7.1. Background
7.1.1. Epidemiology
There are three variants of eosinophilic folliculitis: classic, infancy-associated and immunosuppression-associated (mostly HIV-associated).
The prevalence of HIV-associated eosinophilic folliculitis varies greatly across different populations. The estimated prevalence in HIV-infected adults attending hospital-based dermatology clinics was 18.6% (13 of 70) in Seoul, Korea (Kim et al., 2010), 4% (21 of 528) in Florida, USA (Goldstein et al., 1997), 4.2% (four of 96) in Singapore (Goh et al., 2007) and 2.6% (four of 150) in India (Sud et al., 2009). The prevalence of HIV-associated eosinophilic folliculitis has diminished with the widespread use of ART (Rajendran et al., 2005).
The development of HIV-associated eosinophilic folliculitis is strongly associated with advanced immunosuppression, especially CD4 counts under 250 cells/mm3, and low CD4 nadir (Rajendran et al., 2005) (see GRADE tables in WEB APPENDIX 1). Immune dysregulation and abnormal type 2 T-helper cell immune responses in advanced HIV disease have been implicated in the aetiology of HIV-associated eosinophilic folliculitis. It has been suggested that mast cells (Buchness et al., 1989) and target antigens in serum, such as chemotactic factors for eosinophils (Otley et al., 1995), also play a role. In children, the condition has been classified as an AIDS-defining illness.
7.1.2. Clinical features
HIV-associated eosinophilic folliculitis manifests as 2–3 mm erythematous, highly pruritic wheal-like papules, most frequently affecting the shoulders, trunk, upper arms, neck and forehead. Lesions are follicular and are often markedly excoriated. Pruritus adversely impacts on quality of life and may cause sleep impairment, distress and depression (Yosipovitch et al., 2000; Zachariae et al., 2004; Zachariae et al., 2008). Clinically the differential diagnosis of eosinophilic folliculitis is between papular pruritic eruption or other dermatoses – for example, scabies, urticaria, drug rashes and eczema (see ).
DIFFERENTIAL DIAGNOSIS OF EOSINOPHILIC FOLLICULITIS.
Owing to the wide differential diagnosis of eosinophilic folliculitis, a skin biopsy and histopathological examination is often recommended for diagnosis. The histology shows a folliculocentric inflammatory infiltrate, predominantly of eosinophils and lymphocytes.
7.2. Recommendations
ART should be considered as the primary treatment of eosinophilic folliculitis in eligible patients (see
SECTION 3).
(Strong recommendation, low quality evidence)
All HIV-infected adults (including pregnant women), adolescents and children who have been initiated on ART and who subsequently develop HIV-associated eosinophilic folliculitis should not discontinue the ART.
(Conditional recommendation, very low quality evidence)
Additional symptomatic therapy is recommended for the duration of the persistent symptoms with, depending on severity:
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oral antihistamine; if no adequate response, add
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topical corticosteroids (class 3, 4, 5 or 6, e.g. betamethasone valearate); if no adequate response, add
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oral itraconazole; if no adequate response, add
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permethrin 5% cream applied above the waist.
(Conditional recommendation, very low quality evidence)
Remarks
Drugs: Even though the quality of evidence is very low, betamethasone should be used if pruritus persists; if betamethasone is not available, other class 3, 4, 5 or 6 potent topical corticosteroids can be used instead.
Caution should be exercised in the use of oral antihistamines in young infants. Dosage should be adjusted by age and weight.
Itraconazole is excreted into human milk and therefore is not recommended for breastfeeding mothers. Cases of congenital abnormalities have been shown following itraconazole treatment.
Relevant drug interactions are described in
ANNEX 2.
7.3. Review question and summary of evidence
The systematic review (Chua et al., in preparation) was based on the PICO question: in HIV-infected adults and children (receiving or not receiving ART) (P), does ART or other interventions with or without ART (topical, systemic or phototherapy) (I) compared with a placebo, other interventions, no intervention or a combination of two or more interventions (C) lead to resolution of pruritus, rash or both (primary outcome); or reduction of pruritis, or body surface affected by rash, or improved quality of life (secondary outcome) (O).
No RCTs related to eosinophilic folliculitis treatment were identified. However, a large number and a wide range of interventions have been described in both ART-treated and non-ART-treated adult participants to be beneficial in the treatment of HIV-associated eosinophilic folliculitis.
Three non-randomized uncontrolled open trials of oral itraconazole (Berger et al., 1995), oral isotretinoin (Otley et al., 1995) and topical permethrin (Blauvelt et al., 1995) were included. The effect of a combination of ART and oral isotretinoin was described in a prospective study (Annam et al., 2010). A prospective study by Lim and colleagues (1997) of the efficacy of UVB phototherapy in HIV-positive participants with pruritus included 14 participants with HIV-associated eosinophilic folliculitis. All other included studies were open trials, retrospective chart reviews, case series or case reports with fewer than ten participants.
It is difficult to be certain if the response reported is attributable to the intervention(s) described due to the lack of a comparison group, randomization, allocation concealment, and blinding of participants, investigators and outcome assessors. Findings from the studies included in this review are not easily generalizable due to small sample sizes and high risk of bias.
Based on the findings of prospective studies and open (uncontrolled non-randomized) trials, there is some evidence for the use of oral isotretinoin (40–80 mg/day or 0.5–1.2 mg/kg per day), initiated simultaneously with ART (Annam et al., 2010) or in ART-treated patients (Otley et al., 1995), oral itraconazole (Berger et al., 1995), UVB phototherapy (Lim et al., 1997) and topical 5% permethrin cream (Blauvelt et al., 1995).
ART alone or with other treatments
The favourable impact of ART was outlined in two case reports (Michigami et al., 2009; Sears et al., 2012). The combination of ART and oral dapsone (100 mg per day) resulted in a good response in one patient according to a case report (Filippetti & Muzi, 2012). Annam and colleagues (2010) reported complete response in 16 of 23 participants and partial response in seven participants with the concurrent initiation of ART and oral isotretinoin (40–80 mg/day or 0.5–1.2 mg/kg per day).
Oral itraconazole
Oral itraconazole at doses between 100–400 mg per day was studied in 28 HIV-positive adult participants. Sixteen of the participants were followed up at six months; five participants had complete remission of skin lesions and pruritus after discontinuation of therapy, two were controlled on topical corticosteroids only, five were fully controlled and four were partially controlled on oral itraconazole (Berger et al., 1995). There was one case report of complete remission of pruritus and skin lesions after two months of treatment with oral itrazonazole (Parker et al., 2006).
Oral isotretinoin
An open uncontrolled trial of oral isotretinoin (40-80 mg/day, 0.5–1.2 mg/kg per day) in seven HIV-positive male adult participants already receiving ART showed complete remission for up to nine months after one course of therapy in four participants and after the second course of therapy in three participants (Otley et al., 1995). The efficacy of isotretinoin was described in a case report and one case series of seven participants (Downs et al., 1998).
Permethrin
Topical 5% permethrin cream above the waist was reported to be effective when used without interruption in the treatment of HIV-associated eosinophilic folliculitis in six participants (Blauvelt et al., 1995).
7.4. Rationale for recommendations
The GDG considered that the evidence base for all of the interventions was of very low quality, because the studies reviewed either had small sample sizes or were reports of individual cases or small case series. However, although the evidence is of very low quality, there appears to be some benefit from isotretinon, oral itraconazole with or without oral antihistamines, with or without topical corticosteroids, antihistamines with or without topical corticosteroids, permethrin 5% cream, or UVB phototherapy.
The GDG excluded isotretinoin because of its teratogenic effect, its high cost and unavailability in most low-resource settings. Similarly UVB phototherapy is also unavailable or unaffordable in most resource-limited settings and therefore is not recommended.
Even though itraconazole is not in the WHO Model list of essential medicines,1 the panel considered it important for symptomatic treatment of eosinophilic folliculitis as well as other skin conditions. Oral antihistamines, topical corticosteroids, topical permethrin 5% and doxycycline have also been recommended because of their effectiveness, affordability and availability.
Although the evidence is of very low quality, the GDG strongly recommended the use of ART as a primary treatment of eosinophilic folliculitis based on expert opinion and consensus. This recommendation would probably be acceptable to key stakeholders. In addition, the resources required to implement this recommendation are small (see ANNEX 3).
The recommendation for all HIV-infected adults (including pregnant women), adolescents and children who have been initiated on ART and who subsequently develop HIV-associated eosinophilic folliculitis, not to discontinue the ART is based on expert opinion and GDG consensus and therefore stated as conditional. One constraint is that accurate diagnosis of the disease may not be easy in resource-limited settings due to the lack of access to pathology and dermatology services.
The recommendation for oral antihistamines and/or topical corticosteroids and/or oral itraconazole and/or topical 5% permethrin as additional symptomatic therapy for the duration of the persistent symptoms is also based on expert opinion and GDG consensus and therefore stated as conditional. Although the available evidence is very low quality, overall the desirable effects of this recommendation were assessed as probably large relative to any undesirable effects.
Adverse effects, costs, availability and other implementation considerations
As for other conditions, the present WHO recommendation (WHO, 2013) is ART initiation for all symptomatic patients. ART would be acceptable to most patients who are eligible for treatment and the incremental cost is probably small. There is free access to ART in most settings.
Topical corticosteroids are easily available at low cost. However, effective topical corticosteroids do have the potential for side effects, such as striae and telangiectasia, especially with long-term use. Potent topical steroids should not be used for more than three weeks continuously. If a longer duration is needed, the steroid should be gradually tapered to avoid rebound symptoms, and treatment should be resumed after a steroid-free period of at least one week. This intermittent schedule can be repeated chronically or until the condition resolves. Side effects are rare when topical steroids are used for three months or less.
Antihistamines are also easily available at low cost. Antihistamines have been in clinical use for six decades and are relatively free of adverse effects, although no long-term safety studies have been published.
Itraconazole is excreted into human milk and is therefore not recommended for breastfeeding mothers. Cases of congenital abnormalities have been shown following itraconazole treatment. Itraconazole is highly protein bound and inhibits cytochrome p450 enzymes. Therefore drug interactions should be considered when prescribing this drug. Relevant drug interactions are described in ANNEX 2.
7.5. Research gaps
The research gaps identified were similar to those for papular pruritic eruption:
Well-designed, prospective, blinded RCTs in HIV-infected adults and children to provide high quality evidence upon which to base clinical decision-making;
Establishment of a standardized outcome measure (e.g. time to resolution of the lesions or resolution after three months) to ensure studies are easier to compare.
Establishing recurrence rates, time frame and circumstances under which these conditions recur.
Improvement of assessment of other clinical conditions/manifestations, CD4 and viral load associated with these conditions.
