Акценти от 2-ри ден
12 JUNE 2019
Microbiome and atopic dermatitis, Disorders of Hyperpigmentation, Superficial fungal infections
Dr. Nicole JOUAN
Dermatologist, Brest, France
The skin microbiome
Microbiome and atopic dermatitis (AD)
Even though human skin has an acid pH and is constantly peeling, it is abundantly colonised by bacteria, fungi and viruses. The composition of this ecosystem varies from one individual to the next, and forms the microbiome. At least 19 bacterial phyla belong to the skin microbiome.
Most bacteria identified are corynebacteria, propionibacteria and staphylococci. 5 commonly found fungi include those of the genera Malassezia and Candida. Viruses are less well-known.
What is the exact role of “antimicrobial interventions” in AD?
AD flare-ups are characterised by staphylococcus aureus colonisation. Recent European guidelines published in June 2018 in the JEADV however drastically limit the use of antibiotics and antiseptics. It is well recognised that the treatment of AD flare-ups by corticosteroids or calcineurin inhibitors reduces colonisation by staphylococcus aureus. Systemic antibiotics are only indicated in case of established secondary infection; antiseptics have failed to demonstrate their relevance - and are often sensitising - as have local antibiotics - which also trigger bacterial resistance.
Underestimated sources of bacterial superinfection include cream and ointment containers, up to 53% of which are contaminated, and up to 25% with staphylococcus aureus. Therefore the following recommendations may be of use to our patients: keep moisturisers in the refrigerator; use pumps rather than jars; refrain from sharing personal hygiene items.
While silver-impregnated fabric has demonstrated significant antimicrobial activity as well as an improvement in localised SCORAD as part of a controlled clinical trial, further studies are needed.
Why not attempt to re-colonise the epidermis with “good bacteria” by introducing probiotics or microorganisms in creams? This has been achieved with vitreoscilla filiformis. These strategies are regularly discussed but have yet to result in a validated practical application.
What about the use of bleach in AD?
Intuitively, one might assume that 0.025% sodium hypochlorite baths, used in the USA in AD maintenance treatments, act as antiseptics. That is just not the case, as the concentrations used are neither antiseptic or antibiotic. The improvement in SCORAD is not concomitant with the disappearance of staph aureus. It seems that NaOCl has anti-inflammatory effects (as highlighted in irradiated mice), improves the skin barrier and reduces itching, probably by changing the skin’s pH.
With regard to viral infections: herpes simplex, chickenpox-shingles, molluscum contagiosum and coxsackievirus infections are more frequent and severe in atopic patients. Prior topical corticosteroid treatment does not seem to result in an increased risk of developing a severe form of viral infection, unlike topical calcineurin inhibitors which must therefore be immediately discontinued.
Chickenpox-shingles lesions are bacterial gateways for atopic children. Consequently, parents should be encouraged to get them vaccinated against chickenpox, outside AD flare-up periods of course. And the rest of the immunisation schedule should also be respected. Eczema coxsackium (EC) is a disseminated form of infection with the coxsackievirus-A6 strain.
With regard to fungal infections: local antifungal treatments with topical ketoconazole or ciclopirox olamine, or systemic treatments (itraconazole or fluconazole) are recommended in patients suffering from head and neck dermatitis.
Chronic mucocutaneous candidiasis and atopy: do not overlook an inherited immunodeficiency syndrome.
Chronic mucocutaneous candidiasis (CMC) is characterised by recurrent Candida albicans infections. It is associated with an altered response to IL-17 and IL-22, as a result of autosomal dominant gain-of-function mutations (signal transducer and transcription activator).
CMC can also be a sign of a hyper-IgE syndrome, an autosomal dominant disease caused by impaired STAT3 signalling. In this case, CMC is associated with high serum IgE levels, recurrent bacterial infections, pneumatocele after pneumonia, skeletal symptoms (scoliosis) and eczema.
Other syndromes involving immune deficiency, hyper-IgE and eczema include Omenn syndrome, Wiskott-Aldrich syndrome, Comel-Netherton syndrome, septic granulomatosis, for which mutations have been identified.
What about the virome?
Little is known about it; it consists of prokaryotes (bacteriophages which destroy bacteria) and eukaryotes with a structured nucleus (HPV, polyomavirus or HpYV, circovirus)
Polyomaviruses are small (30-60nm), non-enveloped viruses with circular DNA and an icosahedral capsid composed of 72 capsomeres. They are widespread among humans and should be considered opportunistic pathogens.
4 polyomaviruses have been identified in dermatological pathology: MCPyV, TSPyV, HPyV type 6 and HPyV type 7:
- Merkel cell carcinoma, a tumour with poor prognosis associated with old age and immunodeficiency. The prevalence of the MCPyV subclinical infection increases with age, with a seroprevalence in adults of approximately 60–80%. More than 80% of Merkel tumours contain polyomavirus genome. PD-1 checkpoint inhibitors have been somewhat effective on this tumour which is difficult to treat.
- Trichodysplasia spinulosa, a rare condition in immunodeficient subjects which affects the face and responds to cidofovir, associated with the TSPyV virus infection.
- Chronic diffuse pigmentogenic itchy rash in transplant patients, associated with HPyV type 7 viraemia, with histological tests showing parakeratosis characterised by “peacock plumage”. The treatment involves acitretin and, more importantly, a reduction of immunosuppression.
- Cases have been described in immunocompetent patients, and linked to HPyV type 6.
Dr. Rémi MAGHIA
Dermatologist, Brest, France
Disorders of Hyperpigmentation
An extremely intense session focused on hyperpigmentation, first of all on melasma, for which many advances are being made in terms of physiopathogeny and treatment options (topical, systemic and laser).
Approach: Melasma: Etiopathogenesis, and Update
Dr. Andrew ALEXIS (Dermatologist, United States)
An address by Andrew ALEXIS from New York emphasised the following:
- Melasma is a chronic, highly relapsing disease (there is no real curative treatment), which poses a therapeutic challenge.
- Melanocytes are not the only elements involved, as fibroblasts, endothelial cells and sebocytes also come into play (Passeron, 2018). The role of visible light is now being highlighted. As clearly shown in the study by Thierry Passeron’s team (2018, Journal of Investigative Dermatology), blue light stimulates Opsin-3, which activates melanogenesis. Blue light can induce long-term hyperpigmentation in subjects with a phototype 3 and above. The efficacy of sunscreens featuring UV + visible light protection (containing iron oxide) vs UV sunscreens without iron oxide has been demonstrated.
- The vascular component of melasma is an important consideration, and explains that the combination of triple topical treatment and pulsed dye laser yields a better result than the topical treatment alone (Passeron, 2011).
- Tranexamic acid also acts on this vascular component. This haemostatic agent (plasminogen inhibitor), inhibits the synthesis of melanin by inhibiting the conversion of plasminogen into plasmin.
Topical Management of Melasma
Dr. Mercedes FLOREZ-WHITE (Dermatologist, United States)
Mercedes FLOREZ-WHITE told us about melasma management using topical treatments.
While numerous topical agents have been used, hydroquinone remains the gold standard (alone or in combination).
There is a long list of other agents: azelaic acid, kojic acid, topical retinoids, niacinamide, corticosteroids, glycolic acid, resveratrol, resorcinol, emblica, arbutin and plant-based agents: soya beans, curcumin, rosemary, green tea, morus alba, coffee, strawberry, etc.
New topical treatments include topical tranexamic acid, methimazole, thiamidol.
All these agents can be classified as follows:
Antioxidants: ascorbic acid, vitamin E, ferulic acid, phloretin, green tea, soya beans.
Tyrosinase inhibitors: hydroquinone, azelaic acid, kojic acid, mequinol, methimazole, thiamidol, arbutin, glucosamine, emblica, tranexamic acid, liquorice.
Exfoliants: tretinoin, glycolic acid.
Melanin transfer inhibitors: niacinamide, soya bean.
Alpha-MSH blockers: undecylenoyl phenylalaline.
Anti-inflammatory agents: corticosteroids, i.e. non-selective melanogenesis inhibitors.
Photoprotection: must cover UV rays, visible light and infrared light
For this purpose, daily application of broad-spectrum mineral sunscreen with iron oxide, re-applied every two hours. Antioxidants (Vitamin C + ferulic acid) are applied before the sunscreen. Protective clothing is also important.
The speaker presented her melasma treatment algorithm.
She told us that, in the event of severe melasma, she starts with a 0.005% clobetasol propionate solution, for just 2 weeks.
Followed by a combination of tyrosinase inhibitors (including hydroquinone as triple combination) + antioxidants + copper chelators + anti-inflammatory + melanin transfer inhibitor + sunscreen with iron oxide.
If the condition improves, a maintenance treatment is needed: retinol + 3% tranexamic acid + 1% kojic acid + 5% niacinamide.
In the event of a poor response or absence of response, the following must be added: chemical peels or non-ablative laser + brimonidine + antioxidant (vitamin C).
Oral Skin Lightening Agents
Dr. Evangeline HANDOG (Dermatologist, Philippines)
Evangeline HANDOG talked about oral skin whitening agents.
As this is also a very long list, I suggest we essentially focus on tranexamic acid (TA).
It is widely used in Asia, notably in Japan. It is a plasmin inhibitor, and its long-term usage safety has never been clearly demonstrated.
The usual dose is 250 mg twice a day (low dose). Clinical trials take two to six months, with a demonstrated notable improvement after using TA for just one month.
Data from a meta-analysis (Kim et al.) showed that oral TA results in the largest reductions in the MASI score vs topical or intralesional TA. TA has no effect on non-melasma lesions such as lentigines or ephelides.
Side effects are infrequent and minor: nausea, diarrhoea, abdominal pain, palpitations, skin rash, headaches. No thromboembolic events reported during the administration of low-dose TA.
Other oral agents include:
Oral procyanidin, polypodium leucotomos, melatonin, carotenoids, L-cysteine peptide, glutathione.
Prof. Christian MUTEBA BASEKE
Dermatologist, Kinshasa, Democratic Republic of the Congo
Superficial fungal infections
My second day at WCD2019 was dedicated to « Superficial fungal infections ».
Onychomycosis: What can I do when nothingworks
Dr. Myrto-Georgia TRAKATELLI (Dermatologist, Greece)
- Confirm diagnosis by clinical examination and laboratory, treat the reservoir
For onycomycosis check correct dosage, drug interaction and bioavailability
- Patient compliance
- Interruption in transportation drug (onycholysis, lateral nail disease, dermatophytoma, patient with histiry if prior infection….
- Trichophyton resistance to terbinafine treatment is an amerging problem, and switch to azolebased treatement may be necessary to cure such cases of onychomycosis
- Supplemental therapy combination therapy should be considered in the following situations : slow nail growth, severe onychomycosis, immunosupression, dermatophytoma…..
- Supplemental therapy : terbinafine booster is administrated for an extra 4 weeks, between month 6 and 9 from start of treatment, itraconazole booster for an extra pulse, during same period, pharmacokinetic data
- Combination therapy advantage : synergy,wider spectrum, improved activity, increased cure razes, suppression of resistant mutants….
- Miscellaneous : devices lasers are approved by the FDA for temporary increase of clear nail patient not cure.
Epidemic of Dermatophytosis in India
Dr. Shyam VERMA (Dermatologist, India)
- Tinea(T) an epidemic like situation in india, predominantly : T cruris et corporis, T cruris, T Facei
- Some contributor to chronicity : superficial dermatophytes of self limitation, poor sanitation, household dust-spores survive for month, difficult to see treatment…
- Lawlessness/bending of rules ? safety and efficacy data required for any new drug or combination but rules not followed, permissions given by state controllers not answerable to anyone
- Many faces of steroid modified tinea (double edged tinea, no central cleaning, eczematous centers, bizarre shapes….
- Inflammation in tine ais beneficial : a fungus has to replicate faster than keratinocytes in order to survive and grow, TCS-Suppresses local immunity to growth of fungus inflammation
- Addition of a corticosteroid to an antifungal agent at the initiation of Rx (can attenuate the inflammatory symptoms of the infection, thought to increase patient compliance, reduce the risk of bacterial superinfection and enhance the efficacy of the antifungal agent
- Has not applied topical steroid containing FDCs
- Antifungal resitance ; most strains don ?t seem to be resistant, high MICs seen in griseofulvin, fluconazole and terbinafine.
Dermatophyte infections in immunocompromised patients
Dr. Ditte Marie SAUNTE (Dermatologist, Denmark)
- Pathogenesis of dermatophyte infection : athroconidia inoculation, enter stratum corneum, release keratinase/protease, immune response
- Type of dermatophytosis patient in patients with immunodeficiency
* Common forms but a higher prevalence or rare manifestation (onychomycosis, PSO caused by trichophyton, adult tinea capitis)
* Severe form invasive(perifollicular, majocchi ‘s granuloma, deep dermatophytosis), disseminated dermatophytosis, wide spead
- Multiple abcess in the lower extremities caused by T.rubrum
- Primary immunodeficiency inherited caspace recruitment domain family, members 9(CARDP9) deficiency, acquired immunodeficiencies (solid organ transplatation, autoimmune desease requiring immunosuppressive treatment, hiv infection)
- Treatment challenge :
* Systemic : terbinafine, itraconazole, griseofulvine
* Topical : terbinafine, naftifine,miconazole…
* Potential problems : risk of antifungal resistance, drug-drug interaction, especially a problem in organ transplant patient
* Other : surgical treatment of localized leions, pause immunosuppressive medication ?
- Important to educate all patients receiving immunosuppressant therapy on skin care, pre-transplan skin examination, immunocompetent patient with an unusual manifestation
Antifungal stewardship: superficial fungal infections
Dr. Abir SARASWAT (Dermatologist, India)
- The concept of antifungal stewardship for superficial mycoses has received scan attention so far. The emergence of new, virulent and drug resistant strains of dermatophytes and molds makes it a urgent requirement
- Urgent need of data to understand the reason s and mechanisms behind the spread of superficial mycoses; collaboration with agricultural scientists essential,
- Capacity building for rapid and reliable diagnosis of superficial mycosis in the clinic is the need of the hour
- Controlling the empiric or irrational use of topical antifungals is urgently needed. It is only possible if rapid diagnosis is easy, cheap and ubiquitous
- Irrational combinations of corticosteroids with antifungal/antibacterian should be ruthlessly weeded out
- Clear, evidence based guidelines for systemic and topical antifungal use should be taken up on priority.