Demodectic eruptions: More than you mite have imagined
By Warren R. Heymann, MD, FAAD
April 26, 2023
Vol. 5, No. 17
Despite the ongoing debate about the precise role of Demodex in the pathogenesis of multiple dermatoses (pityriasis folliculorum, papulopustular and granulomatous rosacea, perioral dermatitis, seborrheic dermatitis, blepharitis, and others), few would argue about the association of the mites with these entities, or that ivermectin — administered either topically or systemically — can be an effective therapy.
The pathophysiology of Demodex mites is eloquently discussed by Aktaş Karabay and Aksu Çerman: “D. folliculorum and D. brevis, the two Demodex species, are ubiquitously found on the normal skin of adult humans, particularly in the pilosebaceous units of the face. D. folliculorum resides within the hair follicle, whereas D. brevis is found predominantly in the sebaceous and meibomian glands. Demodex mites penetrate into skin cells (particularly the keratinocytes that line pilosebaceous follicles) and ingest their contents. Demodex mites feed on the sebum and cellular proteins that are obtained by protease containing the salivary enzymes of the mites. The lipase enzymes of Demodex are also thought to play a role in digesting bacteria or other microorganisms in addition to the digestion of lipid material. The enzymatic process leads to degradation of the follicular epithelium, which may result in perifollicular inflammation. Demodex mites may also cause mechanical blockage of the follicle opening. Moreover, it is thought that extrafollicular mites may induce a granulomatous foreign body reaction through their chitinous exoskeleton. Dying mites are thought to trigger an immune response in the host by releasing their internal contents and the chitinous exoskeletons of degrading, dying mites, followed by inflammatory changes. Demodex mites may also suppress the innate immune response of the hosts that provide for their survival. It has been shown that the Tn antigen, which is a carbohydrate coating providing protection for cancer cells and parasites from immunity, is expressed by Demodex mites. Demodex mites are also shown to affect the secretion of inflammatory cytokines, such as IL-8 and TNF-alpha and TLR expression, through the interaction with cells of the pilosebaceous unit.” (1) Factors that influence the proliferation of D. folliculorum and D. brevis include age, marked immunosuppression, sebaceous gland hyperplasia, and hypervascularization-related factors. (2)
The role of immunosuppression (or immunodysregulation) in demodectic eruptions (demodicidosis) cannot be overemphasized. Recent examples include:
Demodicidosis accompanying acute graft-versus host disease in a 28-year-old woman with acute myeloid leukemia 28 days after undergoing an allogeneic hematopoietic stem cell transplantation (3);
A 40-year-old woman with chronic mucocutaneous candidiasis due to a novel gain of function STAT1 mutation developed a florid rosacea-like demodicidosis manifesting as diffuse facial inflammatory papules and bilateral blepharitis (4), and;
Two adolescent boys presenting with acute acneiform Demodex folliculitis following administration of dupilumab for atopic dermatitis. (5)
What makes demodectic eruptions so intriguing is their element of surprise in disorders where you were not expecting it. Consider the following examples:
Location. I was not familiar with demodicidosis of the nipple until a colleague sent in a dermatopathology specimen to rule out Paget disease of the breast. Demodex infestation of the nipple may present with pruritus alone (6,7), although histologically perifollicular inflammation accompanies the intrafollicular mites. (6) Vulvar demodicidosis may cause suppurative granulomatous disease on the vaginal labia where Fordyce spots are infiltrated by the mites. These lesions may become tender and drain; in the case reported by Hedberg et al, there was a good therapeutic response to oral ivermectin and topical metronidazole. (8)
Unusual morphology. Fichtel et al presented an 88-year-old African American woman with a 4-month history of painful, nonpruritic yellowish-green, greasy, adherent plaques along the right cheek (see image). The clinical differential diagnosis included impetigo, demodicidosis, and terra firma-forme. A KOH preparation showed many Demodex mites, and a punch biopsy revealed numerous Demodex organisms and a perifollicular lymphocytic infiltrate extending into the follicular unit consistent with a diagnosis of demodicidosis. A month after instituting metronidazole gel, the patient noticed remarkable improvement. (9)
Demodex-induced follicular mucinosis (FM) mimicking folliculotropic mycosis fungoides. Trager et al present four cases of FM due to Demodex, two of whom demonstrated clonal T-cell receptor gene rearrangements. Cases responded to mite-targeted therapy, which mycosis fungoides would not. Aside from the pathophysiology of Demodex infestations previously discussed, the authors report that “a bacterium, Bacillus oleronius, has been isolated from Demodex. Release of Bacillus proteins leads to increased neutrophil signaling, activation, chemotaxis, and pro-inflammatory cytokine release, possibly contributing to the development of FM.” (10)
What has escaped me (until now) is considering the possibility that demodicidosis may cause facial hyperpigmentation. The usual differential diagnosis includes melasma, post-inflammatory hyperpigmentation, drug-induced hyperpigmentation, lichen planus actinicus, or lupus. Ayres and Ayres encountered 12 patients with “blotchy, brownish pigmentation of the face in association with the characteristic dryness and follicular scaling” attributed to Demodex infestation. (In their treatise, they also discuss similar cases by Dubreuilh from 1919!) (11) Neema et al detail 7 cases of facial frictional melanosis. Demodex was suspected on dermoscopy and confirmed histologically. Patients were treated with oral ivermectin and topical metronidazole. Within a month, facial pruritus resolved in all cases and pigmentation improved significantly in 3 patients. (12) Feuerman et al studied demodicidosis-associated hyperpigmentation in 19 patients (13 male) aged 42-76 years, all with Fitzpatrick skin type 3-4. All presented with mostly asymptomatic dusky, brown-gray, facial pigmentation, localized or diffuse with background erythema in 36.8% of cases, and skin roughness in 26.3%. Dermoscopy demonstrated characteristic findings of white gelatinous or opaque protrusions from hair follicles or infiltration of follicular openings with an amorphic material. A specific finding was perifollicular and reticulated pigmentation of the affected areas. Findings were confirmed on microscopic (n = 7) and histopathologic (n = 5) studies. Anti-demodectic treatment (with 12 patients using 1% ivermectin cream) led to complete (73.6%) or partial (23.4%) resolution of pigmentation within 2 years. The authors propose the term “pigmented demodicidosis” that should be considered in the differential diagnosis of facial hyperpigmentation noted above. (13)
In conclusion, although dermatologists are familiar with “classical” disorders such as rosacea where Demodex might (yes, I meant might) play a role, there are other conditions where the mite might be mighty important.
Point to Remember: Although the precise role of Demodex mites remains to be defined in disorders such as rosacea, these mites could play a role in other diseases, the most under-recognized possibly being so-called pigmented demodicidosis.
Our expert’s viewpoint
Lorraine L. Rosamilia, MD, FAAD
Geisinger Health System – State College, PA
One of my favorite moments of residency was when my co-resident recorded a live video of a Demodex mite wriggling through the oil immersion under the microscope and then set the video to music for one of our conferences. The organism is a quandary; so dynamic and ubiquitous but largely underappreciated and poorly understood in its true role (or bystander role) in many inflammatory conditions. For example, one of my patients was taking ‘horse ivermectin’ (from his farm supply to ward off COVID-19) and stated that his seborrheic keratoses also melted away. Who knows?! One thing is for sure: these mites are everywhere, they are here to stay, and they know how to party. (See the Twitter video from @ScienceChannel for proof!)
Rina Segal, MD
Dermatology department, Rabin Medical Center, Israel
The Demodex mite plays a role in disease pathogenicity of various facial and extra-facial dermatoses, including the many variants of rosacea, but the extent of its contribution to disease pathogenicity is still under debate. While some think Demodex is a key player, others argue it is just an innocent bystander. As a medical dermatologist who successfully treats patients with skin manifestations of demodicidosis using anti-demodectic therapies and studies Demodex pathogenicity in skin diseases for more than 20 years, I belong to the first group; Demodex is a key player in a spectrum of dermatoses given the clinical picture, the demonstration of the Demodex mites in affected skin and the beneficial response to anti-demodectic therapy. Diseases like spinulosis of face, pityriasis folliculorum, demodex dermatitis, perioral dermatitis, acneiform eruptions, facial pustulosis, and the many variants of rosacea are all grouped under the causative agent: demodex.
Recently, we described facial hyperpigmentation associated with Demodex infestation and proposed the name “pigmented demodicidosis.” It is noteworthy that the very first descriptions of Demodex infestation in human were forms of pigmented demodicidosis: “Demodex folliculorum e ipercromia cutanea” described in 1898 by De Amicis and “Pigmentation cutanee par le Demodex folliculorum” (described by Dubreuilh in 1901). In our cohort, all patients had darkly pigmented skin (Fitzpatrick 3-4), some with mild erythema, and dermoscopic evidence of Demodex infestation. Histopathological evaluation showed melanophages and multiple Demodex mites in hair follicles. Thus, the hyperpigmentation probably represents post-inflammatory hyperpigmentation and the Demodex is involved in inflammation. The prompt and beneficial response to anti-demodectic treatment furthermore confirmed this mite as the causative agent.
By acknowledging Demodex as a key player in different clinical manifestations, and with the aid of dermatoscope, it becomes an easy task to diagnose and relief various, mostly facial, annoying dermatoses including rosacea. There are many anti-demodectic agents, and the most potentin my experience is topical ivermectin. Yet, starting with anti-demodectic agent application on inflamed skin infested with Demodex frequently causes disease worsening, (perhaps due to sort of a Herxheimer reaction). Therefore, we recommend starting with a mild steroid cream for few days, followed by miticidal cream for a long period of time. The gratitude of your patients will soon arrive.
Aktaş Karabay E, Aksu Çerman A. Demodex folliculorum infestations in common facial dermatoses: acne vulgaris, rosacea, seborrheic dermatitis. An Bras Dermatol. 2020 Mar-Apr;95(2):187-193. doi: 10.1016/j.abd.2019.08.023. Epub 2020 Feb 12. PMID: 32113677; PMCID: PMC7175027.
Forton FMN, De Maertelaer V. Which factors influence Demodex proliferation? A retrospective pilot study highlighting a possible role of subtle immune variations and sebaceous gland status. J Dermatol. 2021 Aug;48(8):1210-1220. doi: 10.1111/1346-8138.15910. Epub 2021 May 9. PMID: 33969532.
Aytan P, Yeral M, Gereklioğlu Ç, Koçer NE, Büyükkurt N, Kozanoğlu İ, Özdoğu H, Boğa C. Demodicidosis Accompanying Acute Cutaneous Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation. Turk J Haematol. 2018 Nov 13;35(4):313-314. doi: 10.4274/tjh.2018.0057. Epub 2018 Jul 2. PMID: 29983401; PMCID: PMC6256815.
Martinot M, Korganow AS, Wald M, Second J, Birckel E, Mahé A, Souply L, Mohseni-Zadeh M, Droy L, Tarabeux J, Okada S, Migaud M, Puel A, Guffroy A. Case Report: A New Gain-of-Function Mutation of STAT1 Identified in a Patient With Chronic Mucocutaneous Candidiasis and Rosacea-Like Demodicosis: An Emerging Association. Front Immunol. 2021 Dec 20;12:760019. doi: 10.3389/fimmu.2021.760019. PMID: 34987506; PMCID: PMC8721043.
Krakowski AC, Senft SC, Heymann WR. Demodex Folliculitis and Recent Dupilumab Administration. Pediatrics. 2021 May;147(5):e2020029520. doi: 10.1542/peds.2020-029520. PMID: 33879520.
Zeeli T, Sprecher E. Demodicidosis of the nipple. Lancet Infect Dis. 2019 Jan;19(1):112. doi: 10.1016/S1473-3099(18)30403-1. PMID: 30587280.
Hoda S, Cheng E. Itching for Attention: Demodex Infestation of the Nipple. Int J Surg Pathol. 2019 Aug;27(5):524-525. doi: 10.1177/1066896918809415. Epub 2018 Oct 29. PMID: 30370808.
Hedberg ML, Chibnall RJ, Compton LA. Symptomatic vulvar demodicosis: A case report and review of the literature. J Cutan Pathol. 2020 Nov;47(11):1063-1066. doi: 10.1111/cup.13816. Epub 2020 Aug 26. PMID: 33448447.
Fichtel JC, Wiggins AK, Lesher JL Jr. Plaque-forming demodicidosis. J Am Acad Dermatol. 2005 Feb;52(2 Suppl 1):59-61. doi: 10.1016/j.jaad.2004.05.038. PMID: 15692519.
Trager MH, Queen D, Chen D, Hodak E, Geskin LJ. Demodex-induced follicular mucinosis of the head and neck mimicking folliculotropic mycosis fungoides. JAAD Case Rep. 2020 Mar 24;6(4):266-272. doi: 10.1016/j.jdcr.2020.01.014. PMID: 32258294; PMCID: PMC7109359.
AYRES S Jr, AYRES S 3rd. Demodectic eruptions (demodicidosis) in the human. 30 years' experience with 2 commonly unrecognized entities: pityriasis folliculorum (Demodex) and acne rosacea (Demodex type). Arch Dermatol. 1961 May;83:816-27. doi: 10.1001/archderm.1961.01580110104016. PMID: 13685388.
Neema S, Subramaniyan R, Kinra P. Demodex induced facial frictional melanoses. Australas J Dermatol. 2020 Nov;61(4):e490-e492. doi: 10.1111/ajd.13378. Epub 2020 Jul 20. PMID: 32686077.
Feuerman H, Atzmony L, Glick M, Sherman S, Snast I, Hodak E, Segal R. Pigmented demodicidosis - an under-recognized cause of facial hyperpigmentation. Int J Dermatol. 2022 May;61(5):564-569. doi: 10.1111/ijd.15992. Epub 2021 Dec 13. PMID: 34897670.
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