**1. Introduction**

TFOS DEWS II [1] has defined dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles. The prevalence of dry eye disease (DED) is currently between 5% and 50% globally and particularly high in Asian countries [2–4]. The causes of DED are very complex, including age, systemic immune disease, visual display terminal, and meibomian gland dysfunction (MGD) [1]. MGD is one of the most common causes of DED overall and is also the main underlying factor leading to evaporative dry eye (EDE). Thus, DED caused by MGD is also known as MGD-related DED. Epidemiological investigations showed that 80% of DED patients have either developed this condition from MGD or are also su ffering from this a ffliction [3]. Prevalence rates of MGD-related DED in Asian populations over the age of 40 range between 46.2% and 69.3% [4]. It is clear that MGD-related DED is characterized by terminal duct obstructions and/or qualitative/quantitative changes in glandular secretions; this latter e ffect reduces lipid secretion to tear film and increases evaporation, resulting in tear hyperosmolarity. These tear changes further induce inflammatory cascade reactions which then cause a series of clinical symptoms. Changes in tear fluid also aggravate destruction of the eyelid margin and meibomian gland, conditions which then go on to develop into a vicious cycle [5–7].

A variety of methods are utilized for the treatment of MGD-related DED, including physical therapies such as meibomian gland massage, intraductal meibomian gland probing, lipiflow, intense pulsed light, and local anti-inflammatory drugs. Although these approaches are all effective to a certain extent, problems remain including the inconvenience of application, high financial costs, insignificant effects, and some side effects [5,8]. It is therefore necessary to consider ways to explore new therapies that are safe, effective, and convenient in order to improve MGD-related DED treatment.

Traditional medicine has often been used for the clinical treatment of DED in China, and a grea<sup>t</sup> deal of documentation supports the fact that this approach achieves positive therapeutic effects [9]. Ultrasonic atomization is a method that destroys liquid surface tension and atomizes droplets into fine molecules via ultrasonic vibration. It is the most commonly utilized ophthalmological method in Chinese traditional medicine for DED treatment. This therapy for 20 min enables the drug to fully contact and penetrate the ocular surface and take e ffect. Stimulation of an atomized steam can promote blood and lymph circulation in eyelid tissue and thus enhance the discharge of meibomian gland secretions [10]. The majority of Chinese hospitals possess specialized ultrasonic atomization units and traditional medicine is the most commonly applied treatment. Although several studies have evaluated the therapeutic e ffects of ultrasonic nebulization for the treatment of MGD, DED, and MGD-related DED [10–12], clear clinical evidence is lacking from a standardized multicenter, double-blind, randomized, controlled clinical study.

The plant *Houttuynia cordata* is used in traditional Chinese medicine because it induces anti-inflammatory e ffects. This therapy mainly reduces the levels of inflammation-related cytokines and chemokines by inhibiting the Nuclear Factor Kappa-B (NF-κB)/Mitogen-Activated Protein Kinase (MAPK) pathway, leading to anti-inflammatory e ffects [13–15]. Thus, *Houttuynia* eye drops have been widely used across China for the treatment of DED. A number of non-double-blind, non-randomized, single-center small sample studies have shown that ultrasonic atomization using *Houttuynia* eye drops is both safe and e ffective for treating dry eye [16,17]. Therefore, building on this earlier work and in order to evaluate the specific therapeutic e ffects and safety of ultrasonic-atomized *Houttuynia* eye

drops for the treatment of MGD-related DED, the China Association of Traditional Chinese Medicine (CATCM) organized the novel multi-center, randomized, double-blind, placebo-controlled trial reported in this study. So far, this is the first multicenter, randomized, double-blind, placebo-controlled study to evaluate the e fficacy and safety of traditional Chinese medicine for the treatment of DED.
