Iatrogenic DED may be caused by topical or systemic medications, CL wear and different surgical and non-surgical procedures. Several large-scale epidemiologic studies have investigated the prevalence and incidence of DED as are discussed in the TFOS DEWS II Epidemiology report [8,9,11,578–581]. Additional studies and epidemiological surveys are needed to evaluate iatrogenic dry eye. Appropriate evaluation at pre- and post-intervention and improved knowledge of diagnostic criteria for DED [157] will contribute to the elucidation of unmet medical needs in patients suffering from iatrogenic DED.
Ophthalmic preservatives, such as BAK, are frequently used for their anti-bacterial effects and have been recognized as a risk factor for corneal and conjunctival inflammation [339,582–585]. Combined formulations to reduce the total amount of ophthalmic preservatives may help glaucoma patients who need multiple medications [586,587]. Preservative-free eye drops reduce iatrogenic dry eye [136,588–592]. There is a trend for the development of new multidose preservative-free systems, such as ABAK and COMOD bottles, that can improve patient compliance [593,594]. The establishment of more preservative-free drugs and the development of novel combination products of anti-glaucoma eye drops and anti-inflammatory eye drops with long acting compounds are possible strategies to decrease frequency of instillation [383,587,595].
Oral medications with an anticholinergic effect, such as antihypertensive and antidepressant agents, may decrease tear production via binding to receptors on the lacrimal glands and also meibomian glands [20,23,217]. Punctate keratitis is often observed in patients treated with anticancer agents, including tegafur gimeracil oteracil potassium (TS-1®) [596]. Improvements in preventing systemic action of drugs as a causative factor for dry eye will come from further research focused on the development of more highly engineered systemic drug molecules designed to avoid receptor targets that affect tear production or secretory gland function for a more tissue-specific effect and to develop topical antagonists that counter the activity of systemic medication. Technical advancements in the development of combination products and their dose-adjustment to minimize side effects of systemic medications are required as well as improvement of early identification of drug-induced dry eye by patients and physicians via drug labeling and education [19,79].
The literature describing CL-associated DED is largely reliant upon subjective reports of ‘dryness’, a symptom confounded by overlap with that of discomfort during CL wear [597] and for which the cause is multifactorial. Therefore, a fundamental consideration for researchers who intend to study DED in CL wearers is the need to validate their cohorts against the TFOS DEWS II diagnosis of dry eye [157], versus CLIDE/-CLADE, by verifying the existence of signs and symptoms of DED before and during CL wear.
The concept of the lid wiper [171,178] has led researchers towards developing a greater understanding of the nature of the essential interface between the anterior CL and ocular surfaces [598]. However, equivocal reports of the association between the extent of lid wiper staining and the severity of dry eye in CL wearers, with reports prior to 2011 claiming to have demonstrated an association [159,169,178–181] and post-2011 papers failing to demonstrate an association [182–185], raise questions about the relevance of lid wiper epitheliopathy in assessing CLIDE [171]. Large scale, well-executed, masked, randomized and statistically validated clinical trials are needed to elucidate the clinical utility of this recently-described ocular reaction and to determine its value as a surrogate marker for CLIDE.
Dumbleton et al. [599] reported that 23% of CL wearers in Canada ceased wearing lenses between 2008 and 2010. Such a large drop-out rate comes at considerable cost to the CL industry and eye care practitioners, in addition to the inconvenience and frustration of CL wearers who are unable to continue with their preferred mode of vision correction. As CLIDE is a major cause of drop-out from CL wear [597,599], more focused research into the cause of this condition should continue to identify an effective solution.
Corneal hyposensitivity by corneal denervation during refractive surgery such as PRK and LASIK, which occurs by direct corneal nerve injury and following abnormal neuronal remodeling [600], has been recognized as a major risk factor for postoperative DED, although the pattern of nerve injury in the cornea differs with different types of surgery [601–604]. Recent advances in surgical procedures, including SMILE, have served to minimize corneal denervation during surgery and reduce the incidence of postoperative DED [208]. At the same time, discovery of topical medications that augment regeneration of corneal nerves after refractive surgeries to lessen the neurotrophic effects would be helpful [605–611]. Research is needed to determine whether refractive surgery can cause permanent worsening of dry eye in some patients, or whether the surgery exacerbates only underlying inflammatory dry eye, which returns to baseline when neurotrophic effects resolve with nerve regeneration [600]. Novel research is also needed into the detection of early dry eye prior to refractive surgery, so that patients with underlying dry eye are properly pretreated for dry eye to improve the outcomes of refractive surgery [612].
Impaired corneal nerve sensation after PK can induce DED and persistent corneal epithelial defects, which can lead to a corneal ulcer and eventual graft failure [613]. To guide nerve growth to the graft after keratoplasty, the application of various of neurotrophic factors including substance P, insulin-like growth factor 1 (IGF-1) and semafpholin-3A inhibitor have shown promising outcomes [411,607,614]. A more ideal therapeutic approach to induce neuronal regeneration after keratoplasty using novel molecules should be pursued to realize functional restoration of corneal sensory nerves, without possible complications of neovascularization and hypersensitivity due to excess innervation, as well as the development of advanced surgical techniques to minimize nerve damage during procedures [607,615].
Although current cataract surgery with clear corneal microincisions has been recognized as one of the most promising surgical procedures, studies have reported that postoperative ocular discomfort exists in a majority of patients due to DED [242,247,252]. The changes in multiple ocular and systemic factors, including tear film dysfunction due to reduced corneal sensitivity [254,616–618], and loss of conjunctival cells via topical medication with preservatives [125,241,242] and anesthetics [619], the increase in inflammatory factors [255,256], and the morphological changes in lids and meibomian glands, are all involved in the onset of cataract surgery-induced dry eye [246]. Efforts to establish appropriate therapeutic strategies taking into consideration the effect of these concomitant pathological changes may contribute to better clinical outcomes after cataract surgery in the future [591].
Oculoplastic surgery, including blepharoplasty, ptosis repair, lid tumor removal and aesthetic reconstruction of the lateral canthus, has been recognized as a risk factor for postoperative DED [265–269]. Investigation of the details of pathological alterations of eyelid movement before/after surgery and postoperative changes in peripheral ocular tissues, such as the conjunctiva, meibomian glands and lacrimal glands, will be required to better understand and diagnose lid surgery-induced dry eye [276,282,285,309,620]. Moreover, a multicentric large-scale epidemiological study with the participation of oculoplastic surgeons is needed to precisely determine true prevalence, identify risk factors and define effective educational approaches for clinicians and patients.
While it has been reported that BTX-A injection for treatment of blepharospasm, after periorbital surgery, and cosmetic correction of crow's feet is a possible cause of dry eye [103,463,475,547], this procedure also has been used as a therapy for DED by decreasing lacrimal drainage [451]. Identification of predictive factors for the onset of postoperative DED after BTX-A injection for early diagnosis will contribute to the establishment of therapeutic intervention strategies [104].
A host of elective and cosmetic ophthalmic procedures (such as eyelash growth, fillers, conjunctival whitening, eyelid/conjunctival tattooing, jewelry/piercings, and the use of adjunctive MMC and/or anti-VEGF agents) have emerged in the marketplace. Many of these procedures are performed by providers other than eye care specialists and have been associated with iatrogenic dry eye as well as other ophthalmic complications. As these procedures continue to evolve and increase in popularity, future directions in this space are unclear, but will probably not cease to interest the public. In light of the associated complications (some severe and sight-threatening), a greater effort to regulate and oversee these procedures needs to be considered.