Viewpoint by Professor Minas Coroneo AO.
In a remarkable era and as physicians at risk by the nature of our profession (1), our relative impotence in dealing with COVID-19 is sobering. A year after the outbreak of the COVID-19, we remain without a cure, despite the advances in medical science of our era. That “viral outbreaks have killed off virtually entire populations …, medical interventions (principally vaccines) and stringent public health measures have often altered the outcome, but not necessarily in predictable ways” (2) has been noted. Our inability to prevent successive waves of widespread community infection and our almost complete reliance on a solution based on vaccination begs a rethink. Surprisingly, the areas of personal protection and pharmacological intervention remain controversial. Is something missing in our approach?
Central to effective interventions is an understanding of disease transmission, yet controversy remains on this point as well as the pathophysiology of initial human viral invasion. A recent appeal by international experts for recognition of the potential for airborne spread, states that it has been “demonstrated beyond any reasonable doubt that viruses are released during exhalation, talking, and coughing in microdroplets small enough to remain aloft in air and pose a risk of exposure at distances beyond 1 to 2 m from an infected individual”(3). The precedents for airborne transmission of other viruses, including respiratory syncytial virus (RSV), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and were cited and reference was made to the failure of most public health organizations, to recognize airborne transmission except for healthcare-related aerosol-generating procedures. Furthermore, the long-term persistence of SARS-CoV-2 aerosols for least 16 hours has been quantified and the virus has shown greater infectivity than did SARS-CoV and MERS-CoV (4). The greatest risk is in crowded, inadequately ventilated indoor/enclosed environments for which airborne transmission is the only plausible explanation for documented superspreading, despite adherence to recommended precautions. The presumed viral invasion modalities involve inhalation and/or hand contamination of mucosal surfaces, despite very early studies to the contrary in the influenza literature (5).
A recent small observational study (6), reported an apparent protective effect from SARS-CoV-2 infection, conferred by routinely wearing spectacles for more than eight hours/day. It was hypothesized that spectacles act as a barrier, reducing the frequency with which people touch their eyes. The authors review but do not reconcile the apparent paradox of the presence of viral invasion enabling receptors (ACE2, TMPRSS2 and BSG) on the ocular surface and the relatively low prevalence of ocular surface disease. The accompanying Commentary (7) provides an epidemiologist’s caution of avoiding the inference of a causal relationship from a single observational study. The study however satisfied the criteria of temporality: spectacles were worn prior to viral exposure and biological plausibility: viral transmission via the eye with spectacles as a direct barrier or indirectly against digital contamination, a factor emphasized as a means of transmission.
Research efforts appear agnostic of a landmark study carried out by Maxcy in 1919 during the third wave of the Spanish flu pandemic (5). Using an atomised solution of Bacillus prodigiosus (Serratia marcescens) as a marker, he demonstrated that in adequately masked patients but with exposed eyes, bacteria could be cultured from the nasopharynx. He had previously shown that bacteria instilled into the conjunctival sac were recoverable from the nose 5 minutes later, from the nasopharynx after 15−30 min and from stools 24 hrs later (as is the case for SARS-CoV-2). This ocular surface – nasolacrimal duct-nasopharyngeal system, particularly permits access of “respiratory” viruses, perhaps more appropriately termed oculoptropic viruses (1,8) to the respiratory system, gut and circulation. That the nasopharynx can act as a microbial reservoir is ignored with the supposition that viruses reach the lungs via direct inhalation from the atmosphere.
Another critical factor is that human eyes are located at a vantage point, simultaneously sensing information at high band width but also being exposed to the risk of airborne material (1). Ocular surface area, including periocular structures such as the eyelids is large compared to that of the mouth and nares (5) – we have recalculated this to be ~10,000 mm2 or 2 orders of magnitude greater than for the nares and mouth – a large and mostly open target for promiscuous spraying of viral particles (1). Furthermore, the more specific role of the tear film in firstly protecting the cornea and ocular surface as well as providing a vehicle for viral carriage has not been well recognized. Thus, the most superficial lipid tear film layer is likely to attract SARS-CoV-2 by both electrostatic and lipophilic properties (1). A seemingly paradoxical low rate of conjunctivitis and keratitis of ~ 12% (9), despite the presence of ocular surface viral invasion enabling receptors (albeit with lower levels than in the lung) could be explained by the physical barrier of the tear film, tear film antiviral activity, particularly the effects of lactoferrin as well as corneal type III interferon-related inhibition. Tear film dynamics with a turnover rate of 5–21% of its volume per minute may explain why the virus is so very rarely detected in infected individuals.
An unexpected consequence of the COVID-19 pandemic has been to highlight the inadequacy of personal protection. While “the obvious means of protection is the wearing of a large lens or pair of goggles in addition to the gauze mask” (5), it is interesting to note that during the great Old World plague epidemics, “masking of the whole face, eyes included, has been wonderfully effective”. However, to this day, the relative importance of protecting each component of the T-zone (eyes, nose, mouth) remains unexplored.
Many of the protective devices in use were not designed for the task to which they currently have been put and their efficancy has been questioned: the “brute-force” approach involving physical barriers, “masking“ the presumed T-zone portals of viral entry. Face masks of variable protective capacity and ease of use and comfort may be associated inadequate protection when worn for extended periods of time as well as poor compliance. Supposedly, masks serve a dual purpose of both preventing the spread of aerosolized droplets by the wearer. However, a recent meta-analysis concluded that the wearing of surgical masks by individuals in non-healthcare settings is not significantly associated with reduction in acute respiratory illness incidence (10). Furthermore, a study of mask efficacy during influenza seasons of 2011- 2015 found that there was no significant difference in the incidence of laboratory-confirmed influenza among two groups in outpatient health care personnel (8.2% for the N95 respirator and 7.2% for masks). Reports of mask efficancy in high risk hospital environments do not appear to have taken the extent of concomittant eye protection into account.
It has even been suggested the wearing of goggles, a face shield, or even eyeglasses might pose an increased risk of touching one’s eyes more frequently and potentially contaminating them when removing, replacing, or adjusting the eye protection, especially if a person is not accustomed to wearing them. Self-contamination when doffing PPE is a well- documented risk that must be carefully considered before advising people to wear a new type of PPE (7).
A variety of other eye protectors, while covering much of the face do not exclude air currents that can circumvent the device, such as the human convective boundary layer. Protectors can obstruct vision (like the original plague masks), fog up, get in the way (particularly when using optical instruments), are uncomfortable (hence liable to diminished or improper use) and when worn as part of a helmet-device, reduce communication with others. Attempts at preventing aerosol droplets from entering the air mass in front of the eye, has resulted in the use of hermetically sealed eye protection, generally designed for short to medium term usage rather than a shift in a hospital intensive care unit. However, a major problem is limited usability due to the well-known phenomenon of fogging, the main cause of poor compliance (11). Condensation occurs on the inner surface of the goggles of evaporating tears, continuously secreted by the ocular adnexae and sweat from the periocular skin into the contained space. Goggles fog significantly by 5 minutes and despite the use of a filtration system, some fogging is present at one (11) and longer term “real world” studies have yet to be carried out.
Thus, there are significant factors limiting efficacy of PPE. This may help in explaining why front-line health care workers who, despite wearing apparently adequate gloves, gowns and face masks are at least a three times increased risk of infection compared to the general population (12).
Finally, if it transpires that the predominant viral entry portal is via the eye, we have proposed that the ocular surface may serve as an ideal site from which to treat early infection or as a prophylactic intervention, while the virus is confined to the nasopharynx and upper respiratory tract. The principle reason for this is that the angiotensin converting enzyme 2 (ACE2) and associated enabling receptors are located on the apical rather than basolateral cell surfaces and are therefore best accessed via topical rather than systemic treatment. Thus, drugs such as chloroquine/hydroxychloroquine whose effects are mediated in part via the ACE2 receptor are likely to be more efficacious when used in this way. Furthermore, the risk of systemic side effects is minimised as is the likely treatment cost and we have previously pointed out that many of these drugs can be safely used in the eye, repurposed from use for other ocular conditions (1).
Conclusion: Taken together, there is circumstantial evidence that person to person transmission is mediated via viral-laden aerosols that access the eye’s tear film and are relatively quickly transmitted via the lacrimal drainage system to a nasopharyngeal reservoir. That this pathway had been “disregarded in planning measures for the prevention of the spread of contagious diseases” was recognized in 1919 and little has changed. The importance of a strong evidence base to any intervention is understood, as is the advent of highly specialized medical practice and research, yet the apparent Black Letter approach, within narrow silos of knowledge evident in this pandemic may not have served us well. The failure to acknowledge historical precedent may also have served to delay an effective response to this crisis. There is an urgent need to develop better eye protective strategies based on an understanding of ocular interactions with the environment (including eye and face touching) and to reconsider early topical interventions.
References
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- Sommer A. Humans, viruses, and the eye—an early report from the COVID-19 front line. JAMA Ophthalmol. 2020;138(5):578-579.
- Morawska L, Milton DK. It is Time to Address Airborne Transmission of COVID-19. Clin Infect Dis. 2020 Jul 6:ciaa939.
- Fears AC, Klimstra WB, Duprex P et al. Comparative dynamic aerosol efficiencies of three emergent coronaviruses and the unusual persistence of SARS-CoV-2 in aerosol suspensions. medRxiv [Preprint]. 2020 Apr 18:2020.04.13.20063784.
- Maxcy KF. The transmission of infection through the eye. J Am Med Assoc. 1919;72:636–9.
- Zeng W, Wang X, Li J, Yang Y, Qiu X, Song P, Xu J, Wei Y. Association of Daily Wear of Eyeglasses With Susceptibility to Coronavirus Disease 2019 Infection. JAMA Ophthalmol. 2020 Sep 16. doi: 10.1001/jamaophthalmol.2020.3906. Epub ahead of print.
- Maragakis LL. Eye Protection and the Risk of Coronavirus Disease 2019: Does Wearing Eye Protection Mitigate Risk in Public, Non-Health Care Settings? JAMA Ophthalmol. 2020 Sep 16. .
- Belser JA, Zeng H, Katz JM et al. Ocular tropism of influenza A viruses: identification of H7 subtype-specific host responses in human respiratory and ocular cells. J Virol. 2011;8`5:10117-25.
- Ahuja A, Mahajan S, Tong L et al. Ocular surface manifestations of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. PLoS One. 2020 Nov 5;15(11):e0241661.
- Wang MX, Gwee SXW, Chua PEY etal. Effectiveness of Surgical Face Masks in Reducing Acute Respiratory Infections in Non-Healthcare Settings: A Systematic Review and Meta-Analysis. Frontiers in Medicine. 2020 ;7:564280.
- Douglas D, Douglas R. Addressing the corona virus pandemic: will a novel filtered eye mask help? Int J Infect Dis. 2020;95:340-344.
- Nguyen LH, Drew DA, Graham MS, et al. Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study. Lancet Public Health. 2020;5:e475-e483.