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A mysterious case
One of the authors of this editorial developed conditions that refused to get better with evidence-based approaches. They first presented with severe dry eye disease (DED) symptoms in their late 30s. They rotated brands and types of topical medications to no avail. At every visit, they were told their epithelium was becoming more and more unstable and that they needed to reduce computer time and use more aggressive medical therapies to combat symptoms and signs. Simultaneously, other conditions quickly started to appear: thyroid abnormalities, widespread pain, postural tachycardia, oesophagitis and gastroparesis, to name a few, all of which required an increasing number of medical therapies with little response.
Why do we get sick?
A host of variables, including intrinsic and extrinsic conditions, impact our health and well-being. These include genetics, diet, stress and environmental exposures. Pollutants and contaminants in the air we breathe, in the water we drink, in the food we eat, and noise and radiation we are exposed to can all make us sick. However, our exposure to these pollutants and contaminants can go unnoticed due to our ignorance and lack of (real-time) data and information on the levels and types of pollutants and contaminants and their associated health risks. Moreover, there is a tremendous degree of uncertainty in the levels, types and duration of adverse environmental exposure(s) as they pertain to onset/persistence and severity of disease(s). However, when multiple conditions present at disparate sites, a holistic approach to the diagnosis, treatment and management of a person’s disease is warranted.
What do people do when they get sick?
Generally, people seek medical care from doctors when they get sick. The desire to help our patients and make their lives better is common to all providers regardless of their training and/or specialty. However, most physicians rely on tools and techniques available in the clinics. Often, such tools provide a diagnosis for disease presentation in one site. But these tools are often inadequate to assess and identify the underlying causes of multifaceted presentations. Given the complex aetiologies of chronic diseases, it is critical not only to treat the disease but also identify its causes. Continued intensification of medicinal regimes often does not lead to satisfactory results in such patients.
How can DED be used as a model to examine our current approach to the diagnosis and treatment of complex chronic diseases?
DED is a unique model that can be used to study the role of the environment as a contributor and possible solution to complex diseases as the eye is an easily accessible site. DED is a prevalent ocular condition that imparts a significant societal burden as its symptoms of pain and poor vision negatively impact productivity and mental health.1 DED symptoms can have multiple contributors including tear film, anatomical and neurosensory abnormalities. As such, it is not surprising that there is heterogeneity in pathophysiological pathways that underlie disease onset, severity and persistence. In line with DED heterogeneity, many risk factors have been linked to disease, including demographics (eg, female gender, older age), comorbidities (eg, autoimmune diseases, sleep apnoea, pain conditions), medications (eg, antidepressants, antihistamines) and environmental exposures (eg, low humidity, air pollution).1
Treatment of DED is likewise complex and involves over-the-counter products (eg, artificial tears, eyelid hygiene products), prescription medication (eg, anti-inflammatories, tear stimulators, oral and topical antibiotics) and in-office procedures (eg, devices that target periocular skin health, clean the eyelids, heat the Meibomian glands), all of which have been studied over the years with thousands of resulting publications. These medications and procedures impart a significant cost to the patient, estimated at $6.08 billion for national expenditures and $1.18 billion for out-of-pocket expenditures in 2015–2016 (per capita expenditures $499.42 and $96.67, respectively) based on a study that examined the US Medical Expenditure Panel Survey database.2 Despite the fact that environmental manipulations may be more cost-effective than medical therapy, no studies have investigated the benefits of targeting environmental contributors to DED, despite this approach being viable in diseases related to DED, such as allergy. How can we achieve a more balanced approach?
What do we know about DED and the environment?
For starters, we know that both outdoor and indoor conditions (temperature, relative humidity (RH) and air pollution (both organic and inorganic sources)) relate to aspects of DED.3 With respect to temperature, chamber studies have found that increased temperature impacts the tear film by increasing lipid layer thickness.4 On an epidemiological level, DED has been related to both increased5 and decreased6 temperature. These discrepancies suggest that the relationship between temperature and DED is non-linear, and that a ‘U’-shaped curve is more likely, with both high and low temperatures being detrimental to ocular surface health. In fact, the American Society of Heating, Refrigerating and Air-Conditioning Engineers has recognised this concept and recommends an indoor temperature of 20–25°C.
RH has also been linked to tear film status and DED. Chamber studies have demonstrated that low RH (5%) increased tear evaporation, decreased tear production and decreased lipid layer thickness as compared with normal (40%) conditions.4 While the majority of epidemiological studies have likewise found inverse relationships between DED and RH,5 our data on indoor RH were contradictory. We found associations between high RH and DED symptoms, Meibomian gland dropout and low tear production.7 We hypothesise that the noted associations were not driven by RH alone, but by the interaction between RH and air pollution (high RH increases the size of particular matter (PM), a component of air pollution). Irrespective of the explanation, these data suggest that, like temperature, a U-shaped curve may describe the relationship between RH and DED. In fact, the Environmental Protection Agency recommends an RH level between 30% and 50%.
Outdoor and indoor sources of air pollution have also been shown to impact DED. One study exposed 10 individuals to clean and polluted (dusty) air and noted that tear stability was worse when individuals were exposed to air pollution.4 Epidemiological studies have noted similar findings. A Chinese case-crossover study of 5062 individuals diagnosed with DED identified that same-day exposures to PM2.5 (OR=1.02, PM less than 2.5 µm in size) and PM10 (OR=1.01, PM less than 10 µm in size) were risk factors for a DED-diagnosed clinic visit, along with decreased RH.8 We reported similar findings with respect to indoor air pollution. Our study of 97 individuals reported that a one-unit increase in PM2.5 was associated with an increase in DED symptoms (β=0.59) and a decrease in tear production (β=−0.67).7
In total, these data suggest that extremes of temperature and RH and exposure to air pollution can impact the tear film and associate with both DED symptoms and signs. Despite these findings, no studies have examined whether addressing outdoor and indoor exposures can impact DED presentation.
How can we incorporate the consideration of environmental manipulations in addressing DED?
Considering and targeting environmental exposures in DED requires a multistakeholder approach with specific solutions. First, research is needed to identify triggers of disease, and study time-lag between exposure and disease onset. Second, mass translation and communication of this research to the general public and healthcare professionals is needed to inform decision-making. Third, medical education training in environmental health is needed; specifically, training physicians to understand the environmental conditions that make people sick and their potential management strategies. Fourth, access to real-time data on outdoor and indoor environmental conditions and their associated health risks must be available for both physicians and patients so decisions regarding remediation strategies can be personalised.
These ideas can be translated to the management of DED. While changing the outdoor environment is not a practical goal, wearing wraparound glasses or goggles and avoiding prolonged outdoor activities on days where air pollution level is high can be considered.9 But first, physicians and individuals must know how to access available data on air quality from publicly available sources, such as airnow.gov or pollen.com. Moreover, people can buy inexpensive thermometers and RH metres. They can also buy inexpensive mould testing kits to assess indoor mould exposure.
Mitigation strategies for the indoor environment are more plausible given that the space is smaller and more controllable. Maintaining temperature and humidity in the ‘Goldilock’ zone (with the use of air conditioning and humidifiers), managing indoor sources of pollution (replacing filters on central heating and cooling systems, installing air purifiers, avoiding unvented stoves and fireplaces) and removing sources of mould are all viable strategies, but individuals must first identify their personal sources of pollution to plan for sensible remediation strategies.
These ideas are not far-fetched as similar approaches have been applied to DED-related diseases. In one study of 937 children with asthma, caretakers in the intervention group performed mitigation behaviours tailored to each child’s skin test results. Interventions included installation of high-efficiency air purifiers, placement of allergen impermeable covers on mattresses and pillows, and pest control approaches in children with cockroach allergies. No interventions were undertaken in the control group. Families were contacted every 2 months and asked about the number of symptom days (wheezing, chest tightness, cough, poor sleep or decreased play) over a 2-week recall. Over the year, the intervention group, on average, had fewer asthma symptom days compared with controls (3.39±0.12 days vs 4.20±0.12 in a 14-day period, p<0.001).10 Such an approach could be considered in individuals with DED.
Back to our mystery case
The moment that these numerous conditions rendered our patient unable to live their usual life, they sought out an integrative medicine provider trained in environmental medicine who identified mould toxicity as the culprit of their conditions. Unable to remediate mould from their home, they proceeded to move to a mould-free home and have optimised their indoor environment, including maintaining RH at 45% to prevent mould growth. Three years later, DED symptoms and signs have completely disappeared and DED medication is no longer required. This is an example of treating the cause of the disease, not just the clinical presentation of the disease. We realise in hindsight that the eyes were signalling that something was not right in their indoor air, but their treating clinicians were not trained to identify the link between the environment and DED, nor how to diagnose and manage our patient.
This case illustrates that clinical training in environmental health is critical. Clinicians must be trained in taking an environmental exposure history and identifying potential environmental causes of a disease. If they suspect environmental triggers, patients can be referred to environmental (and/or occupational) health experts to evaluate a patient’s exposures and recommend environmental interventions along with medical ones. We currently have information on how different environmental exposures affect health and well-being. We need to translate this information into clinical practice and people’s behaviour and choices to make a dent in the environmental disease burden (figure 1). This will involve research on emerging environmental conditions, such as nanoparticles and environmental stressors exacerbated by climate change to inform decision-making, medical training that incorporates environmental considerations, and physicians and public who are aware of how to leverage publicly available environmental data and measure individual-level exposure. These pathways are vitally needed to translate this idea into reality and better serve our patients.
Patient consent for publication
Contributors All authors contributed to the drafting and review of the manuscript.
Funding Supported by National Eye Institute (R01EY026174; AG and NK). Other support came from: Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (R&D), Clinical Sciences R&D (CSRD) (I01 CX002015; AG), Biomedical Laboratory R&D (BLRD) Service (I01 BX004893; AG), Rehabilitation R&D (RRD) (I21 RX003883; AG), Department of Defense Gulf War Illness Research Program (GWIRP) (W81XWH-20-1-0579; AG), Vision Research Program (VRP) (W81XWH-20-1-0820; AG), National Eye Institute (U01 EY034686, U24EY035102, R33EY032468; AG), NIH Center Core Grant (P30EY014801 (institutional)) and Research to Prevent Blindness Unrestricted Grant (GR004596-1 (institutional)).
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.