis as an initial presentation of an unknown primary. Clin Cancer Investig J 2015;4:399-401.

9. Wong CYB, Helm MA, Kalb RE, Helm TN, Zeitouni NC. The Presentation, Pathology, and Current Management Strategies of Cutaneous Metastasis. North American Journal of Medical Sciences. 2013;5(9):499-504. doi:10.4103/1947-2714.118918.

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10. Karki S, Pathak R, Manandhar U, Koirala S. Metastatic cutaneous and subcutaneous lesions: Analysis of cases diagnosed on fine needle aspiration cytology. J Pathol Nepal 2011;1:37-40.

11. Dey A, Sinha RT. Cutaneous metastasis as an initial presentation of an unknown primary.

Clin Cancer Investig J. 2015;4:399-401.

12. American Joint Committee on Cancer. Larynx. In: AJCC Cancer Staging Manual. 7th ed.

New York, NY: Springer; 2010: 57-62.

13. A.D Heroiu, C. E Danciu, C. R Popescu. Multiple cancers of the head and neck. Mædica 8.1 (2013): 80–85.

14. H Kavgaci, B Yildiz, U Cobanoglu, E Fidan, F Ozdemir, Fazil Aydin. Laryngeal Squamous Cell Carcinoma with Knee and Heel Skin Metastases: A Case Report. Acta Dermatovenerol Croat 2010;18(1):32-34 15. Kumar N, Kumar R, Bera A., Kumar P, Angurana S. L., Ghosal, S. (. Palliative and Supportive Care in Acrometastasis to the Hand: Case Series. Indian Journal of Palliative Care, 2011:7(3), 241–244.

16. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116-1127.

17. Mesía R, Rivera F, Kawecki A, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2010;21:1967-1973.

18. L. K. Simpson, L. S. Ostlere, C. Harland. S. Gharaie. Treatment with carbon dioxide laser of painful skin metastases from a laryngeal neuroendocrine carcinoma. Clin Exp Dermatol. 2009 Dec;34(8):e873-5 19. Karrer S, Szeimies RM, Hohenleutner U, Landthaler M. Role of lasers and photodynamic therapy in the treatment of cutaneous malignancy. Am J Clin Dermatol. 2001;2(4):229-37.

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Observations about epidemiology, clinical- dermoscopic correlations and some comorbidities related to a group of Romanian Rosacea patients

OBSERVATIONS ABOUT EPIDEMIOLOGY, CLINICAL- DERMOSCOPIC CORRELATIONS AND SOME COMORBIDITIES RELATED TO A GROUP OF ROMANIAN ROSACEA PATIENTS OBSERVAȚII DESPRE EPIDEMIOLOGIE, CORELAȚII CLINICO-DERMATOSCOPICE ȘI COMORBIDITĂȚI ÎNTR-UN GRUP DE PACIENȚI CU ROZACEE Alin Laurențiu Tatu (1,2), Ana Maria Veronica Draganiță(3), Victor Gabriel Clatici (4) University Dunarea de Jos,Faculty of Medicine and Pharmacy,Galati,Romania; (2) CMI Dr.Alin Laurentiu Tatu,Galati,Romania (3) Medical Practice Zimnicea, Romania (4) Dermatology Department, ELIAS Universitary Emergency Hospital, Bucharest, Romania (1)

Corresponding author: Alin Laurențiu Tatu, 39 Al.I.Cuza street, 800101, Galați, Romania, Telephone: 0040728267435, Fax number: 0040236415705, Email:dralin_tatu@yahoo.com Aknowledgements: This paper is supported by the Sectoral Operational Programme Human Resources Development (SOP HRD),financed from the European Social Fund and by the Romanian Government under the contract POSDRU/159/1.5/S/137390/.

Open Access Article

Abstract Keywords: Rosacea, Dermoscopy, Spinulosis, Demodex Folliculorum, comorbidities, metabolic disorders Cite this article: Alin Laurentiu Tatu, Ana Maria Veronica Draganita, Victor Gabriel Clatici Observations about epidemiology, clinical- dermoscopic correlations and some comorbidities related to a group of Romanian Rosacea patients RoJCED 2015; 2(4):266-269

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Introduction: The aim of the study was to establish epidemiologic data regarding rosacea, to evaluate the dermoscopic features, clinical- dermoscopic correlations and comorbidities related to a group of rosacea patients.

Methods: 115 patients with rosacea after anamnesis were examined clinically and dermoscopically, and by scraping .

Results: The subtypes of Rosacea were: erithemato-telangiectatic 41,73% , papulopustular 51,30%, phymatous 9,56% , ocular rosacea as ocular signs-blepharitis and conjunctivitis at 10,43 % and as ocular symptoms : sensitivity to light, foreign body sensation or itching at 36,52%. All of the patients showed telangiectasias, 70,43% showed red diffuse areas and 59,13% showed Demodex dermoscopic features .

Discussion: Dermoscopy improved the detection of Demodex Folliculorum features from 51,3% (with clinical spinulosis) to 59,13% of patients, and of pustules from 51,3% to 62,6%. All patients with spinulosis showed Demodex features at dermoscopy of the area and were confirmed by scraping. The most important comorbidities of rosacea patients were: airborne allergy-54,78%, gastrointestinal disturbancies -51,3% and metabolic diseases-46,8%

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Alin Laurentiu Tatu, Ana Maria Veronica Draganita, Victor Gabriel Clatici

Rezumat Cuvinte-cheie: Rozacee, Dermoscopie, Spinulosis, Demodex Folliculorum, comorbiditati, disfuncții metabolice.

Scopul studiului a fost de a stabili datele epidemiologice referitoare la rozacee, evaluarea caracteristicilor dermatoscopice și a corelațiilor clinico – dermatoscopice precum și a comorbidităților la un lot de pacienți cu rozacee.

Metodă: 115 pacienți cu rozacee stabilită pe baza datelor anamnestice au fost examinați clinic și dermatoscopic, precum și prin examen parazitologic.

Rezultate: Subtipurile de rozacee au fost eritemato – telenagiectazică 41,73 %, papulo-pustuloasă 51,30 % , forma de tip fima 9,56%, rozacee oculară sub formă de semne oculare (blefarită și conjunctivită) 10,43% și sub formă de simptome ( sensibilitate la lumină, senzație de corp strain, prurit) 36,52%. Toți pacienții au prezentat teleangiectazii, 70,43% au prezentat zone de eritem difuz iar la 59,13% s-au evidențiat caracteristici dermatoscopice ale infecției cu Demodex Folliculorum.

Discuții: Dermatoscopia îmbunătățește depistarea infecției cu Demodex Folliculorum de la 51,3% (cu forme clinice de spinuloză) la 59,13% dintre pacienți, și a pustulelor de la 51,3% la 62,6%.

Toți pacienții cu spinuloză au prezentat elemente caracteristice ale infecției cu Demodex la examenul dermatoscopic și au fost confirmați prin examen parazitologic. Cele mai importante comorbidități la pacienții cu rozacee au fost alergii respiratorii – 54,78%, afecțiuni gastrointestinale 51,3% și boli metabolice – 46,8%.

Introduction Rosacea is an inflammatory facial condition with a prevalence between 0,5 to 10% and a female-male ratio of 3:1(1),(2),(3). From the clinical point of view, the diagnosis of Rosacea is based on papules, pustules, telangiectasias, flushing, blushing, phymas and ocular signs(4). We sometimes need better ways to observe this condition on the skin and to detect earlier some infra-clinical features. Dermoscopy is a very useful tool for a better view and recognition of the specific conditions, of the disease severity and also for the follow up of the treatment result (5). The aim of the study was to establish some epidemiologic data regarding rosacea, to find the dermoscopic features, some clinical- dermoscopic correlations and to find some comorbidities related to a group of Romanian rosacea patients.

Material and Methods m115 patients with variable rosacea clinical manifestations and subtypes were admitted in our outpatient clinic and in private practice and were examined clinically and dermoscopically. We have taken clinical pictures with a digital camera (Sony Cybershot DSC 450) and dermoscopic pictures were taken using Dermlite (3Gen; LLC, Dana Point, CA, USA) at ×10 magnification and an attached Nikon Coolpix P5100 camera. The dermoscopic criteria was based from literature and also from the authors experience in dermoscopy. Clinically, patients presented some features such as telangiectasia, flush, erythema, papulopustules, spinulosis, phyma and scales. We observed on dermoscopy vessels (linear, tortuous, poligonal), follicular plugs, scales, red areas, Demodex Folliculorum tails and pustules. All patients stopped the

Figure 1.

Erythemato-telangiectatic Rosacea

previous treatments at the time of the taken pictures.

During this time interval, they used just soft emollients or thermal water spray. Scales harvesting was done by scraping technique improved with scotch tape. Thus, for microscopic examination material was harvested from the affected area using a piece of 2 cm transparent scotch, it subsequently displayed on a microscope slide that has been sent to the laboratory labeled pouch. Scotch tape preparation was examined microscopically with objectives 10x, 20x and 40x, appreciating parasitic load.

The local ethics committee approved this study.

Results: In this group of Rosacea patients, 79 (68,69%) were women and 36 ( 31,31)% men with a ratio of 2,19 for women to men and the mean age was 46,2 years. From a clinical point of view we observed November 2015

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Case Presentation

Figure 2.

Observations about epidemiology, clinical- dermoscopic correlations and some comorbidities related to a group of Romanian Rosacea patients

Papulo pustular rosacea

these subtypes of Rosacea: Erythemato-telangiectatic, Papulopustular, Phymatous and Ocular Rosacea.

The erithemato-telangiectatic clinical subtype (Fig.1) was characterized by flushing, burning or stinging associated with flushing, persistent erythema on central parts of the face, eritrosis, telangiectasias(6) and it was found in 48 patients (41,73%) -33 women and 15 men (2,2 to 1 ratio).The papulopustular clinical subtype (Figure.2) was characterized by tiny pustules, dome-shaped erythematous papules, erythema, edema (7) and it was found in 59 patients (51,30%), 49 women and 10 men (4,9 to 1 ratio). The phymatous clinical subtype (Figure.3) showed the thickening of the skin with irregular surface contours, pustules, open pores, erythema which affects the nose ,chin, forehead(8) and it was found in 11 patients (9,56%), 2 women and 9 men (a 1 to 4,5 ratio). Ocular Rosacea was found as ocular signs- blepharitis and conjunctivitis (9) in 12 patients (10,43 %), 9 women an 3 men (a 3 to 1 ratio) and as ocular sensations like sensitivity to light, foreign body sensation ,burning, stinging or itching of the eyes (10) in 42 patients (36,52%), 31 women and 11 men (a 2,81 to 1 ratio). By dermoscopy, we found on the face of Rosacea group the following dermoscopic features: vessels, red areas, follicular plugs, Demodex tails, scales, pustules. All of the patients showed clinically telangiectasia, which is seen more clearly and specific with dermoscopy as red dilatated, reticular, linear, tortuous or polygonal vessels (Figure.4). This is the most important dermoscopic sign in Rosacea and it is considered specific (11),(12). m81 patients (70,43%) showed red diffuse areas with or without telangiectasia. Because even a light pressure on the skin by the dermoscope with the disappearance of the erythema on some dermoscopic areas (Fig.1.b) as an indicator of a vascular erythema, it is better to use a polarized non- contact dermoscope to prevent the pressure on vessels or erythema but also a contact and non-polarized dermoscope can be used with a gentle touch. m68 patients (59,13%) showed Demodex dermoscopic features and the Demodex features were follicular plugs and Demodex tails. The follicular plugs were found in 59 patients (51,3%) as semi round oval or triangular brown, white or grey structures corresponding to Demodex. They should be distinguished from open comedones –they are brown homogenous circles sometime also seen with the

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Figure 3.

Rhinophyma

naked eye .The follicular plugs were intricated with Demodex tails. We observed the Demodex tails in 51 patients (44,34%) as creamy gelatinous threads protruding out of follicular openings representing the presence of the mite itself (under ×10 magnification): three or more tails on a dermoscopic area were considered specific for Demodex ( Figure.5). The Demodex tails should be distinguished from normally white hairs on the face. Those are smaller in diameter and size, regular, are present in almost all the follicles of a dermoscopic area and they don’t have semi round oval or triangular brown ,white or grey structures at the proximity of the skin corresponding to Demodex body(13). All the 59 patients with areas of spinulosis (Figure.6) showed Demodex features at dermoscopy of the area confirmed by scraping .(Figure.7)(14). m59 from 115 patients (51,3%) showed pustules clinically and 72 patients by dermoscopy (62,6%).Dermoscopy revealed tiny pustules not yet clinically apparent as central white circular areas sometimes surrounded by an erythematous hallo -if we pushed too hard on the dermoscope the halo might not be visible or can be incomplete.

Scales were present clinically in 42 patients (36,52%) but dermoscopic in 49 patients (42,60%) because tiny scales are not seen every time with the naked eye but they are seen by dermoscopy as white polygonal or irregular border areas or lines. The scales are whiter than follicular plugs and there are no tails as a marker for Demodex and they should also be distinguished from white hairs.

Comorbidities In this group of Rosacea patients, the anamnestic and clinical data obtained showed that the most important comorbidities were: metabolic disease (including diabetes, hypertension, hyperlipidemia, and obesity defined by a body mass index >30 kg/m2) in 53 patients (46.8%),gastrointestinal disturbancies (including gastroesophageal reflux disease,gastritis,ulcer,irritable bowle sindrome) in 59 patients (51,3%) and airborne allergy(included as IGE levels to allergens > 0.35 KUA/l) (15) in 63 patients (54,78%) especially with high IGE levels to dust mites-Dermatophagoides pteronissius and Dermatophagoides Farinae – 29 patients

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Alin Laurentiu Tatu, Ana Maria Veronica Draganita, Victor Gabriel Clatici

Figure 4.

Telangiectasias. Dermoscopy

Figure 5. Follicular plugs and Demodex tails.

Dermoscopy

(25,21%) (16).

Discussion In this group of Rosacea patients, 68,69% were women and 31,31% men with a ratio of 2,19 for women to men and the mean age was 46,2 years.

The Rosacea clinical subtype and ratio between women to men were : mPapulopustular 51,30%-4,9 to 1 ratio. mErythemato-telangiectatic 41,73% -2,2 to 1 ratio. mPhymatous 9,56%- 1 to 4,5 ratio) msymptomatic Ocular Rosacea 36,52% -2,81 to 1 ratio.

Dermoscopy revealed the following features: vessels (100%),red areas 70,43%,follicular plugs and Demodex tails 59,13%, pustules (62,6%), scales (42,60%). Dermoscopy improved the detection of Demodex Folliculorum features from 51,3% (with clinical spinulosis) to 59,13% of patients, of pustules from 51,3% to 62,6% and of scales from 36,52% to 39,13%. All the patients with areas of spinulosis showed Demodex features at dermoscopy of the area and were confirmed by scraping. Dermoscopy is a tool for early detection of the infra-clinical signs of rosacea,to document the flares and as perspective for the follow up process of repairing of the skin after the treatment. The most important comorbidities on Rosacea patients were: airborne allergy-54,78%, gastrointestinal disturbancies-51,3% and metabolic diseases-46,8%, but obviously more studies should be done in this field.

Figure 6. Spinulosis

Conclusion Rosacea patients must be evaluated from a comorbidities point of view and dermoscopy is a valuable tool for diagnosis of Demodex infection.

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

Bibliography 1. Rohrich RJ, Griffin JR, Adams WP Jr. Rhinophyma: Review and update. Plast Reconstr Surg 2002;110(3):860– 869; quiz, 870.

2. Scheinfeld NS. Rosacea. Skinmed 2006;5:191–194.

3.Berg M, Liden S. An epidemiological study of rosacea. Acta Dermatol Venereol 1989;69:419–423.

4.Rosacea. In: Marks JG, Miller JJ (eds.). Principles of Dermatology,4th ed. Philadelphia: Elsevier/Saunders; 2006.

5.Zalaudek I, Argenziano G, Di Stefani A, et al. Dermoscopy in general dermatology. Dermatology 2006; 212: 7–18 6. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis,and subtype classification. J Am Acad Dermatol 2004;51(3);327–341.

7. Pray WS, Pray JJ. Differentiating between rosacea and acne. USPharmacist 2004;29(4).

8.Culp B, Scheinfeld N. Rosacea: A Review. Pharmacy and Therapeutics. 2009;34(1):38-45.

9. Stone DU, Chodosh J. Ocular rosacea: An update on pathogenesis and therapy. Curr Opin Ophthalmol 2004;15:499–502 10. Kheirkhah A, Casas V, Li W, et al. Corneal manifestations of ocular Demodex infestation.

Am J Ophthalmol 2007;143:743–749.

11.Lallas, A., Argenziano, G., Longo, C., Moscarella, E., Apalla, Z., Koteli, C. and Zalaudek, I. (2013), Polygonal vessels of rosacea are highlighted by dermoscopy. International Journal of Dermatology. doi: 10.1111/ ijd.12270 12. Rosina P, Zamperetti MR, Giovannini A, et al. Videocapillaroscopic alterations in erythematotelangiectatic rosacea. J Am Acad Dermatol 2006; 54: 100–104 13. Segal R, Mimouni D, Feuerman H, et al. Dermoscopy as a diagnostic tool in demodicidosis. Int J Dermatol 2010; 49: 1018–1023 14. Farina MC, Requena L, Sarasa JL, et al. Spinulosis of the face as a manifestation of demodicidosis. Br J Dermatol 1998; 138: 901–903 15.Robert G. Hamilton. Assessment of Human Allergic Diseases. In Clinical Immunology. Principles and Practice, Mosby, Elsevier, Third Edition, 2008, 1476.

16. Rainer B.M, Fischer A.H, Felipe da Silva D.L, Kang S., Chien A.L. Rosacea is associated with chronic systemic diseases in a skin severity–dependent manner: Results of a case-control study,2015, J Am Acad Dermatol; 739( 4) ; 604 – 608; doi.org/10.1016/j.jaad.2015.07.009

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Case Presentation

Primary cutaneous trichosporonosis caused by Trichosporon asahii in a severe immunosuppressed woman

PRIMARY CUTANEOUS TRICHOSPORONOSIS CAUSED BY TRICHOSPORON ASAHII IN A SEVERE IMMUNOSUPPRESSED WOMAN TRICOSPORONOZĂ CUTANATĂ PRIMARĂ INDUSĂ DE TRICHOSPORON ASAHII LA O PACIENTĂ SEVER IMUNODEPRIMATĂ Irina Mărgăritescu MD, PhD1), Aurel Doru Chiriţă MD, PhD2), Viorica Marinescu MD, PhD2) 1) Laboratory of Anatomic Pathology, “Onco Team Diagnostic”, Monza Hospital, Bucharest, Romania Department of Dermatology, 2) Department of Dermatology, “Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania Corresponding author: Aurel Doru Chiriţă, MD, Dip.ICDP-UEMS, Department of Dermatology, “Carol Davila” Central University Emergency Military Hospital, Bucharest, Romania, 88 Mircea Vulcănescu street, Sector 1, 010825 Bucharest, Romania, Phone/ Fax: +40-788-355-663, , e-mail: dorutchirita@yahoo.com

Open Access Article

Abstract Keywords: Trichosporonosis, Trichosporon asahii, yeast, immunosuppression.

Cite this article: Irina Mărgăritescu, Aurel Doru Chiriţă, Viorica Marinescu.

Primary cutaneous trichosporonosis caused by Trichosporon asahii in a severe immunosuppressed woman RoJCED 2015; 2(4):270-275

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Trichosporon species are non-encapsulated yeasts that commonly inhabit the soil and are part of normal flora of the gastrointestinal tract, upper respiratory tract, and human skin. Sixteen of the 51 species in the genus Trichosporon have been associated with human infection. The vast majority of human infections is caused by T. asahii, followed by T. dermatis. Trichosporon spp. has been increasingly recognized as an important pathogen for systemic infections, affecting mainly immunocompromised patients. Most commonly, the infection presents as fungaemia, and approximately half of the cases are associated with metastatic skin lesions. In immunocompromised patients, trichosporonosis has been increasingly associated with a high mortality rate of up to 55% - 80%. We present a case of primary cutaneous trichosporonosis without systemic involvement despite patient’s severe immunosuppression.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Irina Mărgăritescu, Aurel Doru Chiriţă, Viorica Marinescu

Rezumat Cuvinte-cheie: tricosporonoză, Trichosporon asahii, levuri, immunosupresie.

Speciile de Trichosporon sunt levuri neîncapsulate care populează frecvent solul și fac parte din flora normală a tractului gastrointestinal, a tractului respirator superior și pielii umane. Șaisprezece din cele 51 specii ale genului Trichosporon au fost asociate cu infecții umane. Marea majoritate a infecțiilor umane este cauzată de T. asahii, urmată de T. dermatis. Speciile de Trichosporon sunt tot mai mult recunoscute ca agenţi patogeni importanţi pentru infecţiile sistemice care afectează în principal pacienţii imunocompromişi.

Cel mai frecvent infecția se prezintă ca fungemie iar aproximativ jumătate din cazuri sunt asociate cu leziuni metastatice cutanate. La pacienții imunocompromiși, tricosporonoza a fost asociată cu o rată ridicată a mortalitatii de până la 55% - 80%. Vă prezentăm un caz de tricosporonoză cutanată primară fără afectare sistemică în ciuda imunosupresiei severe a pacientului.

Introduction Trichosporon species (Trichosporon spp.) are non-encapsulated basidiomycetous yeasts that are widely distributed in nature, and commonly inhabit the soil, but can also be isolated from water, decomposing matter, and bird and bat droppings (1) . They are regularly found on normal skin, especially in the peri-genital areas, but also on nails and occasionally as part of the normal gastrointestinal tract or upper respiratory microflora. (1-6).

At present, the genus contains 51 species, but only 16 species have been associated with human infection (1). Trichosporon spp. are considered to be the second most commonly isolated yeast species in clinical laboratories (7-9). The vast majority of human infections is caused by Trichosporon asahii (74%), followed by Trichosporon dermatis (12%) (6,10) . Trichosporon spp. has been classically associated with white piedra, a distal infection of the hair shaft (11), and with hypersensitivity pneumonitis syndrome, particularly in hot and humid climates (1,12-15) . However, in recent decades, Trichosporon spp. has been increasingly recognized as an important pathogen for systemic infections, i.e. fungaemia, endocarditis, peritonitis and meningitis, affecting mainly immunocompromised patients (10,16-18) . Various immunosuppressive states are risk factors for invasive trichosporonosis (10,16,17,19-21).

Most commonly, the infection presents as fungaemia (75%), and approximately 50% of the cases are associated with metastatic skin lesions (10,19). In immunocompromised patients, trichosporonosis has been increasingly associated with a high mortality rate of up to 55% - 80% (10,16,22,23). We present a case of primary cutaneous trichosporonosis without systemic involvement despite patient’s severe immunosuppression.

Patient, Methods and Results A 65-year-old woman presented with a 10-month history of numerous painful cutaneous erythematous papules and nodules on the lower legs, especially on the left calf. The lesions progressively enlarged, and became ulcerated and confluent.

Figure 1A.

Figure 1B.

(A) Painful ulcers and lesions with a vasculitic appearance mainly on the left calf; (B) 1 to 15 cm in diameter ulcers with erythematous and slightly elevated borders that are covered with seropurulent and necrotic debris.

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Primary cutaneous trichosporonosis caused by Trichosporon asahii in a severe immunosuppressed woman

Figure 2. (A) Suppurative and granulomatous dermatitis and panniculitis, pseudoepitheliomatous hyperplasia and areas of hemorrhage in the reticular dermis; (B) granulomatous and suppurative panniculitis; (C) many haloed yeast-like cells in a mucoid background, (D) numerous septate hyphae highlighted by a PAS-D stain.

The patient had been treated intermittently with various systemic antibiotics, including amoxicillin and clavulanic acid, along with various topical treatments such as sulfadiaziadine cream and clobetasol cream. A skin biopsy taken elsewhere raised the suspicion of deep fungal mycosis. Consequently, the patient underwent systemic antifungal treatment with itraconazole 100 mg twice daily for 10 days, but without clinical response.

Importantly, the patient also had associated comorbidities. She had a long history of rheumatoid arthritis, systemic lupus erythematosus, autoimmune thrombocytopenia and autoimmune hepatitis. She received various antimetabolite and immunosuppressive regimens including methotrexate, sulfasalazine, nonsteroidal anti-inflammatory drugs, leflunomide, azathioprine, hydroxychloroquine, and methylprednisolone. She also developed insulin-necessitant diabetes mellitus type 2, chronic peripheral arterial insufficiency, and glaucoma.

Cutaneous examination revealed numerous painful ulcers and lesions with a vasculitic appearance on the left calf (Fig 1, A). The ulcers measuring up to 15 cm in diameter had erythematous and slightly elevated borders and their surfaces were covered with seropurulent and necrotic debris (Fig 1, B). As various treatments did not

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improve her clinical status, the patient requested a new skin biopsy. Ten months after the onset of the cutaneous disease a new biopsy was performed from the periphery of an ulcerated lesion and sent for histological evaluation. The surgical specimen was routinely fixed and paraffin embedded. Four-μm-thick serial sections were stained with Hematoxylin–Eosin (HE) and Periodic acid-Schiff diastase (PAS-D). Examination of the biopsy showed a suppurative and granulomatous dermatitis and panniculitis, pseudoepitheliomatous hyperplasia and areas of hemorrhage in the superficial and mid reticular dermis (Fig 2, A). In the granulomatous and suppurative areas (Fig 2, B) many haloed yeast-like cells in a mucoid background (Fig 2, C), very reminiscent of cryptococcus yeasts, could be appreciated. However, the yeast-like structures were accompanied by numerous septate hyphae which were highlighted by a PAS-D stain (Fig 2, D). Tissue specimens were cultured at 27 °C on Sabouraud dextrose agar (SDA) and yielded numerous yellowish-white, finely wrinkled, and butyrous colonies after one week (Fig 3, A). Slide culture microscopic examination revealed pseudohyphae,

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Irina Mărgăritescu, Aurel Doru Chiriţă, Viorica Marinescu

Figure 3. (A) Sabouraud dextrose agar plate with many cream-coloured smooth, mucoid yeast-like colonies; (B) Culture smear showing blastoconidia, pseudohyphae and true hyphae segmenting into arthroconidia of Trichosporon asahii.

Figure 4. (A) Healed lesions of cutaneous trichosporonosis 6 months after starting fluconazole; (B) small residual ulcer situated on lateral retro malleolar region of left ankle.

branched septate hyphae, arthroconidia, and blastoconidia (Fig 3, B). The isolate was identified as T. asahii based on the phenotypic and genotypic features. An in vitro antifungal susceptibility test was performed and indicated that the strain was very sensitive to amphotericin B, moderately sensitive to fluconazole, and resistant to itraconazole and ketoconazole. Blood and imaging tests, including a chest radiography and an abdominal ultrasonography revealed an elevated ESR and fibrinogen, thrombocytopenia (81,000/mm3), and hypoproteinemia (5.6 g/dl). The biochemical parameters including serum glucose, and liver and renal function tests were within normal limits. Blood and urine cultures did not yield any fungal growth. Our final diagnosis was primary cutaneous trichosporonosis caused by Trichosporon asahii.

The patient immediately started a regimen with fluconazole, 100 mg twice daily (200 mg/day) for 6 month, with a very good clinical response (Fig 4. A, B).

Discussion Trichosporon species are urease-positive, non-encapsulated basidiomycetous yeasts that commonly inhabit

the soil (1), and are part of normal flora of the gastrointestinal tract, upper respiratory tract, and human skin (16) . Sixteen of the 51 species in the genus Trichosporon have been associated with human infection (1). Occasionally, particularly in circumstances of high humidity, the fungus can proliferate, causing an unpleasant hair condition known as white piedra. The species responsible for this condition include T. ovoides, T. inkin, T. asahii, T. mucoides, T. asteroides, and T. cutaneum. Multiple Trichosporon species, including T. asahii and T. mucoides, are associated with summer-type hypersensitivity pneumonitis in Japan (13). Trichosporon spp. have increasingly become important opportunistic pathogens and cause of systemic illness in immunocompromised patients (24). The vast majority of human infections is caused by T. asahii (74%), followed by T. dermatis (12%) (6,10) . The risk factors for invasive infections are underlying malignant hematological diseases with long-term neutropenia (10,17,19), diseases with neutrophil dysfunction such as chronic granulomatous disease (20) , cystic fibrosis (21), hemochromatosis, end-stage renal disease, HIV/AIDS (1,23), diabetes mellitus (25), presence of a central venous catheter, Intensive Care Unit stay, peritoneal dialysis, steroid use and cytotoxic chemotherapy (10,16,19). Even though these November 2015

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Primary cutaneous trichosporonosis caused by Trichosporon asahii in a severe immunosuppressed woman

infections frequently present as fungaemia and the skin is secondarily involved in approximately 50% of the cases (10,19), there are rare reported cases of primary cutaneous trichosporonosis, as was the case with our patient. Indeed, extensive workup did not reveal spread of the infection beyond skin, in spite of the patient’s many immunosuppressive conditions. It is known that trichosporonis is associated with a high mortality rate of up to 55% - 80% (10,16,22,23) . Various virulence factors of Trichosporon species include enzyme products of Trichosporon such as proteinases, lipases, and phospholipases.

Also, Trichosporon cell wall contains a component similar to that of Cryptococcus neoformans (C. neoformans) which inhibits phagocytosis by macrophages (26). Interestingly, in our case the histopathological aspect of trichosporonosis on H&E stain was very reminiscent of a cryptococcal infection that typically presents with haloed yeast-like cells in a mucoid background. However, the concomitant presence of septate hyphae made a cryptococcal infection very unlikely (cryptococcus presents in biopsy specimens only as yeast-like cells) and pointed toward another closely related yeast infection. In tissue sections, the Trichosporon spp. can be recognized as pleomorphic blastoconidia, 3 to 8 micrometer in diameter, along with septate hyphae and arthroconidia that are produced by fragmentation of hyphal segments. Trichosporon spp. and C. neoformans are closely related organisms and share a number of surface antigens. As such, the latex agglutination test results for serum cryptococcal antigen are often positive in the setting of disseminated trichosporonosis (24). This widely used, rapid, and inexpensive test may provide an early clue to a Trichosporon infection. However, the precise identification of the fungus is possible only after the evaluation of phenotypic and genotypic culture characteristics. Similar to our case, purpuric cutaneous lesions are a frequent clinical manifestation. The clinical aspect corre-

sponds histologically to dermal hemorrhage and vasculitic changes due to direct invasion of blood vessels by the fungi. Trichosporon has the capacity to produce a biofilm that facilitates colonization of indwelling devices and permits both adherence to prosthetic material and reduction of the fungus’s exposure and susceptibility to antifungal drugs (26) . Hence, trichosporonosis requires a long term treatment regimen with an association of systemic antifungals.

Conclusions Trichosporon spp. have increasingly become important opportunistic pathogens and cause of systemic illness in immunocompromised patients and are associated with a high mortality rate of up to 55% - 80%. Even though these infections frequently present as fungaemia and the skin is secondarily involved in approximately 50% of the cases, there are rare reported cases of primary cutaneous trichosporonosis, as was the case with our patient. Trichosporon spp. and C. neoformans are closely related organisms and share a number of surface antigens.

The histopathological aspect of trichosporonosis on H&E stain may be very reminiscent of a cryptococcal infection that typically presents with haloed yeast-like cells in a mucoid background. Thus, the precise identification of the fungus is possible only after the evaluation of phenotypic and genotypic culture characteristics.Trichosporonosis requires a long term treatment regimen with an association of systemic antifungals due to fungus capacity to produce a biofilm that permits reduction of the fungus’s exposure and susceptibility to antifungal drugs.

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

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14. Taj-Aldeen SJ, Al-Ansari HI, Boekhout T, Theelen B. Co-isolation of Trichosporon inkin and

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Irina Mărgăritescu, Aurel Doru Chiriţă, Viorica Marinescu Candida parapsilosis from a scalp white piedra case. Med Mycol. 2004 Feb;42(1):87-92.

15. Kiken DA, Sekaran A, Antaya RJ, Davis A, Imaeda S, Silverberg NB. White piedra in children.

J Am Acad Dermatol. 2006 Dec;55(6):956-61.

16. Kontoyiannis DP, Torres HA, Chagua M, Hachem R, Tarrand JJ, Bodey GP, Raad II. Trichosporonosis in a tertiary care cancer center: risk factors, changing spectrum and determinants of outcome. Scand J Infect Dis. 2004;36(8):564-9.

17. Girmenia C, Pagano L, Martino B, D’Antonio D, Fanci R, Specchia G, Melillo L, Buelli M, Pizzarelli G, Venditti M, Martino P; GIMEMA Infection Program. Invasive infections caused by Trichosporon species and Geotrichum capitatum in patients with hematological malignancies: a retrospective multicenter study from Italy and review of the literature. J Clin Microbiol. 2005 Apr;43(4):1818-28.

18. Suzuki K, Nakase K, Kyo T, Kohara T, Sugawara Y, Shibazaki T, Oka K, Tsukada T, Katayama N. Fatal Trichosporon fungemia in patients with hematologic malignancies. Eur J Haematol.

2010 May;84(5):441-7..

19. Fournier S, Pavageau W, Feuillhade M, Deplus S, Zagdanski AM, Verola O, Dombret H, Molina JM. Use of voriconazole to successfully treat disseminated Trichosporon asahii infection in a patient with acute myeloid leukaemia. Eur J Clin Microbiol Infect Dis. 2002 Dec;21(12):892-6.

20. Wynne SM, Kwon-Chung KJ, Shea YR, Filie AC, Varma A, Lupo P, Holland SM. Invasive infection with Trichosporon inkin in 2 siblings with chronic granulomatous disease. J Allergy Clin Immunol. 2004 Dec;114(6):1418-24.

21. Hickey PW, Sutton DA, Fothergill AW, Rinaldi MG, Wickes BL, Schmidt HJ, Walsh TJ. Trichosporon mycotoxinivorans, a novel respiratory pathogen in patients with cystic fibrosis. J Clin Microbiol. 2009 Oct;47(10):3091-7. doi: 10.1128/JCM.00460-09.

22. Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, Pastore D, Picardi M, Bonini A, Chierichini A, Fanci R, Caramatti C, Invernizzi R, Mattei D, Mitra ME, Melillo L, Aversa F, Van Lint MT, Falcucci P, Valentini CG, Girmenia C, Nosari A. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006 Aug;91(8):1068-75.

23. Walsh TJ, Groll A, Hiemenz J, Fleming R, Roilides E, Anaissie E. Infections due to emerging and uncommon medically important fungal pathogens. Clin Microbiol Infect. 2004 Mar;10 Suppl 1:48-66.

24. Tashiro T, Nagai H, Kamberi P, Goto Y, Kikuchi H, Nasu M, Akizuki S. Disseminated Trichosporon beigelii infection in patients with malignant diseases: immunohistochemical study and review. Eur J Clin Microbiol Infect Dis. 1994 Mar;13(3):218-24.

25. Chellan G, Shivaprakash S, Karimassery Ramaiyar S, Varma AK, Varma N, Thekkeparambil Sukumaran M, Rohinivilasam Vasukutty J, Bal A, Kumar H. Spectrum and prevalence of fungi infecting deep tissues of lower-limb wounds in patients with type 2 diabetes. J Clin Microbiol.

2010 Jun;48(6):2097-102.

26. Di Bonaventura G, Pompilio A, Picciani C, Iezzi M, D’Antonio D, Piccolomini R. Biofilm formation by the emerging fungal pathogen Trichosporon asahii: development, architecture, and antifungal resistance. Antimicrob Agents Chemother. 2006 Oct;50(10):3269-76.

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The influence of TB chemoprophylaxis in patients with moderate to severe psoriasis treated with biological agents. A regional experience

THE INFLUENCE OF TB CHEMOPROPHYLAXIS IN PATIENTS WITH MODERATE TO SEVERE PSORIASIS TREATED WITH BIOLOGICAL AGENTS. A REGIONAL EXPERIENCE IMPACTUL CHIMIOPROFILAXIEI TB ASUPRA PACIENȚILOR CU PSORIAZIS MODERAT-SEVER TRATAT CU AGENȚI BIOLOGICI. O EXPERIENȚĂ REGIONALĂ Neamțiu Victor(1),(2),Gug Georgiana(3), Diaconeasa Adriana(4), Solovan Caius(1),(3) 1 University of Medicine and Pharmacy “Victor Babeș”, Timișoara, Romania “Vasile Goldiș” West University of Arad, Faculty of Medicine, Pharmacy and Dentistry, Arad, Romania 3 University Clinic of Dermatology and Venereology, Timișoara, Romania 4 Dermatology Outpatient Care Center, “Grigore Alexandrescu” Children’s Hospital, Bucharest, Romania 2

Corresponding author: Gug Georgiana –MD, dermatology-venereology resident University Clinic of Dermatology and Venereology, Timișoara, Romania Adress: P-ța Mărășești nr. 5, Timișoara, Timiș, Romania Phone number: +40752128832, E-mail address: georgiana_gug@yahoo.com

Open Access Article

Abstract Keywords: psoriasis, biologic treatment, chemoprophylaxis, PASI score

Cite this article: Neamțiu Victor, Gug Georgiana, Diaconeasa Adriana, Solovan Caius The influence of TB chemoprophylaxis in patients with moderate to severe psoriasis treated with biological agents.

A regional experience.

RoJCED 2015; 2(4):276-282

276

Introduction Psoriasis is a chronic immune mediated inflammatory skin condition that can appear at any age and fluctuates in severity. Commonly it affects the scalp, elbows and knees but it can appear anywhere on the body. Modern medicine came with innovative therapies depending on the stage of Psoriasis and its impact on other parts of the body like the joints. The moderate to severe Psoriasis and the Psoriatic arthritis has undergo a major change with the appearance of biological therapies, substances who are targeting immune components of different pathophysiological processes.

Biologic treatments are generally well tolerated and safe but they can predispose the patients opportunistic infections because of their immunosuppressive status due to this therapy. One serious matter of concern is the development of TB in some of the patients treated with anti TNF agents mainly in countries with a higher incidence of tuberculosis. Patients receiving this type of therapy are closely monitored for TB and if a latent infection is found the chemoprophylaxis will be performed.

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Neamțiu Victor, Gug Georgiana, Diaconeasa Adriana, Solovan Caius

Purpose of the study The impact of tuberculosis (TB) chemoprophylaxis on biological treatment in moderate to severe psoriasis - assessed by PASI (Psoriasis Area and Severity Index) score - as well as the incidence of LTBI (Latent Tuberculosis Infection) and the risk for LTBI in patients with moderate to severe psoriasis on biological treatment.

Materials and methods A total of 72 patients with moderate to severe psoriasis were included in this retrospective study. The inclusion criteria was represented by the patients with moderate to severe psoriasis treated with biologic therapy for at least one year of continuous treatment. The study analyses the patients between years 2005 to 2014. We followed patients' PASI score evolution for a period of 12 months starting with the baseline PASI (PASI score at the initiation of biologic therapy). Upon the basis of TB chemoprophylaxis initiation criteria, patients were divided into two groups: Lot 1 consisting of 37 patients who received only biologic therapy during the first year of surveillance and Lot 2with 35 patients to whom TB chemoprophylaxis was applied at least one month before biological treatment initiation.

The exclusion criteria was given by active TB infection, less than 1 year of biologic therapy treatment, discontinued or stopped therapy, PASI < 10 and BSA <10.

Results TB chemoprophylaxis does not significantly influence the efficiency of the biological treatment outcome in moderate to severe psoriasis.

The relative risk of developing LTBI in biologic therapy patients with moderate to severe psoriasis is 122 times higher than in the general population.

Conclusions The association of TB chemoprophylaxis and biological treatment is a necessity in many patients with moderate to severe psoriasis; this should be initiated by the physician in collaboration with the pneumologist, after investigation and correct diagnosis of TB status.

Limitation Positive reactions have not been confirmed by other methods besides TST. Other methods who come to support TST are QuantiFERON® test, in order to exclude active TB infection, clinical examination, chest X-ray and bacteriological studies.

Rezumat Cuvinte-cheie: psoriazis, tratament biologic, chimioprofilaxie, scor PASI

Introducere Psoriazisul este o patologie cronică inflamatorie mediată imun, care poate apărea la orice vârstă având fluctuaţii de severitate. Cel mai adesea afectările cutanate sunt la nivelul scalpului, coatelor şi genunchilor dar poate avea orice localizare. Medicina modernă a venit cu terapii inovative în funcţie de stadiul, gradul de afectare şi impactul Psoriazisului asupra altor părţi ale corpului, precum articulaţiile. Psoriazisul moderat sever şi Artrita psoriazică au trecut printr-o schimbare majoră de abordare odată cu apariţia terapiilor biologice, substanţe ce ţintesc componente imune a diferite procese fiziopatologice. Terapiile biologice sunt în general bine tolerate şi sigure dar pot supune pacientul unor predispozitii de a dezvolta diferite infectii oportuniste, datorită statusului imunosupresiv pe care îl determină.

Unul din motivele serioase de îngrijorare este infecţia tuberculoasă la unii din pacienţii trataţi cu agenţi anti TNF. Această situaţie este mai probabilă în ţările cu o incidenţă crescută a tubeculozei. Pacienţii care urmează

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The influence of TB chemoprophylaxis in patients with moderate to severe psoriasis treated with biological agents. A regional experience

acest tip de terapie sunt monitorizaţi îndeaproape pentru TB, şi în cazul unei infecţii latente, va fi introdusă terapia chimioprofilactică.

Scopul studiului Impactul chimioprofilaxiei TB (evaluat prin scorul PASI) în cazul pacienților cu Psoriazis moderat sever aflați în tratament cu agenți biologici cât și incidența infecției TB latente și riscul de dezvolta TB latentă a pacienților cu Psoriazis moderat sever tratat cu terapie biologică.

Materiale și metode În acest studiu retrospectiv a fost evaluat un numar de 72 de pacienți cu Psoriazis moderat sever. Au fost incluși toți pacienții cu Psoriazis moderat sever tratați cu agenți biologici pe durată de cel puțin un an (tratament continuu). Analiza pacienților a fost facută în intervalul anilor 2005 – 2014 urmarindu-li-se evoluția scorului PASI pe o perioadă de 12 luni începând cu scorul PASI inițial. Pe baza criteriilor de includere și a chimioprofilaxiei TB, pacienții au fost împărțiți în două loturi: Lot 1 format din 37 de pacienți care au urmat tratament doar cu terapie biologică în primul an de evaluare și Lot 2 alcătuit din 35 de pacienți cărora le-a fost administrată chimioprofilaxia TB înainte cu cel puțin o lună de inițierea terapiei biologice.

Criteriile de excludere au constat în Infecția TB activă, mai puțin de 1 an de terapie biologică, întreruperea parțială sau totală a tratamentului, scor BSA și scor PASI <10.

Rezultate Chimioprofilaxia TB nu influențează semnificativ eficiența tratamentului biologic în Psoriazisul moderat sever.

Riscul relativ de infecție TB latentă, este de 122 ori mai mare la pacienții aflați pe terapie biologică față de populația generală.

Concluzii Asocierea tratamentului biologic cu chimioprofilaxia TB reprezintă o necesitate în cazul multor pacienți cu Psoriazis moderat sever; această chimioprofilaxie ar trebui inițiată de medicul curant în colaborare cu pneumoftiziologul, după investigații amănunțite și diagnoticul corect al statusului TB. Limitări Reacțiile pozitive nu au fost confirmate prin alte metode în afara intradermoreacției la PPD.

Introduction Psoriasis is a systemic immune-inflammatory, chronic disease with a complex genetic conditioning and influenced by environmental factors. The prevalence of psoriasis in 2013 was estimated between 0.9% and 8.5% worldwide. Age, gender, environment, lifestyle, geography, ethnicity and genetics are factors that intervene in this prevalence.

Before age of 9 Psoriasis is uncommon and it varies from 0 to 0,55%, in adults the peak of psoriasis is between 20-29 or 30-39 years old and it appears that in western countries is estimated to affect 2-4% of population (1). Targeted biologic therapy became the most important tool in the treatment of this disease especially in moderate to severe forms. There is a relationship between TB infection and biologic therapy in psoriasis, especially in terms of the risk of reactivation LTBI (Latent Tuberculosis Infection)(2),(3).Romania ranks first in the EU in terms of prevalence of tuberculosis(4).

The guidelines recommend stopping the biological therapy and introducing chemoprophylaxis for LTBI based on tuberculin skin testing (TST) (positive or suspected anergy) and/or positive QuantiFERON® test, plus the exclusion of active TB infection (by clinical examination, chest Xray and bacteriological studies) (5),(6),(7).TST anergy was investigated regarding other diseases like

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Sarcoidosis or immunosuppressive conditions or therapies. In this paper, the authors propose to assess the impact of TB chemoprophylaxis on biological treatment in moderate to severe psoriasis-assessed by PASI(Psoriasis Area and Severity Index) score-as well as the incidence of LTBI and the risk for LTBI in patients with moderate to severe psoriasis under biological treatment.

Materials and methods Our work presents a retrospective study, targeting all patients with moderate to severe psoriasis who received biologic therapy between years 2005-2014 and followed in their first 12 months of treatment at the University Clinic of Dermatology and Venereology Timișoara. At the initiation of the biological treatment every patient was screened for TB infection. The initiation of TB chemoprophylaxis and the efficacy of the biological therapy during the first 12 months of treatment, with or without TB chemoprophylaxis, were monitored.

As the monitoring period spread from initiation to month 12 of treatment, all adult patients who initiated biologic therapy for moderate to severe psoriasis (PASI ≥ 10, BSA ≥ 10) and who have completed at least 12 months of continuous biological treatment, entered the study. The exclusion criteria was given by active TB infection, less than 1

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NeamČ&#x203A;iu Victor, Gug Georgiana, Diaconeasa Adriana, Solovan Caius

Table 1. Biological therapy administrated to patients Lot 1

Lot 2

PRODUCT

WITHOUT LTBI

LTBI

TB

WITOUT LTBI

LTBI

TB

TOTAL Distribution of patients according to treatment

Etanercept

8

0

0

0

6

0

14

Adalimumab

15

0

0

0

17

0

32

Infliximab

5

0

0

0

7

0

12

Ustekinumab

9

0

0

0

5

0

14

TOTAL

37

0

0

0

35

0

72

year of biologic therapy, discontinued or stopped therapy, PASI<10 and BSA <10. In conformity with the national biologic therapy protocols at the moment of admittance in the program, every patient signed and agreed with the inform consent. Studypatients were separated in 2 lots. Lot 1 included patients who received only biological treatment.

Lot 2 consisted of patients who received TB chemoprophylaxis for at least six months. After at least one month of chemoprophylaxis, the biological treatment was initiated. According to the protocols, at the initiation of biological treatment, all patients were screened for TB infection. This consisted of careful investigation of previous exposure, history and risk factors, TST, chest radiograph as well as pneumological examination. The decision to start TB chemoprophylaxis was made by the pneumological diagnosis of LTBI. This diagnosis was identified according to the protocol, through interpretation of Mantoux test (IDR= intradermal reaction) to 2UI PPD test (TST).In the national protocol of biological therapies for moderate to severe psoriasis, a value equal or greater than 5mm is signaling a positive diagnosis. Negative or false negative results are not considered a major problem for chemoprophylaxis. Chemoprophylaxis for LTBI was performed according to the Romaniaâ&#x20AC;&#x2122;s protocol. This consisted of monotherapy with Isoniasid, given daily 10mg/kg/day or 200mg/m2 body surface area in children, 5mg/kg/day, in adults (maximum 300mg/day) for at least 6 months. To assess the biological therapy efficiency, PASI score was studied in both Lots at baseline, month 3, month 6, month 9 and month 12 of biological treatment.

PASI evolution was studied by comparing the two lots. Twelve months after the biological therapy, patients without TB chemoprophylaxis (Lot 1) were controlled by performing TST and studying this tuberculin conversion.

Data was processed by SPSS.14.0 for Windows, Epi Info Analysis, MedCalc in order to establish the incidence of LTBI, the variance of the lots according to the initiation of biologic therapy, TST positivity and to assess PASI scores recorded at baseline and during treatment.

Results Based on the above mentioned, criteria the study included 72 patients with moderate to severe psoriasis. On the basis of initiating TB chemoprophylaxis, patients were divided into two lots: patients without TB chemoprophylaxis (Lot 1) consisted of 37 patients who had received only biologic therapy during the first year and patients with TB chemoprophylaxis (Lot 2) consisting of 35 patients who have undergone initiation of TB chemoprophylaxis followed by the biological treatment at least1 month later. The lot with patients without TB chemoprophylaxis (Lot 1) includes 17 male patients and 20 females; mean age = 50.81 years (min 25, max 74). The lot with TB chemoprophylaxis (Lot 2) has 19 male patients and 16 female patients; mean age = 53.55 years (min 33, max 71).

Global average age is 52.18 years, Standard deviation being 12.68 years. Patients who followed the monotherapy with biological products, received their classical doses as recommended by the national program (Order No. 218/2010). The results are listed in table 1 and a certain heterogeneity in product usage with a higher tendency to Adalimumab can be observed. The TB chemoprophylaxis treatment taken by patients in Lot 2 was decided on a positive TST in all 35 cases. In figure 1 and Table 2 can be observed the PASI score evolution in both groups. In Lot 1,which contains the patients without TB chemoprophylaxis a decease in PASI score can be observed, from 26.17, at the moment of biologic therapy initiation to 4.33 after 12 months, statistically validated (One sample t test-t=3.080 df=4, p=0.0369, 95% CI-1.198 to 23.10, KS normality test p> 0.10). In Lot 2, which contains the patients with TB chemoprophylaxis it is observed a decrease in PASI score from 22.85 at initiation to 13,81 after 12 months, statistically validated (One sample t test-t=16.26 df=4, p<0.0001, 95% CI: 12.77 to 18.03, KS normality test, p>0.10).

By comparing the lots evolution it results that there is a more significant decline in the case of patients without TB chemoprophylaxis (Lot 1) <PASI score decreased 82.90%>. However, in the case of patients with TB chemoprophylaxis (Lot 2) this downNovember 2015

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Figure 1.

The influence of TB chemoprophylaxis in patients with moderate to severe psoriasis treated with biological agents. A regional experience

Evolution of PASI score each 3 months in the two lots

Table 2. PASI score evolution in Lot1 and Lot2 PASI Lot 1 Baseline PASI value

26,17

22,87

Start value

100%

100%

PASI value 3

13,84

18,31

Decrease in PASI score compared to baseline value (m3)

47,12

19,92

PASI value 6

8,22

15,60

Decrease in PASI score compared to baseline value (m6)

68,56

31,76

6,3

17,29

Decrease in PASI score compared to baseline value (m9)

75,93

24,39

PASI value 12

4,33

13,81

Decrease in PASI score compared to baseline value (m12)

83,44

39,59

PASI value 9

ward trend also persists, PASI score being 30.49%.

After one year of monitoring patients without TB chemoprophylaxis from Lot 1, following retest TST and pneumology surveillance, 9 cases presented tuberculin conversion and were diagnosed as LTBI.

Discussions According to the results, we discuss the following issues: A. PASI scores evolution for each group in month 3, month 6, month 9 and month 12, and the comparation of the PASI scores evolution between the two lots.

B. The relation between TB infection and biological treatment in psoriasis, and the default relative risk for LTBI in patients with biological therapy.

280

PASI Lot 2

o

A. Comparing different types of evaluation/ score, Puzenat concluded that the PASI score is yet the most comprehensive method used for assessing changes of the psoriasis skin lesions.(8) If we analyze the evolution of PASI scores in Lot 1 of patients, without TB chemoprophylaxis, we observe a linear decrease of these values. For Lot 2 of patients with TB chemoprophylaxis, a decrease from baseline can be observed, in month 3 and month 6 interval. This period is followed by the interruption of chemoprophylaxis with Isoniasid when there is a slight exacerbation of psoriasis symptoms, translated by an increase of PASI score in month 9. After this, the PASI score returns to a downward pattern, in month 12 the PASI score becomes lower than the one in month 6. PASI scores evolution, respectively therapeutic efficiency of biological therapies

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Neamțiu Victor, Gug Georgiana, Diaconeasa Adriana, Solovan Caius

was similar in male and female patients. Thereby the initial PASI value / PASI after 12 months in female patients was 27.27/4.76 compared to male patients who had values to 29.84/5.32; these findings were according to the literature (9),(10). After the analysis of PASI values in Lot 1, only on biological therapy, we observe a reduction in baseline scores of 6.04 times after 6 months. Analyzing PASI values in Lot 2 who received TB chemoprophylaxis, we notice a reduction in baseline scores of 1.65 times after 6 months of biologic therapy. A linear relationship between the values of PASI scores at month 12 can be observed (R Squared.021) by comparing the PASI score values of the two groups (Lot 1 vs Lot 2). We notice that the initial (baseline) PASI in Lot 2even if is though lower compared to Lot 1, it did not reach the month 12 PASI value of the Lot 1. By globally analyzing data, it can be said that the association of TB chemoprophylaxis reduced the intensity of psoriasis biologic therapy response. This theory has to be analyzed furthermore on different age stages, health status and a larger number of patients. This is unlikely to be caused by the TB chemoprophylaxis itself. There are even reports of cases in which the treatment of tuberculosis infection resulted in improvement of psoriasis even in the absence of specific therapies(11). In those cases the infection/TB would be a triggering factor as it is the well-known streptococcal infection, in which case psoriasis responds well to antibiotics. Other papers suggest that anti-TNF alpha treatment is also effective in psoriatic arthritis patients with concomitant LTBI and none of the chemoprophylaxis or LTBI influence the treatment response (23). Analyzing the PASI values for Lot 2 we noticed that, although PASI values after the ending of six months of chemoprophylaxis were low, they had a stagnation or even a statistically insignificant small increase (to control at month 9).It is possible that the chemoprophylaxis had a positive effect on PASI score in those patients, as it is reported that antibiotherapy improves psoriasis in streptococcal associated infections. Another possible explanation could be immuno-inflammatory repositioning after chemoprophylaxis, reducing hyperergia dependent on interferon (Th1) as it may happen upon interferon therapy of hepatitis that is known to frequently trigger psoriasis eruptions in children (12).The QuantiFERON® test that measures IFN gamma, is still linked also to Th memory cells. Thus due to the TB vaccination memory the test could not be so useful for screening in our country. The average value of the baseline/before biological therapy PASI scores and at the assessment of TB infection status are correlated r=0.421, which means that 42.1% of the variance is due to psoriasis. The percentage of 57.9% was due to associated diseases or other factors like economical status, smoking, TB contact.

B. It is known that there is a connection between population with chronic inflammatory pathology and tuberculosis. Gomez-Reino described the link between rheumatoid arthritis treated with anti-TNF and the predisposition to tuberculosis, revealing that the

risk of active TB increases in this cases(2); this connection was demonstrated also by Askling. The author described in his study the characteristics and the risk of tuberculosis reactivation in patients treated with anti-TNF for rheumatoid arthritis in Swedish population (3). We mention that Romania’s population benefits of TB prevention through BCG vaccine which is included in the National Immunization Program and given at birth. Due to the level of protection, more or less significantly, against the development of tuberculosis in children and a possible decrease in mortality from tuberculosis in high endemic countries, WHO (World Health Organization) recommends the vaccination of infants in Romania. Efficacy of BCG vaccine is still a highly disputed topic; some authors consider it to be varying from unknown to15-20 years (13),(14) .We can conclude that our patients don’t benefit from the effect of immunization. However we cannot exclude memory of the Th lymphocytes that secrete interferon, which can influence the interpretation of both TST and interferon-gamma based test/ Quantiferon® (15),(16). According to the Tuberculosis Network European Trials Group (TBNET) chemoprophylaxis for LTBI include: Isoniasid treatment for 6-9 months, 3 months rifampicin and isoniasid or 4 months rifampicin (17).The Protocols of Romania follows the scheme with Isoniasid alone for at least 6 months. Patients included in our study followed this scheme, as mentioned above. Is important to specify that the pneumologist can individualize the therapy according to each case. Therefore, in some situations they decide that the chemoprophylaxis treatment duration is needed for 9 months. In other cases they can postpone the initiation of biologic therapy after 2 months of chemoprophylaxis. We also would like to mention that the TST method was modified from 2UI PPD to 5UI PPD. Our study patients are not affected by this protocol change because we evaluated the Lots between years 2005 - 2014. It is noteworthy that in Romania’s protocols in case of the patients with hypersensitivity, intolerance, allergies or contraindication of Isoniasid it doesn’t exist a second line chemoprophylaxis for LTBI. In other countries protocols, Rifampicin is the second line chemoprophylaxis medication. Although the therapy response of the patients after the 1st year of treatment is not the subject of this study, is noteworthy that at 12 month surveillance, in Lot 1 without chemoprophylaxis, 9 cases of tuberculin conversion appeared (based on positive TST).This cases were diagnosed as LTBI. Despite tuberculin conversion and according to the literature, the biological therapy was effective in the treatment of moderate to severe psoriasis (18).Is important to mention that in this case patients were no longer bio-naive and even with positive Quantiferon test, the approach in this situation should be carefully monitored. Based on obtained data in our study, the attack rate for LTBI after biologic therapy is 13.88%. This value is above the average for the general population of 11.23/10.000 in Timiș County.

Although the most common method of diagnosing TB in Romania is TST, in many cases an over-reaction to this test in patients with psoriasis was reported. It November 2015

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The influence of TB chemoprophylaxis in patients with moderate to severe psoriasis treated with biological agents. A regional experience

is difficult to say whether these hyperergic tuberculin test cases are specific to LTBI or TB or whether there is a cross-reaction with the immune system that triggers this hyperergic tuberculin reaction. Generally, in psoriasis patients, it is considered to be an over diagnosis of LTBI. In the literature are mentioned the TST limitations in the case of patients who are immunosuppressed due to several autoimmune diseases or medications (24). Given the relative risk of developing LTBI in patients with biological therapy, we compared it with the relative risk of developing LTBI for the general population for Timiș County, Romania.

The result was surprising: the patients relative risk of developing LTBI under biologic therapy is 122 times higher than the general population (P <0.0001, 95%, z statistic 16.257, CI 68.5627 to 218.5324).

Several studies that compared the incidence of TB in patients treated with TNF-alpha inhibitors versus the general population were published. High rates of TB cases associated with anti-TNF therapy (Infliximab®) were reported for Spain(2), Korea(19), Japan(20) and Portugal(21). Lowest rates are found in USA(22) and Sweden(3). According to this study, Romania shows a similar rate as Spain.

Conclusions Considering Romania’s epidemiological status, the association of TB chemoprophylaxis is a necessity so the treatment initiation requires TB investigation. This study confirms the hypothesis that the incidence of

LTBI is increased in patients with moderate to severe psoriasis proposed for biological treatment, which increases the relative risk and the chances for LTBI. Although there is a high relative risk of developing LTBI, biological therapies have emerged as a highly effective option of increasing the quality of life for patients and reducing comorbidities in psoriasis.

Hence, subsequent studies to better decipher drug interactions and co-morbid implications in order to optimize biological treatment, with better scores of benefit / risk and therapeutic indication / side effects are urgently required.

Disclosure The authors report no conflicts of interest in this work. Every patient signed and agreed with the inform consent at the moment of admittance in the program. Neamtiu Victor, Caius Solovan contributed in data collection, extraction, analysis of the data.

Georgiana Gug, Adrian Diaconeasa, Caius Solovan in writing and editing the manuscript.

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Histopatological and immunohistochemical aspects (expression of matrix metalloproteinase 9) in polymyositis and dermatomyositis

HISTOPATOLOGICAL AND IMMUNOHISTOCHEMICAL ASPECTS (EXPRESSION OF MATRIX METALLOPROTEINASE 9) IN POLYMYOSITIS AND DERMATOMYOSITIS ASPECTE HISTOPATOLOGICE ȘI IMUNOHISTOCHIMICE (EXPRESIA MATRIX METALLOPROTEINAZEI 9) ÎN POLIMIOZITĂ ȘI DERMATOMIOZITĂ Claudia Cîrstea1, Loredana Elena Stoica², Andreea Lili Bărbulescu², Claudia Valentina Georgescu³, Rucsandra Dascălu4, Georgescu Diana Monica5, Virgil Pătrașcu² University of Medicine and Pharmacy of Craiova - Phd student 2 University of Medicine and Pharmacy of Craiova 3 Pathology Departament – Emergency County Hospital of Craiova 4 Dermatology Clinic - Emergency County Hospital of Craiova 5 University of Medicine and Pharmacy of Craiova Craiova student 1

Corresponding author: Claudia Cirstea claudia_cirstea22@yahoo.com, Phone +40761627846

Open Access Article

Abstract Keywords: immunohistochemistry, matrix metalloproteinase9, dermatomyositis, polymyositis Cite this article: Claudia Cîrstea, Loredana Elena Stoica, Andreea Lili Bărbulescu, Claudia Valentina Georgescu, Rucsandra Dascălu, Georgescu Diana Monica, Virgil Pătrașcu.

Histopatological and immunohistochemical aspects (expression of matrix metalloproteinase 9) in polymyositis and dermatomyositis.

RoJCED 2015; 2(4): 284-289

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Matrix metalloproteinases (MMP) are a family of structural and functional related endopeptidases, calcium-dependent, zinccontaining which are responsible for the tissue remodeling and degradation of the extracellular matrix. We performed a retrospective study on 20 patients with poly/dermatomyositis with the aim of detecting the expression of matrix metalloproteinase 9 in these patients. Immunohistochemistry showed that the expression of MMP-9 in degenerate muscle fibers was absent in 4 cases. All other cases (16 cases) had positive weak or moderate intensity in the cytoplasm of degenerate striated muscle fibers. In all cases analyzed of unaffected striated muscle fibers MMP 9 was negative. MMP 9 was intense expressed in lymphocytic inflammatory infiltrate, and intense or moderate expressed in the vessel walls.

The overexpression of matrix metalloproteinases 9 on degenerated muscle fibers may be an important event in the multistep process of dermatomyositis and polymyositis and may play an important role in the development of new therapeutic strategies.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Claudia Cîrstea, Loredana Elena Stoica, Andreea Lili Bărbulescu, Claudia Valentina Georgescu, Rucsandra Dascălu, Georgescu Diana Monica, Virgil Pătrașcu

Rezumat Cuvinte-cheie: imunohistochimie, matrix metaloproteinaza 9, dermatomiozită, polimiozită

Matrix mataloproteinazele sunt o familie de endopeptidaze înrudite structural și funcțional, calciu dependente, cu conținut de zinc, care sunt responsabile de remodelarea și degradarea matricei extracelulare. Am efectuat un studiu retrospectiv pe 20 pacienți cu poli/ dermatomiozită cu scopul de a determina expresia matrix metaloproteinazei 9. Examenul imunohistochimic a arătat că expresia MMP 9 în fibrele musculare degenerate a fost absentă în 4 cazuri. Toate celelate cazuri (16 cazuri) au prezentat imunomarcaj pozitiv cu intensitate slabă sau moderată la nivelul citoplasmei fibrelor musculare striate degenerate. Fibrele musculare striate neafectate au fost negative la MMP 9 în toate cazurile analizate. MMP 9 a fost intens exprimat în limfocitele din infiltratul inflamator și intens sau moderat exprimat în pereții vaselor.

Imunoexpresia crescută a MMP-9 poate fi un eveniment important în procesul patologic ce se desfasoară în mai multe etape în dermatomiozită și polimiozită.

Supraexpresia MMP 9 la nivelul fibrelor musculare striate degenerate din dermato/polimiozită poate avea un rol important în dezvoltarea unor noi strategii terapeutice în cazul pacientilor cu DM și PM.

Introduction Polymyositis and dermatomyositis are conditions based on chronic inflammation of striated muscle (myositis) and characterized by multiple clinical features, predominated by symmetrical proximal weakness, associated with laboratory parameters changes (significant increases of activity muscle enzyme, morphological abnormalities in muscle biopsy and characteristic electromyogram appearance).

The annual incidence of these diseases is 2-10 new cases per million people, and the gender distribution is 2.5: 1 in favor of women report being unitary in children and in cases associated with malignancies (1, 2).

Matrix metalloproteinases (MMP) are a family of structural and functional related endopeptidases, calcium-dependent, zinc-containing which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. MMPs are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. Currently 23 families of matrix metalloproteinase are known. They are classified in six categories: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others (3).

Dermatology Clinic of Clinical Emergency County Hospital of Craiova. The study was conducted in accordance with ethical and moral principles of the “Declaration of Human Rights” Helsinki approved by the local ethics committee. Patients signed informed consent, they met diagnostic criteria and had no exclusion criteria. Histopathological and immunohistochemical examamination were performed in the Department of Pathology of the same hospital.

The excised tissue fragments were fixed in buffered formalin 10% and processed using the classical paraffin embedding technique. The paraffin blocks were sectioned in 3-4 microns thick and sections were initially stained with the usual Hematoxylin-Eosin staining. Subsequently, serial sections were carried out which were displayed on glass slides coated with Poly-L-lysine for the immunohistochemical examination. The immunohistochemical technique used was the two-step technique with streptavidin-biotin as secondary antibody (LSAB plus kit, DakoCytomation, Denmark), and the chromogen used for visualizing the immunoreactions was 3-3´diaminobenzidine. The primary antibody used was represented by mouse monoclonal MMP 9 antibody; clone IIA5, Novus Biological, dilution 1:50. Sections were counterstained with haematoxylin.

Patients and methods

Results

We performed a retrospective study on 20 patients with poly/dermatomyositis collecting biopsy pieces for histopathological examination in

The study group consisted of 14 women and 6 men. Patients age was between 6 years to 79 years. In our study lot 4 patients associated anothNovember 2015

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Figure 1.

Figure 3.

Histopatological and immunohistochemical aspects (expression of matrix metalloproteinase 9) in polymyositis and dermatomyositis

Skin with degeneration of basal layer of epidermis and lymphocytic perivascular infiltrate HE staining, x100

Perifascicular atrophy of muscular fibres and nuclei iternalization, HE staining x100

er collagen disease (systemic scleroderma, lupus erythematosus, rheumatoid arthritis). All patients complained of pain and weakness of the proximal musculature, with varying degrees of functional impotence. Skin lesions were present in 8 cases as facial and chest rash. In two of these cases were described Gottron papules with the available feature. Laboratory tests have shown significant increases in muscle enzyme levels in 13 cases and 17 patients had a moderate biological inflammatory syndrome.

Histopathologic examination of skin biopsy in dermatomyositis, showed epidermal atrophy with vacuolar degeneration of basal keratinocytes and lymphocytic inflammatory infiltrate located predominantly perivascular in the superficial dermis (figure 1). Histological examination of the muscle fragments showed in striated muscle fibers the presence of perifascicular atrophy with enlarged nuclei and internalized nuclei in striated muscle fibers.(figure 2, 3, 5). In some places the muscle

286

Figure 2.

Figure 4.

Perifascicular atrophy of muscular fibres, HE staining, x40

Degenerated skeletal muscle fibers with loss of transverse striations, HE staining X 100

fibers showed degenerative lesions with intracytoplasmic vacuolation along with loss of transverse striations (figure 4). At distance of atrophic muscle fibers, in perimysium and sometimes in endomysium was present lymphocytic inflammatory infiltrate arranged perivascular (figure 6). The blood vessels located in the perifascicular atrophy areas were numerical reduced and had sometimes turgid endothelial cells and reduced lumen (figure 7). The blood vessels located near of muscle fibre atrophy were sometimes dilated.

Immunohistochemistry showed that the expression of MMP-9 in degenerate muscle fibers was absent in 4 cases. All other cases (16 cases) had positive weak or moderate intensity in the cytoplasm of degenerate striated muscle fibers (figure 8). In all cases of unaffected striated muscle fibres analyzed MMP 9 was negative. The MMP 9 immunoexpression in the interstitial inflammatory infiltrate was detected in all cases. MMP 9 expression in inflammatory cells was high but the percentage

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Claudia Cîrstea, Loredana Elena Stoica, Andreea Lili Bărbulescu, Claudia Valentina Georgescu, Rucsandra Dascălu, Georgescu Diana Monica, Virgil Pătrașcu

Figure 5.

Figure 7.

Muscular fibres atrophy with enlarged and internal nuclei, HE staining x200

Capillary with turgescent endothelium and reduced lumen, perivascular lymphocytic inflammatory infiltrate, HE staining, x200

of positive inflammatory cells was relatively low.

Thus, MMP 9 was detected in the cytoplasmic level of the lymphocytes (figure 9).

Expression of MMP 9 was constantly present in the endothelial cells of blood capillaries and into the smooth muscle layer of arteriolar blood vessels. Blood vessels presented moderate and high intensity expression of MMP 9 in the cytoplasm of endothelial cells (figure 10) and in the smooth muscle cells (figure 11).

Discussions Dermatomyositis and polymyositis are inflammatory myopathies with symmetrical muscle weakness that develops in weeks or months. Associate multiorgan involvement (lung, gastrointestinal tract, heart, joints) and both diseases have an increased risk of cancer (ovarian, lung, breast, pancreas, lymphoma non-Hodgkin) (4).

Muscle injuries associate the issues of destruction and regeneration, afterwards muscular atro-

Figure 6.

Figure 8.

Lymphocytic perivascular inflammatory infiltrate, HE staining x200

MMP 9 expressed with moderate intensity in atrophic muscular fibers, x100

phy with perivascular inflammatory infiltrates and perifascicular dysplasia. In chronic forms fibrosis is observed. In perimysium and sometimes in endomysium was observed a perivascular lymphocytic inflammatory infiltrate. The main histopathologic characteristic in dermatomyositis is the degenerate myofibrils and atrophy who are disposed perifascicular. These changes arranged perifascicular result from the destruction of capillaries that populate this region. This capillary depletion leads to hypoxia and injury of myofibrils. Also, in muscle biopsy (in particular juvenile dermatomyositis) careas of neovascularization can be observed, which are induced by the increase in the concentration of endothelial growth factor in serum and muscle.

(VEGF). This increase of VEGF is induced by hypoxia- produced by decreasing capillaries (5).

As for the pathogenesis of these diseases, immunohistochemical studies show that the muscle fiber necrosis derived from the activation of T helper lymphocytes, T suppressor lymphocytes November 2015

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Figure 9.

Figure 11.

Histopatological and immunohistochemical aspects (expression of matrix metalloproteinase 9) in polymyositis and dermatomyositis

MMP 9 intense expressed in inflammatory infiltrate, X 200

MMP 9 positive with moderate intensity in endothelial cells and muscular layer of blood vessels, X 100

accompanied the presence of macrophages in the inflamatory infiltration. Regarding dermatomyositis, it has been demonstrated that the deposition of immunoglobulins and complex membrane attack C5b9 in the muscle's blood vessels, suggesting that humoral damage initiate primitive microangiopathies, which are responsible for a secondary tissue ischemia especially muscle and mucocutaneous.

MMPs are excreted by a variety of connective tissue cells and pro-inflammatory cells such as fibroblasts, endothelial cells, osteoblasts, macrophages, lymphocytes and neutrophils. All these enzymes are also responsible for tissue damage in several pathological conditions including acute and chronic inflammation, skin changes that occur as a consequence of the aging process following acute ultraviolet exposure and also in the destruction of connective tissue in tumor invasions(8, 9, 10).

Most of the MMPâ&#x20AC;&#x2122;s are secreted as inactive proteins which are activated when are cleaved by ex-

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Figure 10.

MMP 9 expressed with moderate intensity in endothelial cells of blood vessels, X 200

tracellular proteases. The encoded enzyme of this gene, degrades type IV and V collagen and other extracellular matrix proteins (11).

MMPs are regulated by hormones, growth factors, cytokines and are involved in ovarian function.

MMP inhibitors (MMPIs) and tissue inhibitors of MMPs (TIMPs) strictly control these enzymes. MMP overexpression is determined by a disorder of balance between MMP and TIMPs, and this leads to a variety of pathological conditions(12). MMP 9 has several important functions including neutrophil activation and extracellular matrix degradation, IL-1β activation and cleavage of several chemokines(13). This, together with elastase, appears to be a factor in regulating neutrophil migration around the basement membrane(14). It can trigger directly inflammation through tissue destruction or indirectly by generating an inflammatory signal or by recruiting inflammatory cells. Infiltration by inflammatory cells is closely associated with an abnormal fibrosis.

In our study 80% of cases had positive immunoexpression of MMP 9 in the cytoplasm of degenerate striated muscle fibers. In all cases of unaffected striated muscle fibers analyzed MMP 9 was negative. In a study conducted by Schoser et al, MMP-9 was highly expressed in atrophic myofibers in all inflammatory myopathies. In dermatomyositis the perifascicular atrophy showed pronounced MMP-9 immunoreactivity, probably reflecting denervated patterns of myofibers(15). According to some studies performed through PCR, MMP-9 is significantly increased in polymyositis and dermatomyositis and in a lesser extent in inclusion body myositis, while the expression of TIMP remained unchanged compared with controls (16). We found a higher expression of MMP 9 in the cytoplasm of the lymphocytic inflammatory infiltrate in patients with dermatomyostis or polimyositis. These findings are similar with those of Kieseier BC which concluded that in inflammatory myopathies MMP1 could be localized around the sarcolemma of

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Claudia Cîrstea, Loredana Elena Stoica, Andreea Lili Bărbulescu, Claudia Valentina Georgescu, Rucsandra Dascălu, Georgescu Diana Monica, Virgil Pătrașcu

diseased muscle fibres and to cells resembling fibroblasts, whereas MMP-9 seemed to be expressed primarily by invading T lymphocytes (16).

Our findings showed that blood vessels presented moderate and high intensity expression of MMP 9 in the cytoplasm of endothelial cells and in the smooth muscle layer of arteriolar blood vessels. This positivity to MMP 9 is the most likely consequence of structural and functional alterations of vascular walls in patients with dermatomyositis and polymyositis. A series of other changes were identified in the blood vessels walls in patients with inflammatory myopathy. Therefore, the upregulation of adhesion molecules (VCAM-1 and E-selectin) has been reported in muscle biopsy of patients with inflammatory myopathies. These molecules are secreted mainly from activated endothelial cells and are expressed from the endothelial cells after stimulation with cytokines in patients with dermatomyositis(17).

Conclusions MMP 9 was intensly expressed in lymphocytic inflammatory infiltrate, intensly and moderately expressed in vessel walls, moderate and poor positive in degenerated skeletal muscle fibers and negative in normal muscular fibres in patients with

dermatomyositis and polimyositis. MMP 9 seems to be expressed more intense in inflammatory infiltrate lymphocytes and less in sarcoplasma of degenerated muscle fibers.

The overexpression of matrix metalloproteinases 9 on degenerated muscle fibers may be an important event in the multistep process of dermatomyositis and polymyositis and may play an important role in the development of new therapeutic strategies.

Acknowledgements There are no conflicts of interest for any of the authors.

This paper received financial support through the “Program of Excellence in doctoral and postdoctoral research in multidisciplinary chronic diseases”, contract no. POSDRU / 159 / 1.5 / S / 133,377, financed from the European Social Fund through Sectoral Operational Programme Human Resources Development 2007-2013.

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

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Caiet de abstracte

INTESTINAL MICROBIOTA, SMALL INTESTINAL BACTERIAL OVERGROWTH AND IMPLICATIONS IN DERMATOLOGY

Mihai Andrei Gastroenterology, Hepatology and Endoscopy Unit, Elias Emergency Hospital

Open Access Article

Abstract Keywords: intestinal microbiota, SIBO, dermatology, rosacea

Small intestinal bacterial overgrowth (SIBO) is defined by the presence of at least 100.000 colony forming units of bacterial in 1 ml of jejunal aspirate. It’s associated with many gastrointestinal pathological conditions: inflammatory bowel diseases, aclorhydria, exocrine pancreatic insufficiency, coeliac disease, post-surgical conditions and with extradigestive pathologies: acromegaly, hypothyreosis, selective IgA deficiency, lymphomas. Recent data sugest that SIBO is involved in may other diseases, especially in dermatology. When breath test is used, association of SIBO with rosacea is 40-50%. Our purpose is to review the most important data in literature regarding intestinal microbiota, small intestinal bacterial overgrowth and the connections between those and dermatological pathologies.

COMPLEXITY OF LABORATORY DIAGNOSIS IN RARE PATHOGENS CUTANEOUS INFECTIONS Violeta Corina Cristea1,2, Ramona Gîlcă1, Gabriela Neacșu1, Roxana Pricop1, Radu Sorin Serea1, Mircea Ioan Popa2 1.

Laboratorul Central de Referință Synevo București Universitatea de Medicină și Farmacie “Carol Davila”, București

2.

Open Access Article

Abstract Keywords: This work is licensed under a Creative Commons Attribution 4.0 Unported License.

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skin infections, A. Neuii, P. oryzihabitans, A. Haemlyticum, A. xylosoxidans

Skin and soft tissues infections represent an important morbidity and even mortality in hospitalized pacients. Early diagnosis and choosing the proper treatment for the microorganism involved in etiology represents of the key for terapeutical success.

Given the context of infectious pathology changes from the last decades it was observed that commensal microorganisms or conditionally pathogens became fully pathogens or even emerged in immunosupressed pacients. Establishing the etiological diagnosis in these situations is possible through advanced diagnostic technologies that allow a fast and accurate identification of microorganisms that are difficult to be identify through classical systems: Actinomyces neuii, Pseudomonas oryzihabitans, Arcanobacterium haemlyticum, Achromobacter xylosoxidans.

In recent specialty literature (2015), numerous studies and case presentations that describe the pathological implications of these microorganisms are published. Identification of pathological agents for these emergent infections and disseminating the information about them, play a key role in understanding the global evolution of infectious pathology.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

A 5-a ediție Interdisciplinară a Conferinței HEALTH MEETING "INFECȚIILE PIELII - DE LA CERCETARE LA IMPACTUL ASUPRA SĂNĂTĂȚII PUBLICE"

COMPLEXITATEA DIAGNOSTICULUI DE LABORATOR ÎN INFECȚIILE CUTANATE DE ETIOLOGIE RARĂ Rezumat Cuvinte-cheie: infectii cutanate, A. Neuii, P. oryzihabitans, A. Haemlyticum, A. xylosoxidans

Infecțiile pielii și ale țesuturilor moi reprezintă o cauză importantă de morbiditate, uneori și de mortalitate, în cazul pacienților spitalizați. Diagnosticul precoce și alegerea tratamentului adecvat tipului de microorganism implicat în etiologie, reprezintă cheia succesului terapeutic. În contextul modificărilor patologiei infecțioase din ultimele decade s-a constatat faptul că microorganisme comensale sau condiționat patogene au devenit patogene sau chiar emergente la pacienții imunodeprimați. Stabilirea diagnosticului etiologic în aceste cazuri este posibilă prin utilizarea tehnologiilor avansate de diagnostic care permit identificarea cu acuratețe și în timp rapid a microorganismelor greu identificabile prin metode clasice: Actinomyces neuii, Pseudomonas oryzihabitans, Arcanobacterium haemolyticum, Achromobacter xylosoxidans. În literatura de specialitate recentă (2015) sunt publicate studii și numeroase prezentări de cazuri care descriu implicațiile acestor bacterii în patologie. Importanța identificării microorganismelor emergente și publicarea acestor cazuri joacă un rol important în înțelegerea evoluției globale a patologiei infecțioase.

METRICII – INSTRUMENTE DE PROMOVARE A CERCETĂRII ȘI CERCETĂTORILOR. Cristina Huidiu Trainer Elsevier pentru Romania si coordonator al programului de pre-evaluare a jurnalelor in vederea indexarii in Scopus pentru Europa de Est si tarile baltice

Open Access Article

Rezumat Cuvinte-cheie: metrici, SNIP, SJR, FWCI, Elsevier

Prezentarea își propune să explice pe scurt care sunt instrumentele de analiză a cercetării folosite de Elsevier, care sunt metricii disponibili (SNIP, SJR, FWCI etc) pe platformele Elsevier de analiză a cercetării și care este utilitatea lor. Pe de o parte se va discuta despre avantajele pe care le oferă utilizarea lor dar și limitele acestora. Metricii vor fi priviți atât din perspectiva cercetătorilor cât și a editorilor de jurnale și se va prezenta modul în care aceștia pot fi folosiți pentru a descoperi hub-uri de inovație sau direcții de dezvoltare a unui domeniu.

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Caiet de abstracte

A 5-a ediție Interdisciplinară a Conferinței HEALTH MEETING "INFECȚIILE PIELII - DE LA CERCETARE LA IMPACTUL ASUPRA SĂNĂTĂȚII PUBLICE"

SOME OBSERVATIONS ABOUT ROSACEA BY DERMOSCOPY AND BACILUS SPECIES FINDINGS Alin Laurentiu Tatu University Dunarea de Jos,Faculty of Medicine and Pharmacy,Galati,Romania;

Open Access Article

Abstract Keywords: Rosacea, Dermoscopy, Spinulosis, Demodex Folliculorum, comorbidities, metabolic disorders

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Background: From clinical point of view sometime the diagnosis of Rosacea it is evident: papules, pustules, telangiectasias, flushing, blushing, phymas and ocular signs(5). Sometime we need better ways to see this condition on the skin and to detect early some infraclinical features. Dermoscopy is a useful tool in this situations for better view and recognize the specific conditions,the disease severity and also for the follow up of the treatment result.Bacillus Oleronius was isolated from Demodex Folicullorum at some Rosacea patients.

Objective of the study was to find the dermoscopic features of Rosacea, some clinico dermoscopic corelations and to find some Bacillus species from Demodex Folicullorum.

Methods: 138 patients with variable Rosacea clinical manifestations and subtypes were examined clinically and by dermoscopy .Demodex was identified by scraping and from 18 patients after vortexing, the sample for bacterial culture was spun two minutes and then was plated on trypticase soy agar culture media and Columbia agar with 5% sheep blood with incubation in normal atmosphere at 37ºC 24 hours. Identification was performed by microorganisms grown mass spectrometry MALDI-TOF (Matrix Assisted Laser Desorption Ionization Time-of-Flight).

Results: 71,73% were women and 28,27% men ; the mean age was 44,7 years. The erithemato-telangiectatic clinical subtype was found at 42,75% of patients, with a rate of 2,68 to 1 for women to men, the papulopustular clinical subtype at 49,27% of patients,with a ratio of 5,09 to 1,the phymatous clinical subtype was found at 9,42% of patients with a ratio of 1 to 5,5 and ocular Rosacea was found at 34,05%,with a ratio of 1 to 2,91; 89,74% of the rosacea male patients had ocular symptoms.

By dermoscopy I found on the face of Rosacea group the following dermoscopic features: vessels, red areas, follicular plugs, Demodex tails, scales, pustules. The most important dermoscopic sign in Rosacea is polygonal vessels, 64,49% showed red diffuse areas with or without vessels. Dermoscopy improved the detection of Demodex Folliculorum features from. 50% (with clinical spinulosis) to 62,31% of patients,of pustules from 49,27% to 56,52% and of scales from 33,33% to 39,13%.

At 4 patients with Demodex Folliculorum we found the following species of Bacillus and at 2 patients with Demodex brevis we found those species of Bacillus.

Conclusion: All of the patients showed clinically telangiectasias They are seen more clearly and specific with dermoscopy as red dilatated, reticular, linear, tortuous or poligonal vessels. 62,31% of the patients showed Demodex features. All patients with areas of spinulosis showed Demodex features at dermoscopy of the area and were confirmed by scraping. Dermoscopy improves the infraclinic detection of Roscea features. We did not find Bacilus oleronius.

Aknowledgements: This paper is supported by the Sectoral Operational Programme Human Resources Development (SOP HRD), financed from the European Social Fund and by the Romanian Government under the contract POSDRU/159/1.5/S/137390/

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

A 5-a ediție Interdisciplinară a Conferinței HEALTH MEETING "INFECȚIILE PIELII - DE LA CERCETARE LA IMPACTUL ASUPRA SĂNĂTĂȚII PUBLICE"

ADULT ACNE – A PUBLIC HEALTH OPPORTUNITY FOR PREVENTING AND REDUCING ANTIBIOTIC RESISTANCE

Victor Gabriel Clătici Dermatology Department, ELIAS Emergency Universitary Hospital, Bucharest, Romania;

Open Access Article

Abstract Keywords: acne, Propionibacterium acnes, antibiotic resistance, guidelines.

Antibiotic resistance is a major concern of patients, families, and physicians, and is an important issue to consider in acne treatment with current guidelinesrecommending both acute intervention and maintenance treatment.

Acne affects the vast majority of the world’s population and acne is considered now a chronic disease requiring adherence to a long duration of treatment, with antibiotics (topicals and sistemic) use for cvasimajority of patients.

In the last few decades Propionibacterium acnes (P. acnes) has become resistant to many different antibiotics, making them less efficacious in treating acne. Historically, in 1976, there was no evidence of antibiotic-resistant propionibacteria on the skin of over 1000 patients with acne and the first report of resistance of P. acnes to antibiotics was in the United States in 1979, by Crawford.

Resistance to antibiotic of P acnes are associated with reduced clinical response to antibiotic therapy, potential increase in pathogenicity of P. acnes and transfer of resistance to more pathogenic organisms.

Resistance of P acnes to antibiotics may manifest as a reduced response, no response, or relapse and the prevalence of antibioticresistant P. acnes strains might also have implications for other potential systemic infections (a transmission of factors conferring resistance to bacteria other than P. acnes is described).

The main objectives of the guidelines for acne are improvement in the care of acne patients, reduction of serious conditions and scarring, promotion of adherence and reduction the antibiotic resistance of P acnes.

The Global Alliance to Improve Outcome in Acne Group recommended the following strategies to limit the development of resistance in P. acnes which included: (1) combine a topical retinoid plus an antimicrobial; (2) limit the use of antibiotics to short periods and discontinue when there is no further improvement or the improvement is only slight; (3) co-prescribe a benzoyl peroxide-containing product or use as washout; (4) oral and topical antibiotics should not be used as monotherapy; (5) concurrent use of oral and topical antibiotics should be avoided, particularly if chemically different; (6) do not switch antibiotics without adequate justification; (7) use topical retinoids for maintenance therapy, with benzoyl peroxide added for an antimicrobial effect if needed; and (8) avoid use of antibiotics for maintenance therapy.

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Caiet de abstracte

CANCER OR INFECTION? MAMMARY PATHOLOGY AT THE BOUNDARY BETWEEN BENIGN AND MALIGNANT Nicoleta CLIM1, Amelia MILULESCU1,2, Andreea Gratiana BOIANGIU1, George Alexandru FILIPESCU1,2 Obstetrics and Gynaecology Department, “Elias” Emergency University Hospital, Bucharest, Romania 2 University of Medicine and Pharmacy “Carol Davila” Bucharest, Romania

1

Open Access Article

Abstract Keywords: inflamatory breast cancer, examinations, breat biopsy, mastitis.

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CANCER SAU INFECȚIE? PATOLOGIA MAMARĂ LA LIMITA ÎNTRE BENIGN ȘI MALIGN Rezumat

Cuvinte-cheie: mastita carcinomatoasa, investigatii, biopsie mamara, inflamatie mamara

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Whether it is about lactational mastitis, breast cellulite, breast abscess, Paget’s disease of the breast, superficial thrombophlebitis, spontaneous gangrene of the breast or bite wound, a high degree of suspicion must be permanently maintained not to overlook a diagnosis of major impact on the patients lives. Inflammatory breast cancer or any other type of breast cancer presenting with infection is the matter of discussion.

Several diseases can be confused with it, leading to delayed diagnosis.

Clinical manifestations such as pain, diffuse erythema, tenderness, with or without systemic symptoms like fever and chills, clinical examination and laboratory tests orientate diagnosis. Persistent or recurrent symptoms after antibiotic and anti-inflammatory treatment in breast pathology apparently infectious require further investigations. Imaging examinations such as breast ultrasound, mammography or magnetic resonance imaging may be useful in the systematical differential diagnosis. Breast biopsy should be performed without delay whenever the degree of suspicion is high.

Fie că este vorba despre mastita de lactație, celulită, abces mamar, boala Paget a sânului, tromboflebita superficială, gangrena spontană a sânului sau plaga mușcata, trebuie menținut în permanență un grad înalt de suspiciune pentru a nu trece cu vederea un diagnostic cu impact major asupra vieții pacientelor. Este vorba despre mastita carcinomatoasă sau orice alt tip de cancer mamar care se prezintă cu infecție. Mai multe patologii pot fi confundate cu mastita carcinomatoasă, ducând la întarzierea stabilirii diagnosticului. Manifestările clinice precum durerea, eritemul difuz, edemul, însoțite sau nu de simptome sistemice precum febra și frisonul, examenul clinic și examenele paraclinice orientează diagnosticul. Persistența sau recurența simptomatologiei dupa tratament antibiotic si antiinflamator în patologia aparent infecțioasă a sânului necesită investigații suplimentare. Examenele imagistice, precum ecografia mamară, mamografia sau rezonanța magnetică pot fi utile în diagnosticul diferențial sistematic. Biopsia mamară trebuie practicată fără întarziere ori de câte ori gradul de suspiciune este înalt.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

A 5-a ediție Interdisciplinară a Conferinței HEALTH MEETING "INFECȚIILE PIELII - DE LA CERCETARE LA IMPACTUL ASUPRA SĂNĂTĂȚII PUBLICE"

MICROBIOME AND MANAGEMENT OF ATOPIC DERMATITIS

Coman Oana Andreia 1. MD PhD, Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, Bucharest, MD, Clinical Hospital of Infectious and Tropical Diseases „Dr. Victor Babeş”, Bucharest;

Open Access Article

Abstract Keywords: atopic dermatitis, human microbiome, dysbiosis, emollients, cutaneous homeostasis

Atopic dermatitis (AD) is the most common skin disease in childhood, but it has been shown that the atopic march can occur at any age.

If AD cannot be controlled by topical therapy, systemic therapy should be considered. Also it is important to prevent relapses with an adequate treatment. Human microbiome is a very complex symbiotic ecosystem of commensal microorganisms, which is in homeostasis with the host, representing an entire living organism in our body.

Skin microbiome includes bacteria, viruses, fungi and protozoa.

Microbiome has a major impact on body functions providing antiinfectious protection, reactivity of the immune system and sometimes can augment the susceptibility to auto-inflammatory diseases. On the skin, microbiome has two ubiquitous members represented

by Staphylococcus epidermidis and Propionibacterium acnes.

Imbalance of skin microbiome or dysbiosis may help maintain the vicious circle of atopy. A possible favorable role of emollients was observed, regarding the relief of symptoms of atopic dermatitis, by increasing microbial diversity. Composition of these emollients improved by adding extracts of saprophytic bacteria. One such example materialized in practice isVitreoscilla filiformis bacterial lysate grown in La Roche Posay Thermal Water (Aqua Posae Filiformis). This approach allows stimulating the immune system of the skin in parallel with the regulation of cutaneous homeostasis, which would break the pathologic vicious circle of atopic dermatitis.

MICROBIOMUL CUTANAT ȘI MANAGEMENTUL DERMATITEI ATOPICE Rezumat Cuvinte-cheie: dermatita atopica, microbiom uman, disbioza, emoliente, homeostazie cutanata

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The images or other Dermatita atopică (DA) reprezintă cea mai frecventă afecțiune third party material in cutanată a copilariei, însă s-a arătat că terenul atopic poate să this article are included apară la orice vârstă. Dacă DA nu poate fi controlată cu terapie in the article’s Creative Commons license, unless topică, tratamentul sistemic trebuie luat în considerare. De asemenea, este importantă prevenția recăderilor cu un tratament indicated otherwise in the credit line; if the material corespunzător. Microbiomul uman este un ecosistem foarte is not included under complex, simbiotic, al microorganismelor comensale, care se află the Creative Commons license, users will need în homeostazie cu gazda, reprezentând un întreg organism viu to obtain permission din corpul nostru. Microbiomul cutanat include bacterii, virusuri, from the license holder to reproduce the material. fungi și protozoare. Microbiomul are un impact major asupra To view a copy of this funcțiilor organismului asigurând protecția antiinfecțioasă și license, visit http:// reactivitatea sistemului imun și uneori poate favoriza predispoziția creativecommons.org/ licenses/by-nc/4.0/

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Caiet de abstracte

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pentru afecțiuni autoinflamatorii.Dezechilibrul microbiomului cutanat sau disbioza de la nivelul pielii poate contribui la menținerea cercului vicios al atopiei. S-a observat un posibil rol favorabil al unor emoliente în ameliorarea simptomatologiei din dermatita atopică, în speță pentru creșterea diversității microbiene. În consecință s-a îmbunătățit compoziția acestor emoliente prin adăugarea extractelor unor bacterii saprofite. Un astfel de exemplu concretizat în practică este lizatul bacteriei Vitreoscilla filiformis cultivat în apă termală La Roche Posay (Aqua Posae Filiformis).Această abordare permite stimularea sistemului imun al pielii în paralel cu reglarea homeostaziei cutanate, fapt care ar întrerupe cercul vicios fiziopatologic al dermatitei atopice DA poate fi văzută ca o combinație între o imunitate înnăscută și dobândită afectate care interacționează împreună în cadrul unui sistem imunitar cutanat cu funcția de barieră suboptimală .Pentru a determina extinderea și severitatea bolii se folosește scorul SCORAD (SCORing Atopic Dermatitis). Dermatologii utilizează acest scor înainte și după terminarea tratamentului pentru a determina eficacitatea acestuia. În ceea ce privește tratamentul dermatitei atopice sunt descrise o varietate largă de modalități. O combinație de terapie cu emoliente, antiinflamatorii și antimicrobiene este considerate optimă pentru majoritatea pacienților aflați în puseu acut al bolii.

Emolientele constituie baza de tratament pentru formele acute și cronice de boală, dar cei mai multi pacienti necesită, de asemenea, terapie antiinflamatoare, fie cu corticosteroizi topici sau inhibitori de calcineurină topici pentru gestionarea, episoadelor acute. Dacă dermatita atopică nu poate fi controlată cu terapie topică, tratamentul sistemic trebuie luat în considerare .Pacienții cu forme severe de boală sunt, în principal, cei cu debut precoce, cei cu leziuni cutanate generalizate și cu evoluție continuă .

Microbiomul uman (din greacă micro-mic, biosviață) reprezintă totalitatea microbilor și elementelor genetice ale acestora aflați în cadrul unui mediu particular. Microbiomul uman este un ecosistem. În timp ce fiecare celulă din corp care conține moștenirea genetică constituie primul genom, putem spune că microbiomul este al doilea genom. Acest microbiom este caracteristic fiecărei celule în parte, putând fi comparat cu o amprentă sau o semnătură. După naștere, pielea umană se colonizează cu diverse microorganisme care în timp formează un ecosistem complex constituit din microorganism indigene (rezidente) sau tranzitorii. Compoziția acestei comunități microbiene este diferită atât între diferiți oameni cât și în cadrul aceluiași individ, în funcție de diverși factori de mediu sau fiziologici cum ar fi vârsta, statusul hormonal, umiditatea locală, localizarea anatomică, producția de sebum și sudoare, etc. Această comunitate microbiană, denumită microbiom cutanat, include bacterii, virusuri, fungi și protozoare, iar stabilitatea sa se datorează echilibrului dintre proporția germenilor comensali și capacitatea de apărare a gazdei.

Microbiomul are un impact major asupra funcțiilor organismului asigurând protecția antiinfecțioasă și reactivitatea sistemului imun și uneori poate favoriza predispoziția pentru afecțiuni autoinflamatorii. La nivel cutanat, microbiomul are 2 membri ubicuitari reprezentați de Staphylococcus epidermidis, care are capacitatea de a produce substanțe antimicrobiene și Propionibacterium acnes, care produce acizi grași cu lanț ușor sub acțiunea unor lipaze de la nivelul foliculilor pilosebacei, având în plus și proprietăți imunomodulatorii. Aceste calități sunt favorabile prin potențarea componentelor înnăscute ale gazdei de apărare imună, menținând compoziția unui microbiom cutanat sănătos. Se pare că pe pielea umană sănătoasă pot fi găsite aproape 1 miliard de bacterii pe cm2, grupate în peste 1000 de specii. Aceste specii codifică de 150 ori mai multe gene decât cele prezente în genomul uman. În ultimii ani tot mai multe studii au avut ca obiectiv cercetarea unei eventuale legături dintre microbiomul cutanat și apariția unor pusee de dermatită atopică. S-a emis ipoteza că modificarea diversității microbiene cutanate poate preceda erupțiile de atopie. Este de presupus că orice dezechilibru în microbiomul cutanat poate duce la posibilitatea apariției unor suprainfecții bacteriene la nivelul pielii . Astfel s-a constatat că înainte de erupție diversitatea florei microbiene saprofite cutanate începe să scadă, fiind urmată rapid de creșterea proporției de stafilococi, moment în care se declanșează erupția cutanată.

O dată cu reducerea intensității erupției, proporția stafilococilor începe să scadă, în paralel cu creșterea diversității microbiene și revenirea microbiomului la compoziția sa normală, fiziologică. Din aceste date se poate concluziona că dezechilibrul microbiomului cutanat sau disbioza de la nivelul pielii poate contribui la menținerea cercului vicios

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

A 5-a ediție Interdisciplinară a Conferinței HEALTH MEETING "INFECȚIILE PIELII - DE LA CERCETARE LA IMPACTUL ASUPRA SĂNĂTĂȚII PUBLICE"

al atopiei. La pacienții atopici diversitatea microbiană de la nivelul pielii a fost mai scăzută, scăderea ei fiind direct proporțională cu severitatea dermatitei atopice. În tratamentul pacienților cu dermatită atopică s-a aplicat un emolient care s-a observat că a influențat microbiomul cutanat, prin reducerea semnificativă a tuturor stafilococilor (epidermidis, aureus, haemolyticus). S-a demonstrat pentru prima oară că tratamentul cu un emolient modifică diversitatea microbiană redusă asociată leziunilor atopice, cu reducerea proporției de stafilococi și restaurarea unei microflore diversificate (creșterea predominanței Corynebaterium sp sau Sterotrophomonas sp.). În legătură cu posibilul rol favorabil al unor emoliente în ameliorarea simptomatologiei din dermatita atopică, în speță pentru creșterea diversității microbiene, s-a pus problema îmbunătățirii compoziției acestor emoliente prin adăugarea extractelor unor bacterii saprofite. Un astfel de exemplu concretizat în practică este lizatul bacteriei Vitreoscilla filiformis cultivat în apă termală La Roche Posay, sau Aqua Posae Filiformis, care este rodul a 26 de ani de cercetare și a făcut obiectul a multorpatente de invenții În concluzie, în urma rezultatelor prezentate în multiple studii din literatura de specialitate se conturează că o abordare terapeutică rațională a dermatitei atopice ar putea consta în modularea microbiomului cutanat, cu creșterea diversității speciilor bacteriene care îl compun, în parallel cu reducerea proporției de stafilococi patogeni.

Această abordare ar permite și stimularea sistemului imun al pielii în paralel cu reglarea homeostaziei cutanate, fapt care ar întrerupe cercul vicios fiziopatologic al dermatitei atopice. Nu în ultimul rând, se poate presupune că reechilibrarea microbiomului cutanat prin aplicarea unor emoliente care să conțină lizate ale unor bacterii saprofite este o abordare mult mai rațională comparativ cu utilizarea unui antibiotic clasic care distruge bacteriile neselectiv și aleator, mai ales în cazul în care nu este demonstrată prezența unei infecții cutanate.

STATUSUL DE IMUNODEFICIENȚĂ AL FEMEILOR SEROPOZITIVE - FACTOR MAJOR DE RISC ONCOGENIC HPV INDUS Mihai Mitran1, 2, Carmen Georgescu 1, Sorin Puia, Maria Comănescu 1,2 1.

Spitalul Clinic de Obstetrică-Ginecologie ”Prof. Dr. Panait Sîrbu” București 2.

UMF ”Carol Davila” București

Open Access Article

Abstract Keywords: HIV, HPV, co-infection, oncogenesis

The HPV-HIV co-infection represents an aggravating circumstance for the development of the cervical neoplasia.

In the co-infection cases, the axiom according to which the HPV infection is asymptomatic and self-limited does not apply due to the immunological status of immunosuppression in the case of HIV positive patients.

The study carried out over a period of 1 year confirms this hypothesis, namely: - The HPV co-infection with clinical manifestation at the HIV positive patients is of 75% - The oncogene potential is much more increased than with the general population – 84,30% - The high-risk HPV roots are present in 67% of the cases A diagnosis and a precocious therapeutic measure is required with this category of patients

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Rezumat Cuvinte-cheie: HIV, HPV, coinfecție, oncogeneză

Confecția HPV-HIV reprezintă o circumstanță agravantă pentru dezvoltarea neoplaziei de col uterin. În cazurile de coinfecție, axioma conform căreia infecția HPV este asimptomatică și autolimitată, nu este valabilă, datorită statusului imunologic de imunosupresie la pacientele HIV pozitive.

Datele studiului nostru efectuar pe o perioadă de 1 an confirmă această ipoteză și anume: - Coinfecția HPV cu exprimare clinică la pacientele HIV pozitive este de 75% - Potențialul oncogen este mult mai crescut decât în populația generală – 84,3% - Tulpinile HPV high-risk sunt prezente în 67% din cazuri Se impune la această categorie de paciente un diagnostic și o sancțiune terapeutică precoce.

NOSOCOMIAL INFECTIONS OF THE SKIN AND SOFT TISSUE IN PLASTIC SURGERY: THE ROLE OF ANTIBIOTIC PROPHYLAXIS Cristian Radu Jecan *,**, Silviu Constantin Badoiu *,**, Laura Raducu *,**, Ovidiu Stefanescu *, Adriana Neagu *, Ioana Dogaru *, Daniel Hernic *, Cristina Cozma * * Department of Plastic and Reconstructive Surgery - “Prof. Dr. Agrippa Ionescu “, Clinical Emergency Hospital, Ion Mincu St., Nr. 7, Postal Code 011356, Sect. 1, Bucharest, Romania ** ”Carol Davila” University of Medicine and Pharmacy, Bd. Eroii Sanitari, Nr. 8, Postal Code 050474, Sect. 1, Bucharest, Romania

Open Access Article

Abstract Keywords:

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nosocomial infections, antibiotic prophylaxis, surgical site infections

Health care-associated infections during hospitalisation represent an important public health issue, increasing the morbidity and mortality of the underlying disease, as well as adding to the financial burden of the case. Haematogenously spreaded infections, pneumonia, urinary tract infections and surgical site infections are most frequently described in literature. Among these, the plastic surgeon is especially faced with the latter.

A surgical site infection is a post-operative infection that occurs in the part of the body where the surgery took place. Antibiotic prophylaxis, as well as other measures, is extensively used to prevent these surgical site infections. Although at present antibiotics are frequently administered, the benefit they bring to the prevention of post-surgical infections should be weighed against the risks of antibiotic treatment.

A clear link has been established between excessive use of antibiotics and drug resistance. This has consequences not only for the patient (through gastro-intestinal symptoms, Clostridium difficile infection, allergic reactions), but also for the health-care setting (increased drug resistance, low antibiotic efficacy). Numerous therapeutic guidelines regarding antibiotic prophylaxis exist, but without being specifically targeted at plastic surgery. The objective of this presentation is to

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describe and evaluate, in conformity with the principles of evidence-based medicine, the efficacy and safety of antibiotic prophylaxis in plastic surgery. A systematic research of MEDLINE, Cochrane Library and Embase databases led to the selection of relevant literature sources. It identified about 50 relevant studies regarding breast surgery, head and neck, rhinoplasty, hand surgery, skin surgery and abdominoplasty. A classification of wounds and surgical procedures including their degree of contamination is presented (clean, clean / contaminated, contaminated and dirty / infected). Results and current recommendations regarding antibiotic prophylaxis are detailed and analyzed, according to the type of surgical site involved.

Systematic antibiotic prophylaxis is advised in the case of contaminated or infected surgical sites in head/neck surgery, and in clean breast surgery. It is not advised in the case of clean head/neck, hand, arm or skin surgery, or in the case of abdominoplasty.

HISTOPATHOLOGIC DIAGNOSIS OF SUBCUTANEOUS MYCOSES IN DAILY PRACTICE S. Zurac* **, C. Popp**, R. Andrei**, F. Staniceanu* **, V. Chitu* **, C. Rosculet***, A. Streinu-Cercel* *** * University of Medicine and Pharmacy Carol Davila Bucharest ** Colentina University Hospital ***Matei Bals National Institute of Infectious Disease

Open Access Article

Abstract Keywords: subcutaneous mycosis, immunosuppresion, PAS stain, Grochott stain

Introduction: Subcutaneous mycoses are infrequent lesions commonly related with immunosuppression of different causes; both clinical and pathologic appearances are inconspicuous, positive diagnosis being difficult. Usually the key of accurate diagnosis stays in adequate use of special stains (PAS, Grochott).

Methods: We illustrate the spectrum of subcutaneous mycoses with several cases involving different types of fungi (mucormycetes, coccidioides imitis, aspergillus) in patients with various causes of immunodepression (corticotherapy, diabetes, autoimmune diseases, HIV infection).

Results: Clinical aspects were variable and unspecific: some cases had pseudo-tumoral appearances, two of them being treated with surgical resection, other had deceptive clinical appearance suggestive of vasculitis, pyoderma gangrenosum or pemphigus vegetans, and one case had systemic involvement with severe evolution (death by septic shock and bronchopneumonia due to ocular involvement and maxillary and ethmoidal sinusitis). Histopathologic aspects included: polymorphous inflammatory infiltrate with small foci of suppurative necrosis and, occasionally, vascular lesions; microscopic diagnosis is sometimes difficult due to the scarcity of fungi identifiable even on special stains. Always, histopathologic examination should be completed with fungal cultures.

Conclusion: Immunodepressed patients have a higher risk of subcutaneous mycosis, frequently with atypical presentation. A high degree of clinical and histopathological suspicion and routine use of PAS stain are very important for this diagnosis, with tremendous importance since systemic mycoses can be life threatening diseases.

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Caiet de abstracte

IMPLEMENTATION OF THERAPEUTIC PROTOCOLS IN ANOGENITAL WARTS TREATMENT Prof. Dr. Radu Vlădăreanu, Șef Lucr. Dr. Simona Vlădăreanu UMF “Carol Davila”, București

Open Access Article

Abstract Keywords: anogenital warts, clinical protocol, treatment algorithm

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Anogenital warts (Condyloma acuminata) is a common and chronic health problem among the population, with a significant impact on quality of life and health costs for the economy. In terms of pathogenesis, CA is represented by squamous epithelium benign neoplasia, highly transmissible, caused by infection with Human Papillomavirus (HPV), particularly with low-risk strains 6 and 11. Lifetime prevalence is estimated about 10%, therefore Condyloma Acuminata is considered a viral disease with the highest rate of sexual transmission.

Therapeutic alternatives are mainly surgical therapy or pharmacological treatment used in hospital, or applied directly to the patient.

Therapeutic methods include curettage or electrocautery and laser ablative procedures or photodynamic therapy. Topically applied substances by the doctor include mostly trichloroacetic acid, in high concentration, and cryotherapy.

Regarding medical treatment administered at home by the patient, they are used mainly three groups of substances: catechins in green tea extract, podophyllotoxin (solution or cream), and imiquimod.

Comparing treatment rates and relapses rate of various therapeutic options is aiming to create a clinical protocol based on available evidence, to create a treatment algorithm useful in everyday clinical practice. Invasive surgical procedures generally provide higher healing rates compared to the pharmacological treatment. Mainly referring to the curettage, the treatment rate is estimated at 89%, similar to electrocautery, the rate of which is between 61-94%. Also ablative laser treatment (23-51%) and photodynamic therapy (66-95%) reported high rates of treatment. The indication for this procedure exists, particularly in large areas and in high rate of relapses. There must be taken into account the risk of complications, namely necrosis as a result of aminolevulinic acid.

For substances applied topically by the physician there are reported treatment rates of 64-88% (trichloroacetic acid) or 50-90% (cryotherapy).

By comparison data, these procedures are associated with higher relapse rates in comparison with local therapy administered at home, especially sinecatehinelor. Regarding the cure rate two studies on sinecatechine (Veregen) Stockfleth et al. and Tatti S et al., showed a high treatment rate of all existing and newly emerging warts during treatment (60.7% and 57.2%). More intense local side effects in the group that received treatment with sinecatechine than the group treated with placebo were highlighted in the study by Stockfleth et al.

(4.0% versus 1.9%). The occurrence of local side effects were associated with a higher treatment rate. Also, studies show the lowest relapse rate (6.5%) following treatment with sinecatechine.

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IMPLEMENTAREA PROTOCOALELOR TERAPEUTICE ÎN TRATAMENTUL CONDILOMATOZEI ANOGENITALE Rezumat Cuvinte-cheie: veruci anogenitale, protocol clinic, algoritm terapeutic

Verucile anogenitale (Condyloma acuminata) reprezintă o problemă frecventă şi cronică de sănătate în rândul populaţiei, cu un impact semnificativ asupra calităţii vieţii şi costuri importante pentru economia sănătăţii. Din punct de vedere al patogenezei, CA este reprezentată de neoplazii benigne ale epiteliului scuamos, cu grad ridicat de transmisibilitate, cauzate de infecţia cu Human Papilomavirus (HPV), în special cu tulpinile cu risc scazut 6 şi 11. Prevalenţa pe parcursul vieţii este estimată la aproximativ 10%, astfel ca Condilomatoza Acuminata este considerată o afecţiunea virală cu cea mai ridicată rată de transmisie pe cale sexuală. Alternativele terapeutice utilizate sunt în principal de tip chirurgical sau medicamentos, utilizate în ambulatorul de specialitate sau aplicate de către pacient direct.

Metodele terapeutice includ chiuretarea sau electrocauterizarea, precum şi proceduri ablative cu laser sau terapie fotodinamică.

Substanțele aplicate local de către medic includ mai ales acidul tricloracetic, cu concentraţie ridicată, precum şi crioterapia. În ceea ce priveşte tratamentul medicamentos administrat la domiciliu de către pacient, sunt utilizate în principal trei grupe de substanţe: catehine din extract de ceai verde, podofilotoxină sub formă de soluţie sau de cremă, precum şi imiquimod. Compararea ratelor de vindecare şi de recidivă a diferitelor opţiuni terapeutice are rolul de a crea o bază decizională bazată pe evidenţele clinice disponibile, pentru a crea un algoritm de tratament util în activitatea clinică cotidiană. Procedurile chirurgicale invazive asigură în general rate mai ridicate de vindecare în comparaţie cu terapiile medicamentoase. În principal ne referim la chiuretare, cu o rată de vindecare evaluată la 89%, similară cu a electrocauterizării, a cărei rată este intre 61-94 %. Şi pentru tratamentul cu laser ablativ (23-52%, respectiv 81%) şi terapia fotodinamică (66-95%) sunt raportate rate ridicate de vindecare.

Indicaţia pentru această procedură există, în special în cazurile pe zone extinse şi recidivante. Trebuie luat în calcul riscul de apariţie a complicațiilor, respectiv a necrozelor, ca urmare a acidului aminolevulinic. Pentru substanțele aplicate local de către medic sunt raportate rate de vindecare de 64-88% (acid tricloracetic) respectiv 50-90% (crioterapie).

This work is Prin comparația datelor, aceste proceduri sunt asociate cu rate de licensed under a Creative recidivă superioare terapiilor locale administrate la domiciliu, în Commons Attribution 4.0 Unported License. special ale sinecatehinelor. Referitor la rata de vindecare, două The images or other third party material in studii efectuate pe sinecatechine (Veregen), Stockfleth et al. și this article are included Tatti S et al.,au prezentat o rată ridicată de vindecare a tuturor in the article’s Creative condiloamelor existente și nou apărute pe durata tratamentului Commons license, unless (60.7%, respectiv 57.2 % ). Efecte secundare locale mai intense în indicated otherwise in the cadrul grupului care a beneficiat de tratamentul cu sinecatechine, credit line; if the material is not included under precum şi al celui tratat cu preparate placebo au fost evidenţiate the Creative Commons în studiul efectuat de Stockfleth et al. (4.0% versus 1.9 %). Apariţia license, users will need to obtain permission efectelor secundare locale a fost asociată cu o rată mai ridicată from the license holder to de vindecare. Totodată, studiile efectuate demonstrează cea reproduce the material.

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Caiet de abstracte

INFECTIOUS FACTORS IN SKIN CANCERS

Prof. Dr. Solovan Caius Dermatologie , Universitatea de Medicina si Farmacie „Victor Babes”, Timisoara

Open Access Article

Abstract In the present presentation we performed a review of the relation between microbioma and immune function of the skin, of the pathways which promote and develope skin neoplasia. All these together define the tumor as an organ. We tried to exemplify those aspects by models from skin and general pathology.

We underlined with evidence the more and more precise relationship between the genomic sequence and the promoting respectiv the progression facts of the neoplasia process

Keywords: microboma, skin immunology, skin neoplasia

FACTORII INFECȚIOȘI ÎN CANCERELE CUTANATE Rezumat Cuvinte-cheie:

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microbiom, imunologie cutanata, neoplazii cutanate

În lucrarea de față ne-am propus o trecere în revistă a relației între microbiom și funcția imună a pielii, a circuitelor care stau la baza inițierii și progresiunii neoplazice cutanate, fapte care definesc tumora ca și un organ. Am încercat sa exemplificăm aceste aspecte cu modele din patologia cutanată dar și generală.

Am scos în evidență cu date relația tot mai precizată între secvența genomică și procesul de inițiere respectiv progresie a procesului neoplazic.

BOLILE CU TRANSMITERE SEXUALĂ ÎN MEDICINA SEXUALITĂȚII

Radu Mihalcaa, Andreea Ruxandra Albub, Endocrinolog-Androlog, Sanamed Hospital, București, Romania b Ginecolog, Spitalul Universitar de Urgență, București, Romania

a

Open Access Article

Rezumat Cuvinte-cheie: BTS, patologii, infertilitate, disfuncții sexuale

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Bolile cu transmitere sexuală (BTS) sunt între cele mai vechi patologii studiate în medicina umană. Importanța acestora de-a lungul istoriei a fost foarte mare.

Prevalanța actuală a BTS la tineri este de circa 15%, cu o incidență anuală la nivel mondial de circa 19.000.000 de cazuri. În secolul XXI BTS nu mai sunt asociate cu mortalitatea semnificativă din trecut dar continuă să reprezinte o problemă de sanătate publică datorită prevalenței și a impactului asupra calității vieții pacientului. Infertilitatea și disfuncțiile sexuale sunt consecințe frecvente ale BTS, prevenția fiind în acest caz modalitatea principală de abordare.

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CIRCUITUL, COLECTAREA ȘI CALITATEA DATELOR DIN SISTEMUL DE SUPRAVEGHERE AL ITS LA NIVEL NAȚIONAL

Dr. Viorica Gheorghiu

Centrul Național de Supraveghere și Control al bolilor Transmisibile

Open Access Article

Rezumat Cuvinte-cheie: boli cu transmitere sexuala,

sifilis, ITS

În România bolile cu transmitere sexuală reprezintă înca o problemă de Sănătate publică, iar pentru sifilis ne aflăm în topul țărilor cu cea mai mare incidență în cadrul Uniunii Europene.

Sistemul de supraveghere al infecțiilor cu transmitere sexuală la nivel național este legalizat prin ordinul MS 1342/noiembrie 2013 și intrat în vigoare de la 1 noiembrie 2014.

Dintre bolile cu transmitere sexuală, sifilisul, gonoreea și infecția genitală cu Chlamydia Trachomatis sunt obligatorii.

La nivel national, datele colectate prin reteua de boli dermatovenerice (D-V)sunt centralizate de Direcțiile de Sănătate Publică județene și transmise la Centrul National de Supraveghere și Control al Bolilor Transmisibile.

Cu toate că modalitatea de colectare a datelor a fost simplificată iar fișa de declarare a cazului nou de ITS este disponibilă și în format electronic, există încă multe lacune în notificarea acestor afecțiuni. Nerespectarea cadrului legal este recunoscută și acceptată de către specialiștii dermato-venerologi ca una dintre cauzele principale ale subraportării. Medicii de alte specialități (mai ales ginecologie) care au dreptul sa diagnosticheze și să trateze cazurile de infecție cu Chlamydia ignoră total obligația raportării acestora la nivel național.

Pentru îmbunătățirea raportării și a supravegherii ITS la nivel național se impune o mai bună colaborare, comunicare și instruire între specialiștii retelei D-V, alți specialiști și epidemiologi de la nivelul DSP județene.

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INTERNATIONAL EVENTS CALENDAR

INTERNATIONAL EVENTS CALENDAR CALENDAR EVENIMENTE INTERNAŢIONALE

2016 mIANUARIE 2016 11-12: 2nd African Dermatopathology Conference Moshi, Tanzania.

Contact: Helmut Beltraminelli : helmut.beltraminelli@insel.ch 21 – 23: EDF (European Dermatology Forum) Annual Meeting 2016. Zurich, Switzerland. www.euroderm.org 28-30: 4th European School of Dermato-Oncology: Updates on Cutaneous Oncology. Berilin, Germany. http://www.dermato-oncology2016.org mFEBRUARIE 2016 19-20: Expert Spring Meeting with Anatomy Preparation Course. Munich, Germany. http://www.isdsworld.com mMARTIE 2016 4-7: 74th Annual Meeting of the American Academy of Dermatology (AAD), Washington, DC – USA www.aad.org 16-20: 1st International Dermatology and Cosmetology Congress (INDERCOS). Istanbul, Turkey. www.idercos.org 30 mar- 2 apr: 14th Aesthetic & Anti-aging Medicine World Congress AMWC 2016, Monte Carlo, Monaco. www.euromedicom.com mAPRILIE 2016 12-14: 5th Continental Congress of Dermatology Dubai Derma. Dubai, United Arab Emirates. http://dubaiderma.com/ 15-17: International Congress of Dermatology, Cometic & Laser. Teheran, Iran. http://crtsdl.tums.ac.ir/ mMAI 2016 11-14: 75th Annual Meeting of the Society for Investigative Dermatology (SID), Scottsdale, AZ – USA www.sidnet.org 19-22: 13th EADV Spring Symposium. Athens, Greece www.eadv.org 26: 13th ESPD (European Society for Pediatric Dermatology) Congress. Paris, France. http://www.espd2016.com/ mIUNIE 2016 16-19: Facial Aesthetic Conference & Exhibition

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FACE 2016. London, UK. www.euromedicom.com 11-15: EAACI Congress. Vienna, Austria. www.eaaci.org 16-18: 3rd International Congress of Aesthetic Dermatology and Healthy Aging Medicine ICAD Brazil. Sao Paolo, Brazil. www.euromedicom.com mIULIE 2016 5-7: 96th Annual Meeting of the British Association of Dermatologists.Birmingham – UK www.bad.org.uk 7-9: 5th Congress of the Psoriasis International Network-Psoriasis 2016.Paris,France.www.pso2016.com 27-31: Summer meeting of the American Academy of Dermatology (AAD). Boston, MA – USA www.aad.org mAUGUST 2016 11-14: International Congress of Tropical Dermatology.

Colombo, Srilanka. http://www.ictd2016.org/ 31 aug-3 sept: 16th World Congress on Cancers of the Skin; 12th Congress of the EADO. Vienna, Austria. www.wccs2016.com mSEPTEMBRIE 2016 8-10: 23rd Biennal Conference on Diseases of the Vulva & Vagina. Chicago, USA. http://issvd.org/event/23rd-biennial-confeence-on-diseases-of-the-vulva-vagina/ 14-17: 13th ESCD ( European Society of Contact Dermatitis) Congress, Manchester, United Kingdom.www.escd2016.com 16-17: 4th Aesthetic & Anti-aging Medicine World Congress Eastern Europe AMWC Eastern Europe. Moscow, Russia. www.euromedicom.com 28-sept-2 oct: 25th CONGRESS OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VEN REOLOGY (EADV) , Vienna – Austria. www.eadv.org mOCTOMBRIE 2016 20-22: 2nd International Conference of dermatology.

Kathmandu, Nepal. www.icderm2016.com mNOIEMBRIE 2016 24-26: International Congress of Aesthetic Dermatology ICAD 2016. Bankok, Thailand. www.euromedicom.com

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