key: cord-0711126-q830h125
authors: Danesh-Meyer, Helen V.; McGhee, Charles NJ.
title: Implications of COVID-19 for Ophthalmologists
date: 2020-09-22
journal: Am J Ophthalmol
DOI: 10.1016/j.ajo.2020.09.027
sha: 0343cc7bc1359e337a704accb42cd8a439a3e388
doc_id: 711126
cord_uid: q830h125

PURPOSE: To describe and explain the implications of COVID-19(SARS-CoV-2) for ophthalmologists in light of the rapid developments in our understanding of the virology, transmission and ocular involvement. DESIGN: Evidence-based perspective METHODS: Review and synthesis of pertinent literature RESULTS: Retrospective studies highlight that less than 1% of patients display COVID-19 related-conjunctivitis. However, prospective studies suggest the rate is higher, approximately 6%. Viral RNA has been identified in tears and conjunctival secretions in patients with active conjunctivitis as well as asymptomatic cases. Overall, conjunctival swabs are positive in 2.5%. Samples taken earlier in the disease course are more likely to demonstrate positive virus. Viral transmission through ocular tissues has not been substantiated. Ophthalmologists are in the high-risk category for COVID-19 infection for several reasons: high volume clinics, close proximity with patients, equipment intense clinics and direct contact with patients’ conjunctival mucosal surfaces. COVID-19 is predominantly contracted through direct or airborne transmission by inhalation of respiratory droplets. Evidence that aerosol transmission occurs is increasing in particularly prolonged exposure to high concentrations in a relatively closed environment. Based on the current evidence ophthalmologists should consider measures that include social distancing, wearing masks, sterilisation techniques and managing clinic volumes. CONCLUSIONS: A major challenge to containing COVID-19 is that many infected people are asymptomatic. Droplet spread, contaminated environmental surfaces and shared medical devices are particular areas that require management by ophthalmologists. More studies are required to explore the role of the conjunctiva and ocular tissues in the transmission of disease.

The practice of medicine has more rapidly changed in the last several months than it 21 has over the past few decades. This has been due to the Coronavirus disease (COVID-22

19) pandemic. COVID-19 has reached at least 124 countries and territories and has 23 emerged as a global health threat. Our understanding of the virus, its epidemiology, 24

transmission and implications for ophthalmology is continually evolving. The goals of 25 this perspective are to address several key questions that are particularly critical for 26

ophthalmologists. Firstly, what is the evidence regarding the proposed modes of 27 transmission of the virus and how transmissible is it? Secondly, how common are 28 ocular symptoms and signs as part of our present understanding of the spectrum of 29 disease? Thirdly, what is the science that supports ocular transmission? Of particular 30

interest is whether there is convincing evidence that tears and the ocular surface of 31 asymptomatic, as well as symptomatic, COVID-19 patients harbor active virus.

Finally, what are the key issues for ophthalmologists in routine clinical practice? 33 34

Virology 35 The cause of COVID-19 is a newly discovered virus termed severe acute respiratory 36 syndrome coronavirus 2 (SARS-CoV-2 COVID-19 is highly contagious in humans although the transmissibility is not 71

precisely known. A meta-analysis suggests that its basic reproduction number (RO) 72 ranges between 1.4-6.49 (mean, 3.23; median, 2.79). 8 Reproduction number 73

represents the average number of people who will catch the disease from one 74 infected person. The seasonal flu is considered to have an RO of 1.2 to 1.4 while 75 measles has a RO of 12-18. 76 77

Coronaviruses are recognized to affect birds and mammals including household 78 animals such as the domestic cat (feline) and dog (canine). However, there is no 79 evidence that pets can spread the virus. Larger mammals such as beluga whales and 80 tigers are also affected by coronaviruses. Infectiousness is estimated to decline quickly within 7 days. 14 15 However, 107

infectiousness commences from 2.3 days before symptom onset and peaks just 108

before symptoms or at the start of symptoms. 14 This pattern is distinct from that of 109 SARS-Cov-1 which shows an increased infectiousness around 7-10 days after 110 symptom onset. 16 In contrast to SARS-Cov-1 but similar to SARS-CoV-2/COVID-19, 111 influenza virus is characterized by increased infectiousness just before and shortly 112 J o u r n a l P r e -p r o o f after symptom onset. 17 Fecal-to-oral route 187

Fecal-to-oral route has been suggested, but little evidence supports it. 37 SARS-CoV-2 188

RNA has been detected in stool, whole blood and urine of patients, but whether 189 transmission via such media is possible is still unknown. Some patients have been 190

shown to experience diarrhea prior to respiratory symptoms. SARS-CoV-1 also was 191 identified in stools of infected patients and thought to survive through sewage that 192

has not undergone adequate disinfection. 38 193 194

Clinical spectrum 195

The majority of patients with COVID-19 experience fever, dry cough and dyspnea 196

with other common symptoms including myalgia, headache and diarrhea. Other shows bilateral pneumonia, with ground-glass opacity and bilateral patchy shadows.

Death most commonly results from acute respiratory distress secondary to a 206 "cytokine storm". When death was the outcome, the period from the onset of 207 COVID-19 symptoms to death ranged from 6 to 41 days with a median of 14 days, 208

with shorter time among patients older than 70 years. 40 

Risk factors for complications include age greater than 65 years, cardiovascular 210 disease, chronic lung disease, hypertension, diabetes mellitus and obesity. It is 211

unclear whether other conditions such as kidney disease, immunosuppression, or 212 cancer confer an increased risk of complications. Laboratory findings associated with 213

worst outcome include increasing white-cell count with lymphopenia, prolonged 214

prothrombin time, and elevated levels of liver enzymes, lactate dehydrogenase, 215

interleukin C, CRP and procalcitonin. 41 216 217

Ocular Involvement in COVID-19 218 219

Conjunctivitis 220

Conjunctivitis has been reported to be a presenting symptom of COVID-19, although 221

Chinese ophthalmologists believe that the extent of ocular involvement has largely 222 been ignored. 42 There are several well-documented case-reports. 43 Future studies should consider the association between serum viral load and viral 318

shedding in tears. 319 320

The mechanism of how virus appears in tears remains unclear and whether there 322

can be transmission through infected ocular tissue or fluid is controversial. 46 One 323 hypothesis is that the nasolacrimal system behaves as a channel for viruses to travel 324 from upper respiratory tract to the eye. Alternatively, since COVID-19 patients have 325

viremia during the acute phase, the presence of viral RNA is likely to be the result 326 from exudation of the virus into the conjunctiva. However, several anatomical and 327 physiological properties of the ocular surface may also facilitate its role both in 328 serving as a gateway for respiratory infections as well as a potential site for viral 329

replication. 64 

The conjunctival epithelium is exposed directly to the external environment that 332 may include droplets containing virus particles and contaminated fomites. Direct 333 inoculation of the conjunctiva from infected droplets results in some absorption by 334 the cornea, conjunctiva and ultimately sclera, but most drain into the nasolacrimal 335 system with the lacrimal duct transporting tears to the inferior meatus of the nose or 336

into the nasopharyngeal space. Hence, ocular tissue and fluid may represent a 337 potential source of, and route for, COVID-19 infection, although the role of the 338 conjunctiva in transmission of the virus currently remains unclear.

Another theoretical avenue that SARS-CoV-2 may access entry through ocular 341 tissues is through ACE2 receptors. SARS-CoV-2 requires access to host cells through 342 the ACE2 receptor. The ACE2 receptor has been identified on the ocular surface as 343

part of a local autocrine function of the renin-angiotensin system (RAS). 65 ACE2 has 344 been found in aqueous humor and the retina. 66 However, the expression of ACE2 in 345 more anterior tissues such as the conjunctiva or cornea is not completely 346

understood. The RAS system has been investigated for the potential development of 347 J o u r n a l P r e -p r o o f to be infectious when mildly symptomatic or even asymptomatic plus viral shedding 359 appears to be highest in the earliest stage. 360 361

Ophthalmologists, anesthetists, dentists and ear, nose and throat specialists, have 362 been identified to be at high risk for infection while carrying out their routine patient 363

care. 58 Ophthalmologists are in the high-risk category for multiple reasons. 364

Ophthalmologists have high volume clinics, and are in particularly close proximity 365 with patients. The CDC defined close contact of being approximately two meters 366 from a patient for a prolonged duration, where any contact longer than 1 to 2 367 minutes of exposure is considered prolonged. 69 There is also the use of equipment 368 by ophthalmologists that requires close patient proximity such as slit lamp, 369

tonometer, fundus camera, ocular ultrasound, perimetry, and laser treatments. 59 In 370 addition, ophthalmologists have direct contact with patients' conjunctival mucosal 371

surfaces during procedures such as using three-mirrored lens and gonioscopes, 372 which potentially may serve as a route for COVID-19 transmission.

Warning regarding non-contact tonometry as a source of micro-aerosols has also 375 been raised. Disruption to the tear film with a pulse of pressurized air and formation 376 of microaesols with non-contact tonometry has been documented using a camera 377 and flash electrically coupled to a non-contact machine. 70 Ophthalmologist who 378 perform endoscopic dacryo-cystorhinosotomy are in contact with the nasal mucosa 379 which as previously noted is a high risk area. 380 381

Several case reports have highlighted the potential risks to ophthalmologists. An 382 ophthalmologist, the late Dr. Li Wenliang at Wuhan Central Hospital, believed he 383 contracted COVID-19 from an asymptomatic glaucoma patient and reportedly 384

succumbed to the disease one month later. 71 Since these early reports there have 385 been many cases of ophthalmologists infected through routine diagnosis and 386 treatment. 46 The mechanism of transmission remains unclear as to whether it was 387 through droplets, direct contact with secretion followed by subsequent inoculation 388 into mucous membranes. 72 Hypothetically, the risk of COVID-19 infection to staff 389 may be compounded in crowded hospitals that serve both eye, and ear, nose and 390 throat conditions. The risk of COVID-19 will fluctuate with the prevalence in each population. The 396 specifics of appropriate personal protection equipment and policies and the failure 397

to provide adequate supplies to health care workers is beyond the scope of this 398 perspective and has been recently addressed. 73 Each country and institution is 399 dealing with the unique challenges of balancing appropriate protection with 400 rationing diminishing supplies. 69 74, 75 However, there are certain over-arching 401

principles of infection control that must be adhered to in order for ophthalmologist 402 to practice safely.

A recent systematic reviewed analyzed the data from studies that considered the 405 role of physical distance, face masks and eye protection in decreasing infection rates 406 from coronaviruses. The investigators confirmed that there is a large reduction in 407

infection rates with physical distancing of 1 meter (3.28 feet). 76 Protection was 408

increased as distance was lengthened so that transmission rates were further 409 reduced at 2 meters. As over-crowding of clinics has been associated with high 410

concentration of airborne particles measures are recommended to modify clinic 411 sizes and maintain social distancing. Several strategies have been suggested 412

including: reducing clinic volumes, alterations to waiting spaces and patient flow 413

with the underlying intention to reduce the volume and increase the space between 414

patients. Other possible ways of maintaining social distancing in small clinic spaces is 415

to have patients wait in their motor vehicles while they undergo pupil dilation or 416 until actual review time, and for patients advised to come alone or be limited to one 417 support person.

Evidence suggests that wearing face masks protect both health-care workers and the 420 general public against infection by coronaviruses. Face masks can be considered in 421 two major categories which have different uses: N95 respirators and surgical 422 masks. 77 The N95 designation means that in testing conditions, the respirator blocks 423 at least 95% of very small particles (0.3um). When assessing patients with known 424 COVID-19 (or who are at high risk), or use of aerosol generating procedures, N95 425 respirators are unanimously recommended by national and international 426

guidelines. 78 Systematic analysis for coronaviruses suggest that N95 masks are 427 strongly associated with protection from viral transmission compared to surgical 428 masks and should be considered in a health care setting. 76 429 430

Surgical masks, on the other hand, are considered to be effective in blocking large-431 particle droplets. They do not necessarily filter small particles in the air but can 432 minimize respiratory transmission and hand-to-face contact but they do decrease 433 the release of the viral load into the environment. Breath shields on slit lamps may act as a barrier to respiratory droplet transmission 497

given that the range of droplet transmission has been shown to be as far as 6 meters 498 from a sneeze. However, such barriers could also become a potential source for 499

contamination and care must also be taken to properly sterilize such barrier shields 500 between each patient. 86 501 502

Guidelines are also available for cleaning and sterilizing perimeters with specific 503

instructions provided by companies for machines. General recommendations 504 include using masks during visual field testing and wiping down interface surfaces 505

with isopropyl alcohol in between each patient including eye patch, chin rest, head 506 rest, patient response button, trial lens holder and trial lenses. In order to clean the 507 bowl of visual field machines, it is important to follow the guidelines provided by the 508 manufacters. 87 88 509 510

Other Implications for Ophthalmologists 511 512

Telehealth 513

The role of telehealth has been evolving over the past decades. However, the COVID-514

19 pandemic has hurled telemedicine into the forefront. 89 The argument is that 515 much of medical decision-making is cognitive and telemedicine allows access to 516 patients who are more appropriately managed from home. Using telehealth where 517 possible reduces the number of health care workers who interact with potentially 518 infected patients. Insurance companies and funding providers are increasingly aware 519 that telemedicine has an important place in providing health care. 520 521

The suitability of telehealth varies significantly from specialty to specialty. 522

Ophthalmology might be one of the most challenging applications of telemedicine 523

given the requirements to measure IOP, examine the anterior segment, gonioscopy 524

and obtain high definition images of the posterior pole and retina. However, 525

technological advances are expanding the potential of tele-ophthalmology. Although 526 tele-ophthalmology is not a replacement for traditional eye care and still faces 527 challenges for adequate implementation, it represents an option to provide effective 528 care for a sub-group of patients which allows the appropriate and timely distribution 529 of service. Regulatory structures, credentialing and implementation are all 530 challenges that will need to be overcome. 531 532

Impact on Non-COVID-19 patients 533 534

The focus of health care has understandably been on tackling the management of 535 COVID-19 patients and protecting others from infection. As a consequence, people 536

with chronic conditions may have been forced to postpone much of their eye care. 537

Therefore, a potential second wave of this crisis may be addressing the chronic 538 ocular conditions that have had delayed care or patients who have been afraid to 539 present with acute conditions. Studies during the SARS-CoV-1 outbreak showed that 540

while hospitalisations for diabetes plummeted during the crisis, these skyrocketed 541

afterwards. 90 During the present crisis, there has already been fewer admissions for 542 stroke and heart-attack. The concern is that the incidence is the same but 543 cautious/frightened patients are not presenting for care. 91 92 Over the coming 12 544

months, ophthalmology will have to assess the fall-out from delayed care and 545

develop triaging strategies to manage health demands. 546 547

Conclusions 548 549

The COVID-19 pandemic has had far-reaching and permanent implications for health 550 care globally with ophthalmology being no exception. While we are still learning 551 about the behavior of the virus it well-established that SARS-CoV-2/COVID-19 is 552

highly infectious and spread predominantly by direct transmission and droplets. 553

Conjunctivitis should be recognized as a possible symptom of COVID-19 although it is 554

presently documented to occur in only approximately 1% of patients.

There are, however several areas of uncertainty. While it is also clear that 557

asymptomatic patients have a significant viral load, the spread from asymptomatic 558 or pre-symptomatic patients has not been quantified. There is increasing evidence 559 emerging on the possibility of aerosol transmission although the extent of this 560 requires further investigation. Although SARS-CoV-2 has been detected in a minority 561 of patients in tears and conjunctival secretions, there are unresolved issues with the 562 timing and testing of these samples. Most conjunctival tests have been done later in 563 the disease course and therefore the role of greater viral load in the early stages of 564 the disease still requires further elucidation. In particular, ongoing research is 565 required to understand the permissiveness of ocular tissue to SARS-CoV-2 and the 566 role it may play as an alternative physiological pathway for COVID-19 infection. 567 568

Ophthalmologist will need to maintain vigilance given the increased risk of infection 569 they face due to close and prolonged proximity to patients in equipment intense 570 examination rooms that provides additional surfaces to be contaminated -thus 571

increasing the risk of exposure. Maintaining social distancing measures, appropriate 572 PPE, and sterilization are all key steps. Tele-ophthalmology will emerge as a 573 prominent part of clinical practice in particular as technology advances allowing 574 opportunities for examination techniques through the digital medium. The COVID-19 575 crisis has also had far-reaching impact on patients with non-COVID-19 conditions, 576

and in the midst of the pandemic we will need to continue to provide high-level 577 quality care to all our patients. 578 579 580

of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort 628 study

Virological 631 assessment of hospitalized patients withCOVID-2019

Temporal profiles of 638 viral load in posterior oropharyngeal saliva samples and serum antibody responses 639 during infection by SARS-CoV-2: an observational cohort study

Viral shedding and 648 transmission potential of asymptomatic and paucisymptomatic influenza virus 649 infections in the community

Influenza A virus shedding 652 and infectivity in households

Estimating 655 the generation interval for COVID-19 based on symptom onset data

Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. 660 NEJM 2020

Evidence for gastrointestinal 663 infection of SARS-CoV-2

Controversy around airborne versus droplet 666 transmission of respiratory viruses: implication for infection prevention

The role of particle size in 670 aerosolised pathogen transmission: a review

Severe acute respiratory syndrome: Pertinent clinical 684 characteristics and therapy

Evidence of 691 airborne transmission of the severe acute respiratory syndrome virus

Aerodynamic Characteristics and RNA 700 Concentration of SARS-CoV-2 Aerosol in Wuhan Hospitals during COVID-19 Outbreak 701

Air, surface 708 environmental, and personal protective equipment contamination by severe acute 709 respiratory syndrome coronavirus 2 (SARS-CoV-2) from a symptomatic patient

Persistence of coronaviruses on inanimate 717 surfaces and their inactivation with biocidal agents

Article full text 720 36. Coronavirus disease 2019 (COVID-19): Environmental cleaning and disinfection 721 recommendations

Molecular and serological investigation of 2019-nCoV 725 infected patients: implication of multiple shedding routes

Concentration and detection of SARS coronavirus in 729 sewage from Xiao Tang Shan hospital andthe 309th hospital of the Chinese people's 730 liberation army

Clinical features of patients infected with 2019 734 novel coronavirus in Wuhan, China

Updated understanding of the outbreak of 2019 novel 738 coronavirus (2019-nCoV) in Wuhan

Mild or Moderate COVID-19

2019-nCoV transmission through the ocular surface must not be 744 ignored. The Lancet

Peking University Hospital Wang Guangfa disclosed treatment status on 747 Weibo and suspected infection without wearinggoggles

Ocular manifestations of a 751 hospitalised patient with confirmed 2019 novel coronavirus disease

Keratoconjunctivitis as the initial medical presentation of the novel coronavirus 756 disease 2019 (COVID-19)

Characteristics of Ocular Findings 759 of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province

The infection evidence of 766 SARS-COV-2 in ocular surface： a single-center cross-sectional study

The severe acute respiratory syndrome 777 coronavirus in tears

Tears and conjunctival 787 scrapings for coronavirus in patients with SARS

Virus-specific RNA and antibody from 792 convalescent-phase SARS patients discharged from hospital

Middle East respiratory syndrome 796 coronavirus(MERS-CoV) causes transient lower respiratory tract infection in rhesus 797 macaques

Assessing Viral 800 Shedding and Infectivity of Tears in Coronavirus Disease

Evaluation of coronavirus in tears and 804 conjunctival secretions of patients with SARS-CoV-2 infection

Ophthalmologic evidence against the 808 interpersonal transmission of 2019 novel coronavirus through conjunctiva. medRxiv

Ocular 812 Findings and Proportion with Conjunctival SARS-COV-2 in COVID-19 Patients

The infection evidence of 816 SARS-COV-2 in ocular surface: a single-center cross-sectional study

Respiratory tract samples, viral 820 load, and genome fraction yield in patients with Middle East respiratory syndrome

Testing Clinical Specimens from Persons Under Investigation 825 (PUIs) for Coronavirus Disease 2019 (COVID-19). 2020. Available

Ocular tropism of respiratory viruses

Receptor recognition by novel 838 coronavirus from Wuhan: an analysis based on decade-long structural studies of 839 SARS

Many Faced of Renin-angiotensin-System-842 Focus on Eye

Precautionary measures needed for 847 ophthalmologists during pandemic of the coronavirus disease 2019 (COVID-19)

Microaerosol formation in noncontact 851 'air-puff' tonometry

Coronavirus kills Chinese whistleblower ophthalmologist. (2020) American 855 Academy of Ophthalmology

Protecting health-care workers 859 from subclinical coronavirus infection

865 866 74. Rutala WA, APIC Guidelines Committee. APIC guideline of selection and use of 867 disinfectants

Effectiveness of 870 precautions against droplets and contact in prevention of nosocomial transmission 871 of severe acute respiratory syndrome (SARS)

Physical distancing, face masks, 874 and eye protection to prevent person-to-person transmission of SARS-CoV-2 and 875 COVID-19: a systematic review and meta analysis

Repirators for Preventing COVID-19 in Healh Care Workers: A Systematic Review and 879

Meta-analysis of Randomised Trials. Influenza & Other Respiratory Viruses 2020

COVID-19 and the Risk to Health Care 883 Workers: A Case Report

Respiratory virus shedding in 887 exhaled breath and efficacy of face masks

ResPECT investigators. N95 891 respirators vs medical masks for preventing influenza among health care personnel: 892 a randomized clinical trial

Principles of selective inactivation of viral genome. I. UV-896 induced inactivation of influenza virus

Far-UVC light (222nm) 898 effiencity and asfely inactivates airborne human coronaviruses

How far droplets can move in indoor 901 environments evisiting theWells evaporation-falling curve. Indoor Air

Assessing the Dynamics and Control of Droplet-904 and Aerosol Transmitted Influenza Using an Indoor Positioning System

Control 908 Measures for Ophthalmology Clinics Based on a Singapore Center Experience

Disinfecting ophthalmic devices-ZEISS medical technology I ZEISS international

Virtually Perfect? Telemedicine for COVID-19

Hospitalization for ambulatory-care-sensitive 927 conditions in Taiwan following the SARS outbreak: a population-based interrupted 928 time series study

Reduction in ST-segment elevation 932 cardiac catheterization laboratory activations in the United States during COVID-19 933 pandemic

Hospital admissions for strokes appear to have plummeted, a doctor 936 says, a possible sign people are afraid to seek critical help. Washington Post