Unmet Needs in the Management of Demodex Blepharitis

Demodex blepharitis is a common inflammatory eye condition involving the skin, eyelashes, lash follicles, and sebaceous glands that is often overlooked.^1-3 The disease is associated with infestation with Demodex mites, which are ectoparasites commonly found on human skin.^4-6 Two distinct species of Demodex mites are found in both symptomatic and asymptomatic individuals: D folliculorum and D brevis.⁶ D folliculorum inhabits the margin of the lash follicle; it is associated with anterior blepharitis. D brevis burrows deep into the sebaceous glands at the base of the lash line; it is associated with posterior blepharitis.^1,7

Symptoms are nonspecific to Demodex blepharitis and may include swollen and irritated eyelids, ocular burning, itching, foreign body sensation, crusting, matting, and loss of eyelashes.^2,8,9 Secondary manifestations include rosacea, chalazion, meibomian gland dysfunction, trichiasis, dry eye disease, keratitis, and inflammatory conjunctivitis.^2,8-12 Demodex mites can be identified using microscopic techniques (eg, slit lamp) and sampling and evaluation of individual lashes (Figure).^4,6 Currently, there are no FDA-approved treatment options for Demodex blepharitis. Available management options are limited and commonly include tea tree oil or its active ingredient terpinen-4-ol, which may be included in eyelid cleansers.¹³ Treatment with this substance may take several weeks to be effective; however, it often is unsuccessful at fully eradicating Demodex mites.⁸ Further, use of tea tree oil can cause mild irritation and discomfort.^8,14

Left untreated, Demodex blepharitis can lead to more serious corneal conditions that may lead to scarring and blindness.^2,5 Despite its worldwide prevalence, Demodex blepharitis remains largely underdiagnosed and underappreciated.^4,5,15 This article describes the clinical burden of Demodex blepharitis and the unmet needs for patients and practitioners, particularly with respect to the lack of effective treatments to improve ocular health and the impact on patient quality of life.

Incidence and Prevalence

Demodex mites may be present on the eye margin in healthy humans, but this presence causes blepharitis only in some cases.^4,6 Studies of the incidence of Demodex blepharitis in the US population are limited. Results of a retrospective study of Demodex-induced collarettes showed that among 1032 patients who visited 1 of 6 US eye clinics, 57.7% had Demodex blepharitis; collarettes were observed in 69.1% of these cases.⁵

Additional estimates of worldwide prevalence of Demodex blepharitis exist, but vary widely.¹⁵ Studies from individual countries reported the presence of Demodex mites in 30% to 90% of patients with blepharitis.^16-24

The difference in frequency of Demodex infestation between sexes appears to be small, if it even exists. In the US study described previously, men had a slightly higher incidence of collarettes (62.9%) than did women (54.5%).⁵ Worldwide, some studies also noted a slightly higher incidence of Demodex in men than in women, although no difference was found in most of the research.^4,16,25-28

Several studies reported a higher prevalence of Demodex blepharitis in older adults.^{4,16,25,28-30} The results of 1 US study suggested that Demodex blepharitis was common in patients of all races, but more research is needed on racial, ethnic, and geographical differences in Demodex infestation.^5,16 A search of MEDLINE, PubMed, EBSCO, Cochrane, PROQUEST, and Google Scholar in June 2022 revealed that there were no known studies measuring Demodex blepharitis in commercial insurance, Medicare, or Medicaid databases. More research is needed to effectively evaluate the frequency of Demodex blepharitis in various patient populations.

Economic Burden

No economic studies on Demodex blepharitis have been published. However, economic data on dry eye disease is available; Demodex blepharitis has been reported in a majority of patients with dry eye disease and may be a precursor to this condition.⁵ The results of a study of the US economic burden of dry eye disease performed in 2011 showed that the condition was associated with a direct overall annual cost of approximately $3.84 billion and an indirect overall annual cost of about $55.4 billion.³¹ Even if Demodex blepharitis only contributes to a portion of dry eye disease cases, as found in the US collarettes study, related costs still could be substantial.⁵

Pathophysiology

Healthy, asymptomatic people can harbor Demodex mites, but an overpopulation of these ectoparasites can lead to inflammation through damage to infested tissue.^4,6 Proliferation of Demodex mites is more common in older patients due to several variables, including abnormal skin barrier (eg, reduced surface hydration), decreased immunity, and poor personal hygiene.⁶

D folliculorum is found in clusters along the lash line, whereas D brevis more commonly is detected in sebaceous glands; both types of these mites consume cell components and oils.^1,26,32 During this process, the mites are believed to release lipases to aid digestion of sebum that may cause irritation to the tissue due to subsequent release of fatty acids.³³ Further, small abrasions caused by the mite’s claws may result in epithelial hyperplasia and keratinization around the base of the eyelashes, forming collarettes (ie, cylindrical dandruff) on the upper lid margin.¹ These waxy cylindrical plugs are present in 100% of Demodex blepharitis cases.^5,34

Demodex mites also have been known to plug the meibomian gland orifices, which could lead to observed meibomian gland dysfunction and tear film disruptions in Demodex blepharitis.^1,7,8 Clogging of the meibomian glands and sebaceous glands by Demodex mites may result in the formation of chalazia and granulomatous reactions; however, chalazia are not always present in Demodex infestation, and further studies are needed to assess this relationship.^7,12

Finally, Demodex mites may trigger blepharitis by acting as vectors for harmful bacteria.^7,35 Bacillus oleronius, a pathogen also often seen in chronic blepharitis, may initiate an immune response in individuals with rosacea.^7,36

Presentation

These pathogenic processes of Demodex blepharitis commonly are associated with itching and redness.⁴ Further, patients with Demodex blepharitis report ocular pain and burning, foreign body sensation, dryness, lacrimation, purulence, irritation, loss of lashes, matted or crusty lashes, and blurry vision.^2,4,8,9,37 Lid margin health can be affected by infection-induced inflammation, and ocular surface manifestations (eg, corneal damage, chalazion, trichiasis, keratitis, conjunctivitis, blepharoconjunctivitis) may occur due to the infection.^2,7,8,9,12

The symptoms and signs of Demodex blepharitis also can affect patients emotionally. Recently, in the Atlas study (part of the phase 2b/3 Saturn-1 clinical trial described below), 311 patients with Demodex blepharitis were surveyed to understand the psychosocial burden of the disease.³⁸ A large proportion of patients (80%) reported that the condition negatively affected their daily life, 47% indicated that they were conscious of their eyes all day, 23% constantly worried about their eyes, and 23% reported that Demodex blepharitis gave their eyes or eyelids a negative appearance to others.³⁸ Patients also stated that this condition affected their daily activities; 47% reported that it made driving at night difficult, 30% said that it added time to their daily hygiene routine, and 34% said that it made it difficult to wear makeup.^38,39

Diagnosis

The definitive diagnosis of Demodex blepharitis is generally accomplished by visual analysis. A common method of determining the presence of mites is to remove several eyelashes, mount them in oil on a microscope slide, and examine the samples. A positive result for Demodex mites includes the presence of an adult mites, larvae, or eggs.^4,27

Although this method is commonly used to determine the number of mites, it has several limitations. For example, it underestimates the number of mites present, as they can float away in the added oil and be retained in the collarettes that remain in the eyelid after lash removal.³⁴ Sodium fluorescein can enhance the microscopic visualization of mites by dissolving and expanding the collarettes, thereby improving visualization of embedded mites and resulting in a more accurate population sample.⁴⁰ The presence of Demodex blepharitis can also be identified via slit-lamp identification of collarettes localized at the base of the lashes at the lid margin.⁵

Risk Factors

Immune-related skin conditions are associated with an increased incidence of Demodex blepharitis. Facial rosacea most frequently is postulated to be related to Demodex infestation, and seborrheic dermatitis also is reported to correlate with Demodex proliferation.^41,42 Immunosuppressive agents (eg, steroids) and diseases such as HIV or leukemia that compromise immunity are associated with an increased incidence of Demodex blepharitis.^7,43-45 However, it remains unclear whether changes in immunity allow for Demodex infestation or whether Demodex mites cause inflammatory disease.⁴⁶ Modifiable factors believed to encourage proliferation of Demodex include poor hygiene, alcohol abuse, and specific skin characteristics (eg, oily, dry).^47,48

Underdiagnosis and Misdiagnosis

Diagnosis of and research concerning Demodex blepharitis are complicated, because the mite resides on both healthy and affected individuals.⁶ There is no standard to determine the threshold of mite infestation that results in blepharitis symptoms, although recent reports suggest that a change in even 1 fewer mite per lash is associated with clinical improvement in patients who have been diagnosed with the condition.^4,49 The disease shares symptoms with other ocular disorders; thus, it is frequently overlooked as a potential diagnosis, especially because clinicians do not routinely screen presenting patients for Demodex mite infestation.^5,37

Results of the Atlas study indicated that 51% of patients had signs of blepharitis for at least 4 years; 52% reported experiencing symptoms frequently or all the time over the previous month.³⁸ However, 58% of respondents reported never receiving the diagnosis even though symptoms led them to visit their doctor 2 to 6 times.³⁸ Further, results of the US-based collarettes study described above determined that 44% of patients with collarettes were not diagnosed with Demodex blepharitis, suggesting a high rate of underdiagnosis and misdiagnosis.⁵ Addressing the issue of misdiagnosis and underdiagnosis in Demodex blepharitis is important; left untreated, the disease can result in punctate keratitis and corneal melting.^5,50 Further, lack of a proper Demodex diagnosis can result in ineffective management options and disease progression and a possible increase in the cost of care.^5,37 For example, management of severe Demodex blepharitis may require use of microblepharoexfoliation, which costs approximately $150 per session and needs to be repeated 4 times per year.^51,52

Current Management Options

Common management options are available for Demodex blepharitis, but no single strategy is always effective for long-term Demodex eradication.^37,53 Recommendations for managing patients with Demodex blepharitis are briefly discussed in the blepharitis clinical management guidelines offered by the College of Optometrists.⁵⁴ Lid hygiene measures are advised to reduce symptoms and prevent relapse. These include lid cleansing to wipe away debris and improve symptoms and use of warm wet compresses to loosen collarettes and crusts in anterior blepharitis.⁵⁴ Patients are advised to avoid cosmetics, especially eye liner and mascara. Cleansing options include microblepharoexfoliation and OTC lid scrubs and wipes.^13,37,55-59 Many of these products contain tea tree oil or its active ingredient terpinen-4-ol; these substances have acetylcholinesterase-inhibiting effects responsible for acaricidal activity to reduce the number of Demodex mites.^{13,14,37,54,60} Linalool (a fragrant, plant-derived monoterpene alcohol that also is an ingredient of many commercial blepharitis cleansers) has acaricidal effects.^13,61 Of note, comorbid conditions may necessitate treatment.⁵

Limitations of Current Management Options

Demodex blepharitis continues to be an undertreated disease with no FDA-approved treatment options.⁵ Because no single management option currently fully eradicates Demodex mites, there are no specific guidelines or a standard of care.³⁷ In the Atlas study, 81% of patients reported seeking treatment, but many discontinued the management options provided due to efficacy or tolerability issues or other reasons.³⁸ In the US collarettes study, patients using tea tree oil and lid wipes continued to have Demodex blepharitis in 75% and 57% of cases, respectively, indicating that current management tools for this disease are largely ineffective.⁵

Tea tree oil has low efficacy; further, it is poorly tolerated and associated with allergies, dermatitis, and ocular irritation.^5,8,14,62,63 Indeed, the results of clinical studies on the use of tea tree oil– or linalool-containing commercial cleansers showed that blepharitis symptoms were not fully resolved, and Demodex mites were not fully eradicated.^13,52,64 Methods to prevent irritation caused by tea tree oil include instructing patients to be less vigorous when scrubbing their eyelids, diluting the tea tree oil with mineral oil, or applying scrubs and saline rinses that have a higher concentration of tea tree oil during an office visit.^53,63 Despite these precautions, poor adherence to these therapeutic options due to discomfort is associated with low Demodex eradication rates.⁶³ Lack of adherence is further complicated by the need for long-term lid hygiene measures to relieve symptoms.^37,53

Treatments Under Investigation

Only a few randomized, clinical trials have been or are being performed to test the efficacy of therapies other than conventional tea tree oil (Table). Active ingredients in these products include the antiparasitic drug ivermectin used with the antioxidant and anti-inflammatory drug metronidazole and the acaricidal drug lotilaner.^65-71

Conclusions and Unmet Needs

Demodex mites are a major contributor to blepharitis and other ocular diseases.^4,5 Several studies have assessed the prevalence of Demodex blepharitis worldwide, but, as of August 2022, only 1 study did so in the United States, suggesting that this disease is overlooked in this country.^4,5,16-24 Although the economic burden of Demodex blepharitis specifically is unknown, based on data for dry eye disease, the annual cost of Demodex blepharitis is likely substantial.^5,31

The paucity of research on the epidemiology of Demodex blepharitis is reflected in a lack of routine screening for Demodex mites and a lack of standardized criteria for diagnosing the disease.^4,37 Likewise, there are no standalone guidelines for managing Demodex blepharitis.⁵⁴ Current management options include products containing tea tree oil, terpinen-4-ol, and/or linalool; however, use of these products may not fully eradicate mites, may only partially relieve symptoms, and may cause irritation.^5,13,14,38 A few studies have examined the use of therapeutic alternatives (eg, ivermectin, metronidazole, lotilaner) and yielded mixed results.^66,68,69 To date, these studies have been small, and larger controlled studies are needed to confirm the efficacy and safety of these agents. In all, though Demodex infestation is a common cause of blepharitis, a dearth of disease awareness, a lack of best diagnostic practices, and an absence of FDA-approved treatments remain as obstacles in the management of this ophthalmic condition.

REFERENCES

1. English FP, Nutting WB. Demodicosis of ophthalmic concern. Am J Ophthalmol. 1981;91(3):362-372. doi:10.1016/0002-9394(81)90291-9

2. Kheirkhah A, Casas V, Li W, Raju VK, Tseng SC. Corneal manifestations of ocular Demodex infestation. Am J Ophthalmol. 2007;143(5):743-749. doi:10.1016/j.ajo.2007.01.054

3. Spickett SG. Studies on Demodex folliculorum Simon (1842). I. Life history. Parasitology. 1961;51(1-2):181-192. doi:10.1017/S003118200006858X

4. Biernat MM, Rusiecka-Ziółkowska J, Piątkowska E, Helemejko I, Biernat P, Gościniak G. Occurrence of Demodex species in patients with blepharitis and in healthy individuals: a 10-year observational study. Jpn J Ophthalmol. 2018;62(6):628-633. doi:10.1007/s10384-018-0624-3

5. Trattler W, Karpecki P, Rapoport Y, et al. The prevalence of Demodex blepharitis in US eye care clinic patients as determined by collarettes: a pathognomonic sign. Clin Ophthalmol. 2022;16:1153-1164. doi:10.2147/opth.S354692

6. Zhong J, Tan Y, Li S, et al. The prevalence of Demodex folliculorum and Demodex brevis in cylindrical dandruff patients. J Ophthalmol. 2019;2019:8949683. doi:10.1155/2019/8949683

7. Liu J, Sheha H, Tseng SCG. Pathogenic role of Demodex mites in blepharitis. Curr Opin Allergy Clin Immunol. 2010;10(5):505-510. doi:10.1097/ACI.0b013e32833df9f4

8. Gao YY, Di Pascuale MA, Elizondo A, Tseng SCG. Clinical treatment of ocular demodecosis by lid scrub with tea tree oil. Cornea. 2007;26(2):136-143. doi:10.1097/01.ico.0000244870.62384.79

9. Nicholls SG, Oakley CL, Tan A, Vote BJ. Demodex treatment in external ocular disease: the outcomes of a Tasmanian case series. Int Ophthalmol. 2016;36(5):691-696. doi:10.1007/s10792-016-0188-5

10. Liang L, Liu Y, Ding X, Ke H, Chen C, Tseng SCG. Significant correlation between meibomian gland dysfunction and keratitis in young patients with Demodex brevis infestation. Br J Ophthalmol. 2018;102(8):1098-1102. doi:10.1136/bjophthal-mol-2017-310302

11. Rynerson JM, Perry HD. DEBS - a unification theory for dry eye and blepharitis. Clin Ophthalmol. 2016;10:2455-2467. doi:10.2147/opth.S114674

12. Schear MJ, Milman T, Steiner T, Shih C, Udell IJ, Steiner A. The association of Demodex with chalazia: a histopathologic study of the eyelid. Ophthalmic Plast Reconstr Surg. 2016;32(4):275-278. doi:10.1097/iop.0000000000000500

13. Cheung IMY, Xue AL, Kim A, Ammundsen K, Wang MTM, Craig JP. In vitro anti-demodectic effects and terpinen-4-ol content of commercial eyelid cleansers. Cont Lens Anterior Eye. 2018;41(6):513-517. doi:10.1016/j.clae.2018.08.003

14. Ngo W, Jones L, Bitton E. Short-term comfort responses associated with the use of eyelid cleansing products to manage Demodex folliculorum. Eye Contact Lens. 2018;44(suppl 2):S87-S92. doi:10.1097/icl.0000000000000415

15. Zhao YE, Wu LP, Hu L, Xu JR. Association of blepharitis with Demodex: a meta-analysis. Ophthalmic Epidemiol. 2012;19(2):95-102. doi:10.3109/0928658 6.2011.642052

16. Zhang AC, Muntz A, Wang MTM, Craig JP, Downie LE. Ocular Demodex: a systematic review of the clinical literature. Ophthalmic Physiol Opt. 2020;40(4):389-432. doi:10.1111/opo.12691

17. Chanlalit W, Yodprom R, Arampinyokul P. Comparison of clinical manifestations between blepharitis patients with and without Demodex infestation. J Med Assoc Thai. 2019;102(6):651-656. Accessed August 29, 2022. http://www.jmatonline.com/index.php/jmat/article/view/9137

18. Zeytun E, Karakurt Y. Prevalence and load of Demodex folliculorum and Demodex brevis (Acari: Demodicidae) in patients with chronic blepharitis in the province of Erzincan, Turkey. J Med Entomol. 2019;56(1):2-9. doi:10.1093/jme/tjy143

19. Zhu M, Cheng C, Yi H, Lin L, Wu K. Quantitative analysis of the bacteria in blepharitis with Demodex infestation. Front Microbiol. 2018;9:1719. doi:10.3389/fmicb.2018.01719

20. Kabataş N, Doğan A, Kabataş EU, Acar M, Biçer T, Gürdal C. The effect of Demodex infestation on blepharitis and the ocular symptoms. Eye Contact Lens. 2017;43(1):64-67. doi:10.1097/icl.0000000000000234

21. López-Ponce D, Zuazo F, Cartes C, et al. High prevalence of Demodex spp. infesta-tion among patients with posterior blepharitis: correlation with age and cylindrical dandruff. Arch Soc Esp Oftalmol. 2017;92(9):412-418. doi:10.1016/j.oftal.2017.01.001

22. Bhandari V, Reddy JK. Blepharitis: always remember Demodex. Middle East Afr J Ophthalmol. 2014;21(4):317-320. doi:10.4103/0974-9233.142268

23. Divani S, Barpakis K, Kapsalas D. Chronic blepharitis caused by Demodex folliculorum mites. Cytopathology. 2009;20(5):343-344. doi:10.1111/j.1365-2303.2009.00639.x

24. Türk M, Oztürk I, Sener AG, Küçükbay S, Afşar I, Maden A. Comparison of incidence of Demodex folliculorum on the eyelash follicule in normal people and blepharitis patients. Turkiye Parazitol Derg. 2007;31(4):296-297.

25. Wesolowska M, Knysz B, Reich A, et al. Prevalence of Demodex spp. in eyelash follicles in different populations. Arch Med Sci. 2014;10(2):319-324. doi:10.5114/aoms.2014.42585

26. Lee SH, Chun YS, Kim JH, Kim ES, Kim JC. The relationship between Demodex and ocular discomfort. Invest Ophthalmol Vis Sci. 2010;51(6):2906-2911. doi:10.1167/iovs.09-4850

27. Sędzikowska A, Osęka M, Skopiński P. The impact of age, sex, blepharitis, rosacea and rheumatoid arthritis on Demodex mite infection. Arch Med Sci. 2018;14(2):353-356. doi:10.5114/aoms.2016.60663

28. Vargas-Arzola J, Reyes-Velasco L, Segura-Salvador A, Márquez-Navarro A, Díaz-Chiguer DL, Nogueda-Torres B. Prevalence of Demodex mites in eyelashes among people of Oaxaca, Mexico. Acta Microbiol Immunol Hung. 2012;59(2):257-262. doi:10.1556/AMicr.59.2012.2.10

29. Kasetsuwan N, Kositphipat K, Busayarat M, et al. Prevalence of ocular demodicosis among patients at Tertiary Care Center, Bangkok, Thailand. Int J Ophthalmol. 2017;10(1):122-127. doi:10.18240/ijo.2017.01.20

30. Clifford CW, Fulk GW. Association of diabetes, lash loss, and Staphylococcus aureus with infestation of eyelids by Demodex folliculorum (Acari: Demodicidae). J Med Entomol. 1990;27(4):467-470. doi:10.1093/jmedent/27.4.467

31. Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea. 2011;30(4):379-387. doi:10.1097/ICO.0b013e3181f7f363

32. Coston TO. Demodex folliculorum blepharitis. Trans Am Ophthalmol Soc. 1967;65:361-392.

33. Jimenez-Acosta F, Planas L, Penneys N. Demodex mites contain immunoreactive lipase. Arch Dermatol. 1989;125(10):1436-1437. doi:10.1001/archderm.1989.01670220134028

34. Gao YY, Di Pascuale MA, Li W, et al. High prevalence of Demodex in eyelashes with cylindrical dandruff. Invest Ophthalmol Vis Sci. 2005;46(9):3089-3094. doi:10.1167/iovs.05-0275

35. English FP, Iwamoto T, Darrell RW, DeVoe AG. The vector potential of Demodex folliculorum. Arch Ophthalmol. 1970;84(1):83-85. doi:10.1001/archopht.1970.00990040085020

36. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007;157(3):474-481. doi:10.1111/j.1365-2133.2007.08028.x

37. Fromstein SR, Harthan JS, Patel J, Opitz DL. Demodex blepharitis: clinical perspectives. Clin Optom (Auckl). 2018;10:57-63. doi:10.2147/opto.S142708

38. Tarsus Pharmaceuticals presents results of Atlas study demonstrating the functional and psychosocial impact of Demodex blepharitis. Eyewire. Published May 3, 2021. Accessed May 20, 2022. https://eyewire.news/articles/tarsus-pharmaceuticals-presents-results-of-atlas-study-demonstrating-the-functional-and-psychosocial-impact-of-Demodex-blepharitis

39. Jackson MA, Yeu E, Matossian C, Kannarr SR, Wesley G, Periman LM. Impact of Demodex blepharitis on patients: Results of the Atlas trial. Abstract presented at: American Society of Cataract and Refractive Surgery Annual Meeting; April 25, 2022; Washington, DC. Accessed June 3, 2022. https://ascrs.confex.com/ascrs/22am/meetingapp.cgi/Paper/81946

40. Kheirkhah A, Blanco G, Casas V, Tseng SCG. Fluorescein dye improves microscopic evaluation and counting of Demodex in blepharitis with cylindrical dandruff. Cornea. 2007;26(6):697-700. doi:10.1097/ICO.0b013e31805b7eaf

41. Karincaoglu Y, Tepe B, Kalayci B, Atambay M, Seyhan M. Is Demodex folliculorum an aetiological factor in seborrhoeic dermatitis? Clin Exp Dermatol. 2009;34(8):e516-e520. doi:10.1111/j.1365-2230.2009.03343.x

42. Zhao YE, Wu LP, Peng Y, Cheng H. Retrospective analysis of the association between Demodex infestation and rosacea. Arch Dermatol. 2010;146(8):896-902. doi:10.1001/archdermatol.2010.196

43. Antille C, Saurat JH, Lübbe J. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol. 2004;140(4):457-460. doi:10.1001/archderm.140.4.457

44. Hachfi W, Slama D, Ben Lasfar N, et al. Demodicosis revealing an HIV infection. New Microbes New Infect. 2019;31:100525. doi:10.1016/j.nmni.2019.100525

45. Seyhan ME, Karincaoğlu Y, Bayram N, Aycan O, Kuku I. Density of Demodex folliculorum in haematological malignancies. J Int Med Res. 2004;32(4):411-415. doi:10.1177/147323000403200410

46. Litwin D, Chen W, Dzika E, Korycińska J. Human permanent ectoparasites; recent advances on biology and clinical significance of Demodex mites: narrative review article. Iran J Parasitol. 2017;12(1):12-21.

47. Zhao YE, Peng Y, Wang XL, et al. Facial dermatosis associated with Demodex: a case-control study. J Zhejiang Univ Sci B. 2011;12(12):1008-1015. doi:10.1631/jzus.B1100179

48. Sener S, Karaman U, Altunisik N, Sarac G, Cumurcu B, Hakverdi G. Demodex spp distribution in patients with alcohol abuse. Mid BSJ Health Sci. 2019;5(3):246-251. doi:10.19127/mbsjohs.655707

49. Luo KS, Xie A, Yang JJ, Shen EP. Critical value of Demodex count per lash for symptomatic and clinical improvement of Demodex blepharitis. Eye (Lond). 2022;36(3):663-665. doi:10.1038/s41433-021-01442-z

50. Luo X, Li J, Chen C, Tseng S, Liang L. Ocular demodicosis as a potential cause of ocular surface inflammation. Cornea. 2017;36(suppl 1):S9-S14. doi:10.1097/ico.0000000000001361

51. Mukamal R. 12 devices for treating dry eyes. American Academy of Ophthalmol-ogy. Published November 12, 2020. Accessed May 20, 2022. https://www.aao.org/eye-health/tips-prevention/how-to-treat-dry-eye-devices

52. Murphy O, O’Dwyer V, Lloyd-McKernan A. The efficacy of tea tree face wash, 1, 2- octanediol and microblepharoexfoliation in treating Demodex folliculorum blepharitis. Cont Lens Anterior Eye. 2018;41(1):77-82. doi:10.1016/j.clae.2017.10.012

53. Gao YY, Di Pascuale MA, Li W, et al. In vitro and in vivo killing of ocular Demodex by tea tree oil. Br J Ophthalmol. 2005;89(11):1468-1473. doi:10.1136/bjo.2005.072363

54. Clinical management guidelines, blepharitis (lid margin disease). The College of Optometrists. Updated January 28, 2021. Accessed May 20, 2022. https://www.college-optometrists.org/clinical-guidance/clinical-management-guidelines/blepharitis_lidmargindisease

55. Cliradex light foam. Package labeling. Cliradex. Accessed May 3, 2022. https://cliradex.com/product/cliradex-light-foam/

56. Oust Demodex cleanser 50 mL. OCuSOFT. Accessed June 4, 2022. https://www.ocusoft.com/oust-demodex-cleanser-50ml

57. Eyelid cleansers. OCuSOFT. Accessed June 3, 2022. https://www.ocusoft.com/eyelid-cleansers-2

58. Oust Demodex swabstix - 12/box. OCuSOFT. Accessed June 3, 2022. https://ocusoft.com/oust-Demodex-swabstix-12box

59. Choi MB, Stein R. Lid hygiene versus lid hygiene plus microblepharoexfoliation for the treatment of Demodex folliculorum blepharitis. Acta Sci Ophthalmol. 2020;3(9):29-35. doi:10.31080/ASOP.2020.03.0159

60. Kabat AG. In vitro demodicidal activity of commercial lid hygiene products. Clin Ophthalmol. 2019;13:1493-1497. doi:10.2147/opth.S209067

61. National Center for Biotechnology Information. PubChem Compound Summary for CID 6549, Linalool. Accessed June 13, 2022. https://pubchem.ncbi.nlm.nih.gov/compound/Linalool

62. Rutherford T, Nixon R, Tam M, Tate B. Allergy to tea tree oil: retrospective review of 41 cases with positive patch tests over 4.5 years. Australas J Dermatol. 2007;48(2):83-87. doi:10.1111/j.1440-0960.2007.00341.x

63. Koo H, Kim TH, Kim KW, Wee SW, Chun YS, Kim JC. Ocular surface discomfort and Demodex: effect of tea tree oil eyelid scrub in Demodex blepharitis. J Korean Med Sci. 2012;27(12):1574-1579. doi:10.3346/jkms.2012.27.12.1574

64. Epstein IJ, Rosenberg E, Stuber R, Choi MB, Donnenfeld ED, Perry HD. Double-masked and unmasked prospective study of terpinen-4-ol lid scrubs with microblepharoexfoliation for the treatment of Demodex blepharitis. Cornea. 2020;39(4):408-416. doi:10.1097/ico.0000000000002243

65. Akamatsu H, Oguchi M, Nishijima S, et al. The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: a possible mechanism of action of metronidazole in rosacea and acne. Arch Dermatol Res. 1990;282(7):449-454. doi:10.1007/bf00402621

66. Ávila MY, Martínez-Pulgarín DF, Rizo Madrid C. Topical ivermectin-metronidazole gel therapy in the treatment of blepharitis caused by Demodex spp.: a randomized clinical trial. Cont Lens Anterior Eye. 2021;44(3):101326. doi:10.1016/j.clae.2020.04.011

67. Snyder DE, Wiseman S, Liebenberg JE. Efficacy of lotilaner (Credelio), a novel oral isoxazoline against naturally occurring mange mite infestations in dogs caused by Demodex spp. Parasit Vectors. 2017;10(1):532. doi:10.1186/s13071-017-2472-2

68. Gonzalez-Salinas R, Yeu E, Holdbrook M, et al. Safety and efficacy of topical lotilaner ophthalmic solution 0.25% for the treatment of Demodex blepharitis: a pilot study. J Ophthalmol. 2021;2021:3862684. doi:10.1155/2021/3862684

69. Salem DAB, El-Shazly A, Nabih N, El-Bayoumy Y, Saleh S. Evaluation of the efficacy of oral ivermectin in comparison with ivermectin-metronidazole combined therapy in the treatment of ocular and skin lesions of Demodex folliculorum. Int J Infect Dis. 2013;17(5):e343-347. doi:10.1016/j.ijid.2012.11.022

70. Treatment of ocular Demodex infestation with topical ivermectin cream 1%. ClinicalTrials.gov. Updated January 28, 2022. Accessed June 13, 2022. https://clinicaltrials.gov/ct2/show/NCT05213585

71. Trial to evaluate the safety and efficacy of TP-03 for the treatment of Demodex blepharitis (Saturn-2). ClinicalTrials.gov. Updated November 5, 2021. Accessed May 20, 2022. https://clinicaltrials.gov/ct2/show/NCT04784091

For other articles and videos in this AJMC^® Perspectives publication, please visit “The Evolving Landscape of Demodex Blepharitis Management.”