Clinical importance of Demodex folliculorum in patients receiving phototherapy

Authors


  • This study was presented as an oral free communication at the 14th EADV Congress, London, 2005


Mustafa Kulac, md Department of Dermatology Faculty of Medicine Afyon Kocatepe University Pembe Hastane 03200 Afyon Turkey
E-mail: drmustafakulac@hotmail.com

Abstract

Background  Patients with immunodeficiency are prone to infestation with Demodex folliculorum mites. Ultraviolet (UV) radiation can lead to immunosuppression and sebaceous gland hyperplasia. Although some cases of demodicidosis related to UV radiation exposure have been reported, no studies have been performed on the incidence of D. folliculorum and its clinical characteristics in patients receiving phototherapy.

Objective  To investigate the effects of phototherapy on the density of D. folliculorum infestation and its clinical characteristics.

Methods  This was a cross-sectional study. Forty-five patients receiving phototherapy and 43 age- and sex-matched healthy controls were enrolled to the study. The sociodemographic characteristics, occupational information, and skin types (2, 3, 4, or 5) of both patients and controls were carefully recorded. The dermatologic diseases requiring phototherapy, type and number of phototherapy treatments, and cumulative UV doses of all patients were noted. The clinical findings that may relate to demodicidosis were recorded. Standardized skin surface biopsies were taken from three anatomic regions (forehead, cheek, and nasal dorsum) and suspected lesions; five or more D. folliculorum mites per square centimeter of skin was defined as demodicidosis.

Results  Twelve (26.7%) patients received psoralen plus UV-A (PUVA) and 33 (73.3%) received narrow-band UV-B. Demodicidosis was detected in 13 (28.9%) patients and three (7%) controls. The difference in the demodicidosis rate between patients and controls was statistically significant (P = 0.01). In eight of the 13 patients (61.5%) with demodicidosis, clinical demodicidosis was present. Demodicidosis was present in seven of the 12 patients (58.3%) receiving PUVA and in six of the 33 patients (18.2%) receiving narrow-band UV-B. The difference in demodicidosis rates between patients receiving PUVA and those receiving narrow-band UV-B was statistically significant (P = 0.02). A statistically significant difference was also found between the mean D. folliculorum densities of patients and controls in all anatomic regions.

Conclusion  Demodicidosis should be included in the differential diagnosis of facial eruptions in patients receiving phototherapy.

Introduction

Demodex folliculorum is a 0.3-mm-long, obligate, hair follicle parasite which lives in clusters in the pilosebaceous duct and is thought to have a pathogenic role in various dermatologic conditions, such as pityriasis folliculorum, perioral dermatitis, blepharitis, rosacea, eruptions resembling rosacea, and pustular and granulomatous folliculitis. Although the parasite is found in large numbers on the face, it can also be encountered in other areas of the body where sebum formation is abundant.1,2 The density of mites in healthy skin is age dependent, increasing with age and reaching up to 100% in elderly people.3

The pathogenic role of D. folliculorum mites in human dermatopathology is still a matter of debate. Dominating dermatologic concepts suggest that there is a control mechanism limiting the population of follicle mites, but that local or systemic factors may create an environment encouraging their proliferation. One of the factors responsible for the transition from a clinically inapparent colonization of mites to dermatosis is the development of primary or secondary immunosuppression.4–8 Thus, patients with immunosuppression [acquired immunodeficiency syndrome (AIDS), hematologic malignancies, local or systemic immunosuppressant medications] are prone to infestation with D. folliculorum mites.3–5,9,10

Phototherapy is one of the most commonly used modalities for the treatment of a variety of skin diseases. Although a detailed understanding of its mechanisms of action is unknown, there is increasing evidence that it acts primarily via its immunosuppressive effects.11,12 In addition, some reports have indicated that phototherapy increases the amount of skin surface lipids by direct activation of the function of sebaceous glands.13 In theory, an increase in the incidence of D. folliculorum mites in patients receiving phototherapy may be expected as a consequence of immunosuppression and the enlargement of sebaceous glands; however very few demodicidosis cases related to ultraviolet (UV) exposure have been presented to date.14 To our knowledge, no studies have been performed on the incidence of D. folliculorum and its clinical characteristics in patients receiving phototherapy. We have investigated these questions in this study.

Materials and Methods

Study design

This was a cross-sectional study.

Selection of patients and controls

Patients diagnosed with psoriasis and vitiligo, and receiving treatment at the Phototherapy Clinic, Department of Dermatology, Medical Faculty, Afyon Kocatepe University, Afyon, Turkey, were recruited for this study between 1 January 2005 and 28 February 2005. The inclusion criterion was the administration of five or more phototherapy treatments. Control subjects were selected from patients admitted to the dermatology outpatient clinic during the same period. The exclusion criteria for both groups were as follows: previously diagnosed rosacea, perioral dermatitis, or any dermatosis related to D. folliculorum, immunosuppression (local or systemic), diabetes mellitus, and the use of antibiotics within the last 3 months. In addition, individuals who had sunbathed within the preceding 3 months were excluded from the control group.

Twenty-four female and 21 male patients (total, 45) receiving phototherapy [average age, 36.61 years; age range, 13–63 years; standard deviation (SD), 13.71 years] and 43 age- and sex-matched healthy controls were enrolled to this study. All patients and control subjects were examined by a dermatologist (MK). The sociodemographic characteristics, professions, and skin types (2, 3, 4, or 5) of both patients and controls were carefully recorded. The dermatologic diseases requiring phototherapy (psoriasis and vitiligo), phototherapy types [psoralen plus UV-A (PUVA) or narrow-band UV-B], number of phototherapy treatments, and cumulative UV doses of all patients were noted. Informed consent was obtained before examination, and approval for the study was granted by the local ethics committee of Afyon Kocatepe University.

Phototherapy protocol applied

A phototherapy cabinet (Waldmann, UV 7001K) providing UV-A and narrow-band UV-B (311 nm) was used for this study. In the PUVA protocol, skin types were determined according to clinical examinations and history. The first treatment dose was based on phototyping (skin type × 0.5 J/cm2), and the patients were treated three times a week. Dose increments were 0.5 J/cm2. A dosage of 8-methoxypsoralen (8-MOP) at 0.6 mg/kg body weight was administered orally 90 min before exposure. In the narrow-band UV-B protocol, prior to phototherapy, the patient's minimal erythema dose (MED) was determined. The initial dose was equal to 0.7 MED. A 20% incremental increase in the previous dose was used at each visit.

Sampling method: standardized skin surface biopsy

A standardized skin surface biopsy, a noninvasive sampling method, was taken from three different facial anatomic regions (forehead, cheek, and nasal dorsum) and suspected lesions. It involved placing a drop of cyanoacrylic adhesive on a microscope slide, applying the adhesive-bearing surface of the slide to the skin, and removing it gently after it had been allowed to dry (about 1 min). Initially, a standard surface area of 1 cm2 was drawn on the opposite face of the slide with a waterproof marker. After removal from the skin, each sample was clarified with two to three drops of immersion oil, and then covered with a coverslip. The samples were studied microscopically at standard magnifications (× 40, × 100).8,15 Because the counting of D. folliculorum may be affected by personal and environmental conditions, to minimize errors in microscopic examinations all measurements in this study were performed by the same investigator (IHC) in a standard environment. Evidence of living D. folliculorum mites at a density of five or more mites per square centimeter of skin surface was defined as an infestation (demodicidosis).

Clinical findings and clinical demodicidosis types

In the patient group, the clinical findings (erythema, telangiectasia, follicular tiny papule, follicular tiny pustule, follicular scaling, papule, pustule, nodule, and abscess) that could be related to demodicidosis were recorded. The clinical demodicidosis types (pityriasis folliculorum, perioral dermatitis, rosacea-like dermatitis, pustular and granulomatous folliculitis, and demodex abscess) were classified according to the literature.2,3,16 The diagnosis of clinical demodicidosis type was made on the basis of the clinical findings and the presence of D. folliculorum mites at a density of greater than five per square centimeter.

Statistical analysis

All parametric results were expressed as the mean ± SD for each group. Data were analyzed by descriptive statistics; in the case of nominal variables, the differences were assessed using χ2 and Fisher exact tests. Intergroup comparisons of the mean D. folliculorum densities were made using the Mann–Whitney U-test. Local statistical significance was assumed to be P < 0.05 for all parameters.

Results

Demodicidosis was detected more frequently in patients receiving phototherapy than in the control group [13 of 45 patients (28.9%) and three of 42 controls (7%), P = 0.01) (Fig. 1). In eight of the 13 patients (61.5%) with demodicidosis, clinical demodicidosis was present. In six patients (two receiving narrow-band UV-B and four receiving PUVA), the clinical demodicidosis type was pityriasis folliculorum, and in two patients (one receiving narrow-band UV-B and one receiving PUVA), the clinical demodicidosis type was rosacea-like demodicidosis. Five patients did not have clinical demodicidosis. The D. folliculorum density was greater than five mites per square centimeter in all suspected lesions, except for one patient. In one patient receiving narrow-band UV-B, pustular lesions on the perioral region were present, but the D. folliculorum count was lower than five mites per square centimeter. This patient was diagnosed with perioral dermatitis unrelated to D. folliculorum. Interestingly, in one patient receiving PUVA for psoriasis, sunburn developed after the seventh treatment and the treatment was discontinued. Erythema, with numerous papules and pustules, appeared on the face whilst the sunburn was healing (Fig. 2). Examination of the lesions by standardized skin surface biopsy indicated the presence of large numbers of D. folliculorum.

Figure 1.

Comparison of the incidence of demodicidosis between patients receiving phototherapy and controls. Df, Demodex folliculorum

Figure 2.

Erythema, with numerous papules and pustules, appeared on the face of a patient during phototherapy

Twelve (26.7%) patients received PUVA and three (73.3%) received narrow-band UV-B. With regard to the number of phototherapy treatments, there was no difference between patients receiving PUVA (mean number of phototherapy treatments, 39.58 ± 30.81; minimum, 5; maximum, 104; median, 28.50) and those receiving narrow-band UV-B (mean number of phototherapy treatments, 48.54 ± 32.01; minimum, 7; maximum, 97; median, 50) (P = 0.38). In patients receiving PUVA, the mean cumulative light dose was 171.22 ± 193.59 J/cm2 (minimum, 5.30 J/cm2; maximum, 492 J/cm2; median, 60 J/cm2), and in those receiving narrow-band UV-B, the mean cumulative light dose was 78.07 ± 69.82 J/cm2 (minimum, 2.30 J/cm2; maximum, 220 J/cm2; median, 61.30  J/cm2). No comparison between the two groups according to the cumulative light dose was performed, as each PUVA and narrow-band UV-B treatment was different, and the treatment protocols and dose adjustments also varied. Therefore, we calculated the mean cumulative doses separately. In addition, there was no difference between the two groups in terms of skin type. In seven of the 12 patients (58.3%) receiving PUVA and six of the 33 patients (18.2%) receiving narrow-band UVB, demodicidosis was present. The difference in demodicidosis rates between patients receiving PUVA and narrow-band UV-B was statistically significant (P = 0.02) (Table 1).

Table 1.  Difference in demodicidosis rates between phototherapy patients and controls (P = 0.01) and between patients receiving psoralen plus ultraviolet-A (PUVA) and narrow-band UV-B (P = 0.02)
 PatientsControls
PUVANarrow-band UV-BTotal
 12334543
Demodicidosis 7 613 3

The mean D. folliculorum density varied according to location. The highest density was found on the cheeks in patients receiving phototherapy. The mean D. folliculorum density on the cheeks was 3.22 ± 3.43 D. folliculorum/cm2 (minimum, 0; maximum, 15; median, 2) in patients and 0.97 ± 1.77 D. folliculorum/cm2 (minimum, 0; maximum, 7; median, 0) in controls; this difference was significant (P = 0.000). The mean D. folliculorum density on the forehead was 1.31 ± 2.14 D. folliculorum/cm2 (minimum, 0; maximum, 10; median, 1) in patients and 0.23 ± 0.57 D. folliculorum/cm2 (minimum, 0; maximum, 2; median, 0) in controls; this difference was significant (P = 0.000). The mean D. folliculorum density on the nasal dorsum was 0.57 ± 1.48 D. folliculorum/cm2 (minimum, 0; maximum, 9; median, 0) in patients and 0.06 ± 0.25 D. folliculorum/cm2 (minimum, 0; maximum, 1; median, 0) in controls; this difference was significant (P = 0.007) (Table 2).

Table 2.  Comparison of the mean Demodex folliculorum density (D. folliculorum/cm2) according to region between patients receiving phototherapy and controls
RegionPatients, mean ± SD (minimum–maximum; median)Controls, mean ± SD (minimum–maximum; median)P
Cheek3.22 ± 3.43 (0–15; 2)0.97 ± 1.77 (0–7; 0)0.000
Forehead1.31 ± 2.14 (0–10; 1)0.23 ± 0.57 (0–2; 0)0.000
Nose0.57 ± 1.48 (0–9; 0)0.06 ± 0.25 (0–1; 0)0.007

Discussion

This is the first study to investigate the relationship between demodicidosis and phototherapy. So far, only one report has been presented concerning an outbreak of D. folliculorum folliculitis on the face and upper trunk during 311-nm UV-B therapy for psoriasis.14 In this study, it was proposed that the increase in D. folliculorum may have been caused by immunosuppression and enlargement of the sebaceous glands as a result of phototherapy. It is well known that rosacea is exacerbated by sunlight and heat. A number of clinical studies have reported that D. folliculorum may play a role in the pathogenesis of rosacea.1,15,17 These studies have highlighted that a high density of D. folliculorum may have a pathogenic role in rosacea, especially in the development of inflammatory lesions, and that a diagnosis may be regarded as positive when the mite density is above five per square centimeter. Although the pathogenic relationship between D. folliculorum, rosacea, and sunlight is still not completely understood, it is possible that increased blood flow in dilated papillary dermal vessels by the effect of solar radiation may provide a favorable environment for the multiplication or invasion of D. folliculorum into the dermis.1,15,17–19 In addition, rosacea is always associated with solar elastosis and often with heliodermatosis.1 In some studies, the rarity of D. folliculorum in the young, its occurrence in sun-exposed sites, and its frequency in fair-skinned individuals suggest that solar-induced degeneration of connective tissue is important in its origin3. Moreover, seasonal fluctuations have been reported. D. folliculorum is detected most often and in highest numbers in spring when most cases of rosacea are exacerbated.17

As D. folliculorum feeds on sebum and cellular proteins obtained by epithelial and glandular cell destruction through its own enzymatic activity, increased amounts of sebum may contribute to its multiplication and invasion.1,15,16 Youn et al.20 reported seasonal variations in facial sebum secretion, with a significantly higher level during the summer. Akitomo et al.13 developed an in vitro model of cultured sebocytes from hamsters, which have similar biological characteristics to human sebocytes, to measure the effects of UV radiation on sebaceous glands. They found that the number of sebocytes increased significantly (120–140%) after 4 days of UV radiation, when compared with nonirradiated controls, and that lipid production in sebocytes was also increased on day 7 in an irradiation-dependent manner to up to 4.1 times the preirradiated level. Further support for the theory of augmentation of sebum secretion by UV exposure comes from cases of seborrheic eczema exacerbated by excessive exposure to sunlight. Although seborrheic eczema has been successfully treated with phototherapy, it has long been acknowledged that sunlight can cause exacerbation of the condition, particularly in mountain guides, who are occupationally exposed to high levels of solar radiation.21,22

Immunosuppression, old age, topical and systemic corticosteroid usage, topical pimecrolimus and tacrolimus usage, and diabetes mellitus are predisposing factors for demodicidosis.3,4,9,16,23,24 The increased incidence of D. folliculorum in patients with hematologic malignancies, AIDS, and diabetes mellitus indicates that immunosuppression may have a major role in the development of demodicidosis. The association between immunosuppressant medications and demodicidosis, as well as that between Cw2 and Cw4 alleles in the phenotype of patients with demodicidosis and a decrease in the number of natural killer cells, strengthens the evidence for the role of immunosuppression.25 Therefore, the general medical view accepts immunosupression as the most important factor in the pathogenesis of demodicidosis. T-cell immunodeficiency, in particular, is an important predisposing factor for mite invasion. Akilov and Mumcuoglu4 have shown that the absolute number of CD3+, CD4+, CD8+, and CD16+ cells, the CD3+/CD20+ ratio, and the functional activity of leukocytes are significantly lower in individuals infested with D. folliculorum. They suggested that colonization of the skin with D. folliculorum may be a reflection of the host's immune response. In addition, the same researchers found that patients with demodicidosis had 2.5 times higher values for CD95+ cells (apoptotic marker) than the control group. Programmed cell death (apoptosis) is the basic mechanism for positive and negative selection of T and B lymphocytes, which are important in the elimination of cells with defective antigen-recognizing receptors. A defect in the coordination of apoptosis often leads to complications in the immune system. Immunosuppressive effects of UV radiation have been extensively investigated with regard to T-cell-mediated immunologic reactions, such as contact hypersensitivity and delayed-type hypersensitivity. There is increasing evidence that phototherapy acts primarily by its immunosuppressive effects.11,12 The increase in D. folliculorum in patients receiving phototherapy may have been expected as a consequence of immunosuppression. Interestingly, Erbagci et al.26 found a high incidence of demodicidosis in eyelid basal cell carcinomas. This association favors the overlap of UV radiation, immunosuppression, and demodicidosis.

In this study, it was found that the incidence of demodicidosis in patients receiving phototherapy (28.9%) was significantly higher than that in the control group (P = 0.01). This rate was similar to that in patients with hematologic malignancies, presented by Seyhan et al.10[14 of 50 patients (28%) with hematologic malignancies]. Interestingly, demodicidosis was detected more frequently in patients receiving PUVA than in those receiving narrow-band UV-B (P = 0.02). Although it may be possible to explain this difference by theorizing that PUVA can penetrate to deeper tissues than narrow-band UV-B, it may be coincidental. Further studies with larger case numbers are needed to investigate whether significant differences in the incidence of demodicidosis exist between patients receiving PUVA and those receiving narrow-band UV-B.

Pityriasis folliculorum and rosacea-like demodicidosis are the most commonly described clinical forms. We observed the same clinical forms (pityriasis folliculorum in six patients and rosacea-like demodicidosis in two patients) in eight of the 13 patients with demodicidosis. Five patients did not have clinical demodicidosis. We did not observe any other forms of demodicidosis. The highest D. folliculorum density was found on the cheeks of patients receiving phototherapy. This is similar to the results obtained in patients with hematologic malignancies and diabetes mellitus.10,24 We also found a statistically significant difference in the mean D. folliculorum density between patients and controls in all anatomic regions studied.

Conclusion

Immunosuppression and sebaceous gland enlargement, which arise from phototherapy, can contribute to the development of demodicidosis. We have shown that the prevalence of demodicidosis increases in patients receiving phototherapy. We believe that demodicidosis should be included in the differential diagnosis of facial eruptions in patients receiving phototherapy. Therefore, we recommend a routine standardized skin surface biopsy examination in patients developing facial eruptions during phototherapy.

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