The prevalence rate of acne in China is continuously increasing in adolescents, young and middle-aged adults. In many cases, those who have refractory inflammatory papules and pustules on the face and mandibular have received long-term antibiotic therapy. Some severe cases have had isotretinoin treatment and even corticosteroid application by either topical or oral administration. The curative effect has not been prominent in these cases, even with combined treatment including antimicrobials and/or isotretinoin and Chinese patent medicines. Papules and pustules even increase and recur during the course of treatment. The phenomena aroused our interest in the possibility of a mixed Malassezia infection. We chose those patients who had had a limited response to traditional acne therapies and recent exacerbation of their symptoms to examine the incidence of Malassezia furfur (M. furfur) in pustules using the potassium hydroxide (KOH) examination technique. However, the results were inconclusive because very few clusters of spores were observed. In order to evaluate an antifungal therapeutic treatment, we administrated the treatment to the patients who accepted it that was approved by the Ethical Committee of Second Hospital of Xi’an Jiaotong University and the patients signed informed consent. Excitingly, acne responded well after discontinuation of antibiotics and combined application of topical and oral antifungal treatments. For example, by oral administration of itraconazole and topical application of naftifine and ketoconazole cream for 2-4 weeks, pustules were significantly decreased, and even disappeared in some cases.
The contradiction between the examination results and response to medication was seemly beyond explanation. However, detailed review could give us insight into the susceptible mechanism of Malassezia infection in the pathogenesis of acne, and mixed infection of bacteria and explain the role of M. furfur as one of the causes of refractory acne.
The current status of knowledge of the genus Malassezia has been reviewed recently.1 It was proposed in 1986 that the yeast phase (Pityrosporum spp.) and the mycelial phase (Malassezia spp.) be combined into the sole genus Malassezia.2 All Malassezia species have distinct morphologic characteristics that allow them to be differentiated from other yeasts. To date 11-12 species have been reported.1,3M. furfur is an obligatory lipophilic organism commonly found on human skin. Roberts4 cultured healthy skin and scalp of 100 Caucasians (primarily adults) and isolated M. furfur from the scalp, chest, and back of 74%, 92% and 100% respectively, of these individuals. The organism was less frequently cultured from a variety of other sites, including the face and limbs.4 Faergemann et al5,6 confirmed these observations by quantitating the number of colonies of M. furfur obtained from skin scrapings in 10 adult volunteers. Counts from the back and chest were >10-fold higher than those from the upper arm, leg, and back of the hand, suggesting preferential growth of M. furfur in sebum-containing skin sites. Using an improved technique for quantitative isolation of M. furfur, Leeming et al7,8 demonstrated that 100% of 16 healthy adults were colonized with M. furfur. Again, the organisms were most abundant in areas containing pilosebaceous glands, a finding that supported that M. furfur colonizes the lumen of the pilosebaceous unit.9
In general, because of their dependence on lipids for survival, Malassezia infections are most often found in sebum-rich areas of the skin such as the trunk, back, face, and scalp. Although part of man’s normal flora, Malassezia yeasts have been implicated in the following diseases such as tinea versicolor, seborrheic dermatitis, folliculitis, atopic eczema/dermatitis, catheter-related fungemia, peritonitis, and meningitis.10
Pathogenesis of acne provides potentiality forMalasseziainfection
Acne is a disease of pilosebaceous units in the skin. It is thought to be caused by the interplay of four factors. Excessive sebum production secondary to sebaceous gland hyperplasia is the first abnormality to occur.11 Subsequent hyperkeratinization of the hair follicle prevents normal shedding of the follicular keratinocytes, which then obstruct the follicle and form an inapparent microcomedo.12 Lipids and cellular debris soon accumu late within the blocked follicle. This microenvironment encourages colonization of Propionibacterium acnes, which provokes an immune response through the production of numerous inflammatory mediators. Inflammation is further exacerbated by follicular rupture and subsequent leakage of lipids, bacteria and fatty acids into the dermis.
Of these factors, sebum, the lipid-rich secretion product of sebaceous glands, has a central role in the pathogenesis of acne, and the severity is generally proportional to the amount of sebum production.13 Previous studies have reported that sebum excretion is increased with the severity of the acne.14,15 In men or women with acne, skin surface lipid levels have been shown to be higher than those of control patients. This is due to enlargement of the sebaceous glands and increased production of sebum, which is stimulated by the increase in production of adrenal and gonadal androgens. Some women with acne also have high serum concentrations of testosterone, dehydroepiandrosterone sulphate or androstenedione.16 Accordingly, excess production of sebum provides suitable growth conditions for M. furfur.
The earliest morphological change is abnormal follicular epithelial differentiation.17 Desquamated cornified cells of the upper canal of the follicle become abnormally adherent. Instead of undergoing the normal process of shedding and discharge through the follicular orifice, these cells form a retained, microscopic hyperkeratotic plug (the microcomedo) in the follicular canal. Sebaceous follicles containing microcomedones provide an anaerobic, lipid-rich environment in which bacteria flourish. Similar to bacterial colonization, the pathophysiologic features of Malassezia folliculitis (M. folliculitis) involve follicular occlusion followed by an overgrowth of yeast that thrives in a sebaceous environment.18,19 The inflammatory response may be a result, in part, of the ability of the M. furfur to hydrolyze triglycerides into free fatty acids.20-23 Thereby, the lipid-rich environment also provides suitable growth conditions for M. furfur.
Host immune condition inducesMalasseziapathogenesis
The M. folliculitis was first described in 1969 in a patient on tetracycline.24 Since then other cases have been reported but almost exclusively in patients who are immunosuppressed due to underlying disorders and/or required therapy, e.g., those in intensive care unit, transplant patients, during pregnancy and AIDS patients. On the other hand, altered host immunity is also thought to play a role in Malassezia infection because 90% of people have M. furfur as a part of their normal skin flora without signs and symptoms of folliculitis or other disease.4,25Malassezia infection is also associated with the use of oral corticosteroids, diabetes mellitus, chemo- therapy and the use of broad-spectrum antibiotics.26-29
Wrong treatments stimulateMalasseziainfection
In some cases, refractory acne is induced by wrong treatments. Exuberant oil secretion which provides suitable growth conditions for M. furfur is always associated with many conditions, such as dry skin caused by excessive cleaning, living in hot and humid weather and application of corticosteroid, etc. The goal of cleansing for acne or acne-prone skin is to gently remove surface debris, sweat, and excessive skin lipids without irritating or drying the skin. However, many acne patients often mistakenly believe that aggressive scrubbing of their skin with soap and water several times a day will alleviate the oiliness and “dirty feeling” on their skin. In fact, the pathology is created by the lipid in the follicular reservoir, which cannot be reached by harsh soaps and detergents or by frenetic washing. The aggressive cleansing aggravates acne and, under certain circumstances, causes “detergent acne”.30Malassezia infection is also more common in hot and humid climates.26,31 The greatest number of patients is seen in the spring and summer. Most of them appeared to sweat excessively, and clinically the disease was more severe when they had used topical steroids recently for other non-serious conditions. It has been reported that topical corticosteroids may produce perioral dermatitis, a localized erythematous papular or pustular eruption.32
M.folliculitis is a common inflammatory skin disorder mimicking acne
Some adolescents with recalcitrant follicular pustules or papules may have acne and M. folliculitis simultaneously. It was first described and noted to be an acneiform eruption associated with antibiotic use by Weary et al.24 It is an infection of the hair follicle thought to be caused by the common cutaneous yeast M. furfur and possibly other strains of Malassezia.4,18,25M. furfur is a dimorphic lipophilic yeast that can be found in small numbers in the stratum corneum and hair follicles of up to 90% of individuals without disease.4,18,25,33 Some individuals colonized with M. furfur develop folliculitis, while others develop tinea versicolor and seborrheic dermatitis.31,34 The papulopustular folliculitis is most commonly found on the chest, back and upper arms, and less frequently on the face which typically appears as 1-2 mm pruritic, monomorphic, pink papules and pustules. Lesions may develop crusting and heal in 3-5 days, but most become chronic, going undiagnosed for up to eight years. Some authors35 claim that M. folliculitis is actually a polymorphic disorder. They describe the most common lesion as a molluscoid, dome-shaped comedopapule (2-3 mm in diameter) with a central “dell” representing the follicle. However, they also report that in severe cases, patients may also have pustules, nodules, and cysts.
Acne can present with a variety of skin lesions, namely comedones, both open and closed, inflammatory papules, pustules, nodules, cysts, conglobate lesions, sinuses, scars and even ulcers. However, several other skin diseases present with very similar-looking skin lesions and a diagnosis is not always as straightforward as it would seem. It is always important to ascertain whether comedones are present because comedones are virtually diagnostic of acne vulgaris and it is very difficult to make this diagnosis in their absence. While acne involves mostly the face, it often extends onto the trunk, most often the back and can also involve the upper arms, thighs and even the buttocks. The scalp is very rarely involved even though it is richly supplied with sebaceous glands.36 In contrast to acne, folliculitis due to M. furfur is often pruritic, lacks comedones, and is unusual in adolescents. Often it is difficult to distinguish clinically from acne and misdiagnosed.19,34 Positive KOH examination showing numerous spores and other yeast forms support the diagnosis. M. folliculitis may be underdiagnosed because it can mimic or is concomitant with acne. Traditional acne therapies, especially antibiotics, may suppress normal bacterial flora and allow overgrowth of M. furfur.
Laboratory examinations support and strengthen the diagnosis
A KOH examination can be prepared by gently scraping one of the pustules with a sterile scalpel blade, smearing the pustular contents on a glass slide, treating it with 1 to 2 drops of 10% KOH before cover-slipping and then examining the smear under the microscope for spores. We found that pustules with significant infection have negative KOH results and very few spores with thick, multilayered cell walls that were dispersedly distributed in the margin of a large number of pus cells. Only in white top comedo-like papules did we sometimes observe a clustering of spores distributed around the corneous emboli. In order to increase the detection rate, an ink- KOH examination could strengthen the diagnosis, such as the Parker-KOH stain. Cultures of M. furfur are compli cated by the yeast’s special culture-medium requirements. M. furfur grows only within a medium rich in C12, C13 and C14 fatty acids, which can be achieved by adding olive oil to the medium.27 In several cases, pustule scrapings were cultured on SAB medium flooded with sterile olive oil. Although fungal culture of these patients showed positive results, the existence of M. furfur in normal skin and hair follicles weakened the diagnosis.
Biopsy also provides direct evidence to support the diagnosis. In most cases, a typical dilated follicle contains abundant round budding yeast cells and sometimes hyphae will be found, and the organism is seen in the absence of other microorganisms.20 These observations strongly support the pathogenic role of Malassezia in the disease. At a histologic level, M. folliculitis is marked by the presence of an inflammatory infiltrate consisting of lymphocytes, histiocytes and neutrophils, along with focal rupture of the follicular epithelium.21,25,37 Spheric and budding yeast cells have been demonstrated in histopathology by methanimine silver and periodic acid-Schiffe stained sections from biopsy specimens.20,37
Also, circulating IgG antibodies against M. furfur are present in high titres.28 The hair follicles themselves also have a characteristic appearance, they tend to be dilated and distended and are often full of keratinous material.35 Particularly, because the phenotypic identification based on microscopic and physiological methods is usually difficult and time-consuming, new methods like molecular identification of Malassezia species isolated from dermatitis affections would give us the chance of rapid diagnosis.38,39
Noteworthy points for diagnosis
Detailed inquiry of the medical history and prior treatments were performed in order to analyze the onset characteristics and clinical features of refractory acne. Some of the results warned us of the incorrect cosmetology ideas and irrational use of medicines by patients and even by doctors. We put forward here some points worth noticing on diagnosis. First, excessive cleaning causes exuberant oil secretion and weakens skin barrier. Most of the patients stated that they normally wash their face four times each day and even wash twice each time using different facial milk cleanser in order to satisfy their perception of cleaning. Second, long-term washing by cleansers containing sulfur and bactericide or oral administration of antibiotics causes dysbacteriosis that aggravated the yeast proliferation. Third, pustules simultaneously found in cervical part, shoulder, chest and/or back always have the same pathogen. Fourth, the character of repeated attack of inflammatory papules and pustules in those patients who received corticosteroid therapy by either topical or oral administration in the early period usually suggest susceptibility to M. furfur. Fifth, significant greasiness provides an environment for lipophilic yeast growth. Sixth, pustules that occupied the main position at the outside of oil overflow sites such as cheek and lower mandible suggest sebaceous hyperplasia and protective sebum excretion in these sites, which provide conditions for Malassezia infection. In middle-aged males this usually occurs on the neck and/or upper body. Seventh, relapsing nodulocystic lesion and scarring are stimulated by the increase in production of adrenal and gonadal androgens or abnormality of immunity, and they usually test positive for M. furfur.
Therefore, the accurate diagnosis of Malassezia infection includes: 1) characteristic clinical manifestations; 2) ink-KOH examination and culture under olive oil; 3) histopathologic examination; and 4) the effect of antimycotic treatment.
Malassezia yeasts are susceptible to a wide range of nonspecific and specific antifungal topical treatments, and several effective oral agents. Older treatments tend to lack antifungal activity and generally possess keratolytic properties. These agents include selenium sulfide, propylene glycol, and sulfur- and tar-containing compounds. However, the activity of selenium sulfide and propylene glycol can be accounted for by their antimicrobial activity.40-42 Several oral agents have also been used successfully to treat Malassezia infections. Faergemann43 has suggested that oral treatment may be more effective than topical treatment for M. folliculitis because it more effectively eradicates the Malassezia yeasts located deep inside in the follicle. Ketoconazole was the first effective oral azole and has been used to treat M. folliculitis.44 Oral administration of itraconazole also appears to delay relapses in M. folliculitis.
Treatment of Malassezia infection is usually prolonged, and relapses may be frequent.18,44,45 For folliculitis, treatment involves application of propylene glycol (50% in water) twice daily for 3 weeks or clotrimazole or miconazole cream daily for 2-3 weeks.46 In severe or refractory cases, oral ketoconazole (200 mg daily for 2-3 weeks) is recommended.18,44,47 Response to therapy may be slow, requiring several months of treatment, and relapses are frequent, particularly in AIDS patients.
Proper selection of drug therapy for patients who had acne and M. folliculitis simultaneously is very important. There is no one specific treatment regimen that can be suggested to eradicate both acne and M. folliculitis. We have noticed a markedly decrease of pustules following continual treatment with antifungals for 2-4 weeks, but with recurrence after continued antibiotic usage. Therefore, close patient follow-up to monitor response to therapy is important. Furthermore, the cycle for both anti-fungal treatment and acne treatment are long and most patients with refractory acne discredit the doctors’ advice due to their long-term history of treatment. Under such condition, psychological counseling is necessary.
Follicular papulopustular inflammation of the face, back and chest may be due to a combination of acne and Malassezia infection, conventionally a common yet less frequently identified disorder. It will often worsen during traditional acne therapy but dramatically respond to antifungal therapy. Dermatologists must keep in mind and reminded from time to time that Malassezia infection is an important cause of refractory acne, because early diagnosis is the key to improve the therapeutic effects.
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