The Academy is sharing important ophthalmology-specific information related to the novel coronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The highly contagious virus causes a severe respiratory disease known as COVID-19.
This page is principally authored by James Chodosh, MD, MPH, with assistance from Gary N. Holland, MD, and Steven Yeh, MD.
What you need to know
- Published reports suggest that SARS-CoV-2 can cause a mild follicular conjunctivitis otherwise indistinguishable from other viral causes, and possibly be transmitted by aerosol contact with conjunctiva. Any patient seen by an ophthalmologist right nocurrentlyw could be infected with SARS-CoV-2, regardless of presenting diagnosis, risk factors, indication for visit, or geographic location.
- SARS-CoV-2 is susceptible to the same alcohol- and bleach-based disinfectants that ophthalmologists commonly use to disinfect ophthalmic instruments and office furniture. To prevent SARS-CoV-2 transmission, the same disinfection practices already used to prevent office-based spread of other viral pathogens are recommended before and after every patient encounter.
- The Academy and federal officials strongly recommend protection for the mouth, nose and eyes when caring for patients during the COVID-19 pandemic.
Background
SARS-CoV-2 is an enveloped, single-stranded RNA virus that causes COVID-19. It is highly transmissible and has a significant fatality rate, especially in the elderly and those with comorbidities such as immune suppression, respiratory disease and diabetes mellitus. Global fatalities are expected to continue to rise worldwide for at least the near future.
Symptoms of COVID-19 typically appear within 2 to 14 days after exposure to the virus. As recently reported by the CDC, these may include cough and shortness of breath (or difficulty breathing), fever, chills, muscle or body aches, headache, sore throat, runny nose, nausea/vomiting, diarrhea, and new-onset loss of taste or smell. Elderly patients may show only lethargy and confusion. Anecdotes suggest that diarrhea is common early in infection; conjunctivitis and severe eye pain have also been reported. Complications in severe cases include pneumonia, renal failure, cardiomyopathy, stroke and encephalopathy. SARS-CoV-2 infection in children can be associated with a severe multi-system inflammatory syndrome with features that overlap with Kawasaki disease and toxic shock syndrome.
A March 10, 2020, study in the Annals of Internal Medicine found that the mean incubation period for SARS-CoV-2 was 5 to 7 days, and patients were typically infectious for several days prior to symptom onset. More than 97% of those who developed symptoms did so within 11.5 days of exposure, findings that further support current 14-day quarantine recommendations.
Transmission
Current understanding about how COVID-19 spreads is based largely on what is known about other similar coronaviruses. The virus is believed to spread primarily via person-to-person through respiratory droplets produced when an infected person coughs or sneezes. Airborne spread has been documented indoors over substantial distances, for example in participants at a ch and in those dining at an indoor . It also could be spread if people touch an object or surface with virus present from an infected person, and then touch their mouth, nose or eyes. Viral RNA has also been found in stool samples from infected patients, but evidence for transmission through the fecal/oral route is lacking.
Evidence suggests that SARS-CoV-2 is most commonly spread by asymptomatic and presymptomatic transmission. A Feb. 21, 2020, report in JAMA details a case of an asymptomatic carrier who possibly infected 5 family members despite having normal chest computed tomography (CT) findings. In an outbreak at a long-term care skilled nursing facility in King County, Washington, 30% of residents tested positive for SARS-CoV-2; half of these were asymptomatic on the day of testing. In another study from China, the transmission rate from those with “undocumented” infections (asymptomatic or symptomatic but not meeting testing criteria) was lower but still significant, with an estimated transmission rate about half that of those with classical symptoms. Because undocumented infections are more common than current testing levels can account for, they likely serve as a greater source of transmission than those of symptomatic carriers who have tested positive. The median duration of viral shedding as determined by RT-PCR in a study of 191 COVID-19 positive inpatients was 20 days; the longest duration observed was 37 days. Li Wenliang, MD, the whistleblower ophthalmologist who sounded the initial alarms on the coronavirus, and later died from the disease, believed he was infected by an asymptomatic glaucoma patient. The sum of these reports points to asymptomatic and presymptomatic transmission as a significant source of spread.
Environmental contamination by SARS-CoV-2 is another cause for concern. In a study published in the New England Journal of Medicine, scientists were able to detect viable SAR-CoV-2 in aerosols up to 3 hours post-aerosolization, although in an experimental setup lacking any ventilation, and not necessarily reflecting how the virus behaves in real-life conditions. The study also found infectious virus remained for up to 24 hours on cardboard, 4 hours on copper, and 2 to 3 days on plastic and stainless steel. In another study by the CDC of the cruise ship outbreaks of COVID-19, SARS-CoV-2 RNA (not necessarily indicating infectious virus) was identified on various surfaces within cabins of passengers who tested positive, for up to 17 days after they disembarked the ship.
In a report from the University of Nebraska, the authors used RT-PCR to test room air, personal articles, and environmental surfaces for SARS-CoV-2 in the hospital rooms of COVID-19 patients. They found evidence of viral RNA throughout the rooms—even on windowsills and in ambient air. SARS-CoV-2 nucleic acid is surrounded by a lipid envelope in the intact virus. This envelope is highly susceptible to dessication and UV light. Damage to the envelope renders the virus noninfectious but still detectable by RT-PCR. In the Nebraska study, infectious virus could not be cultured from air samplers. However, these data reinforce the need to use personal protective equipment (PPE) meticulously, per local guidelines, and to remain vigilant in handwashing and disinfecting surfaces and materials possibly contaminated by respiratory secretions from infected patients.
Personal protective equipment (PPE) for ophthalmic use
There is general consensus regarding what constitutes appropriate PPE for ophthalmologists performing ophthalmic examinations, particularly around the use of masks and goggles. Reports of ophthalmologist deaths, data about environmental virus contamination, and increased awareness of asymptomatic and presymptomatic spread of infections all favor masks and eye protection for eye care providers and masks for patients during every clinical encounter. However, regional shortages of PPE remain an issue. The Academy relies on expert guidance from the CDC with regards to indications for extended mask wear and reuse, but recommends that patients wear masks or face coverings and that physicians wear at least surgical masks and eye protection during all ophthalmic examinations. At present, even though the CDC has relaxed mask wearing for vaccinated persons, they have not altered recommendations for healthcare settings.
Treatment
Currently, there are multiple ongoing clinical trials of agents for prophylaxis or therapy for SARS-CoV-2 infection. In a randomized, placebo-controlled treatment trial, treatment with remdesivir led to a more rapid recovery than treatment with placebo. Subsequently, on May 1, 2020, the FDA issued an emergency use authorization (EUA) for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.
On November 9, 2020, the FDA issued an EUA for bamlanivimab (Eli Lilly), a monoclonal antibody against the coronavirus spike protein, to be used in mild-to-moderate COVID-19 in adult and pediatric patients (12 years of age or older and at least 88 pounds in weight) deemed at high risk of progressing to severe disease. On November 21, 2020, the FDA also granted EUA status to a combination therapy of casirivimab and imdevimab (Regeneron) for the same indication. All of these are laboratory-generated antibodies designed to mimic antibodies generated naturally by patients with COVID-19 against the SARS-CoV-2 spike protein. The FDA also issued an EUA for the use of convalescent sera from COVID-19 survivors as therapy. In addition, anticoagulant therapy is often administered to reduce the risk of thromboembolic events associated with COVID-19, and systemic dexamethasone has been shown to reduce the risk of death in very ill, hospitalized patients. More information about developments in the treatment of COVID-19 by these agents is available from the CDC.
Vaccines
There are now 3 vaccines with FDA EUA for prevention of COVID-19.
The vaccine made by Pfizer and BioNTech, BNT162b2 (Tozinameran), was recommended by an FDA advisory panel for authorization on December 10, 2020, and approved for emergency use on December 11. The vaccine made by Moderna, mRNA-1273, received FDA authorization on December 18, 2020. Both of these vaccines contain an mRNA that codes for the SARS-CoV-2 spike protein and are packaged in lipid nanoparticles. The Pfizer/BioNTech vaccine requires maintenance at -70 degrees Celsius, while the Moderna vaccine requires storage conditions at -20 degrees Celsius or cooler. Each vaccine was shown in phase 3 clinical trials to provide greater than 90% efficacy in preventing COVID-19. Each requires two doses, with an interval of 21 days between doses for Tozinameran, and 28 days between doses for mRNA-1273. These vaccines represent the very first FDA licensed mRNA-based vaccines, but mRNA vaccine technology has been in clinical trials since 2011, predominantly in cancer trials, and with no major safety concerns. Not only do both these mRNA vaccines reduce symptomatic disease, hospitalizations, and deaths due to COVID-19, a recent CDC study showed that both mRNA vaccines also reduce asymptomatic infection. This means that vaccinated persons such as caregivers are less likely to asymptomatically transmit COVID-19 to those around them.
On February 27, 2021, the FDA issued an EUA for its single-dose, adenovirus vector-based vaccine, JNJ-78436735. The vaccine contains a replication-incompetent, recombinant adenovirus type 26, engineered to express the SARS-CoV-2 spike protein. Unlike mRNA vaccines, JNJ-78436735 is stable at refrigerator temperatures for months, and up to 2 years in a standard freezer. JNJ-78436735 showed 86% efficacy against severe COVID-19 disease in the United States and 82% in South Africa. Overall efficacy against COVID-19 in the United States was 72%, lower than the available mRNA vaccines. However, the JNJ vaccine is believed to offer superior protection against a new, more contagious viral variant identified in South Africa and now believed to be circulating worldwide, and it prevented 100% of hospitalizations and deaths in its phase III clinical trial.
On April 13, 2021, use of the JNJ vaccine in the United States was suspended after reports of 6 women developing central venus sinus thrombosis (out of 6.8 million doses given). These 6 cases all occurred in women ages 18 to 48, and from 6 to 13 days after vaccination. A seventh case was later included in the review. After consideration of the data, on April 23, 2021, the CDC and FDA permitted resumption of vaccinations with JNJ-78436735. Women younger than 50 years old were advised to be aware of the rare risk of blood clots with low platelets (thrombosis-thrombocytopenia syndrome, or TTS) after vaccination, and that other available COVID-19 vaccines are not associated with TTS. As of April 24, 2021, a total of 15 cases of TTS have been reported, including the original 6 reported cases. All 15 cases occurred in women between the ages of 18 and 59, with a median age of 37 years. Reports indicated symptom onset between 6 and 15 days after vaccination.
Pregnant women are at an increased risk for severe illness from COVID-19 when compared to those who are not pregnant. Vaccine safety is still being assessed specifically in pregnant women, but as of now, pregnancy is not considered a contraindication to vaccination against COVID-19. Women who are pregnant should consult with their physicians prior to vaccination. COVID-19 vaccines currently authorized are all non-replicating vaccines and do not reproduce in host cells. In general, non-replicating vaccines are believed to pose no risk to breastfeeding mothers or their infants.
Individuals with a history of severe allergic reactions, particularly those previously advised to carry an EpiPen, may be at risk for an anaphylactic reaction to the polyethylene glycol in the two currently approved mRNA vaccines. Facial swelling following vaccination with the mRNA vaccines has also been reported in several individuals previously treated with cosmetic dermal fillers. A history of severe allergic reaction to any of the ingredients in any of the 3 vaccines is a contraindication to use of that vaccine.
There are other vaccines available outside the United States, employing various technologies. The Russian-made Sputnik V vaccine (Gamaleya) relies on adenoviral vectors to generate the SARS-CoV-2 spike protein. A recombinant Ad26-based vaccine is given for the first dose and a recombinant Ad5 vaccine 21 days later for the boosting dose. This vaccine is already in use in Russia and being marketed in various parts of the world despite a paucity of published phase 3 clinical trial data. A Chinese vaccine, Sinovac, produced by the state-owned Sinopharm, uses inactivated SARS-CoV-2. This vaccine is approved for use in China, Bahrain, and United Arab Emirates. A vaccine developed in a collaboration between the University of Oxford and AstraZeneca, AZD1222, uses a modified chimpanzee adenovirus vector. Clinical trials for this vaccine were hampered by an error in manufacturing, which revealed serendipitously that the best results were obtained with half the intended dose given initially, followed by a full dose booster 28 days later.
The SARS-CoV-2 Delta variant has now been shown to cause infections even in previously vaccinated people, although the duration and severity of infection in those previously vaccinated are both considerably less than in unvaccinated people. In response, on August 13, 2021, the FDA amended the Pfizer-BioNTech and Moderna COVID-19 vaccine EUAs "to allow for the use of an additional dose in certain immunocompromised individuals, specifically, solid organ transplant recipients or those who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise." On August, 18, 2021, the FDA and CDC further extended these recommendations to non-immunocompromised individuals who are at least 8 months from their second vaccine shot with one 1 of these two 2 vaccines. No recommendations have been made yet for recipients of the JNJ vaccine, as use of this vaccine began later and data are still emerging on the risk of infection in those vaccinated.
Ophthalmology ties
There are now numerous published reports of patients with COVID-19 who either presented with conjunctivitis as a first or only sign of illness or developed conjunctivitis during hospitalization for severe COVID-19 disease. In many of these reports, SARS-CoV-2 mRNA was identified by RT-PCR on conjunctival swabs. In one study, infectious virus was cultured from an eye swab. ACE2 is the cellular receptor for SARS-CoV-2. Several studies have shown mRNA expression for ACE2 in human conjunctival epithelial cells. The expression of ACE2 protein has been shown in conjunctiva by immunohistochemistry, but whether conjunctival epithelium supports robust viral replication byb SARS-CoV-2 remains controversial. One study purported to show that SARS-CoV-2 could infect human conjunctival explants. It is possible that SARS-CoV-2 is transmitted to the conjunctiva by aerosol or through hand to eye contact, and then replicates locally. But it is also possible that patients exposed to airborne virus by the ocular route may develop COVID-19 when virus is carried to the nasopharynx by the natural drainage of aqueous tears.
- In a Journal of Medical Virology study of 30 patients hospitalized for COVID-19 in China, 1 had conjunctivitis. That patient—and not the other 29—had SARS-CoV-2 RNA in ocular secretions. This suggests that SARS-CoV-2 can cause conjunctivitis, and that infectious viral particles might be present in tears of COVID-19 patients with conjunctivitis. This observation was confirmed in a recent case report from China and another from Italy of patients with conjunctivitis in the setting of COVID-19.
- In a larger study published in the New England Journal of Medicine, researchers documented "conjunctival congestion" in 9 of 1,099 patients (0.8%) hospitalized with laboratory-confirmed COVID-19 from 30 hospitals across China. None of the patients were documented to have seen ophthalmologists, and tears were not sampled.
- In a retrospective case series published March 31 in JAMA Ophthalmology, 12 of 38 “clinically confirmed” hospitalized cases of COVID-19 in Hubei Province, China, had ocular "abnormalities," characterized most commonly as chemosis and/or secretions. Two patients had a positive conjunctival swab for SARS-CoV-2 RNA, one with signs of conjunctival hyperemia and the other with chemosis and epiphora. This paper was discussed in the New England Journal of Medicine Journal Watch, which stated that “a third [of patients in the JAMA Ophthalmology paper] had conjunctivitis.” We disagree with the latter characterization; chemosis in a critically ill patient most likely represents third-spacing or fluid overload, not conjunctivitis.
- Two preprint studies posted on MedRxiv also suggest a relatively low likelihood of infectious virus in tears of COVID-19 patients. In a study by Zhang et al. of 72 confirmed COVID-19 patients at Tongji Medical College, 2 patients had conjunctivitis. One of the 2 with conjunctivitis and none of the other 70 patients had SARS-CoV-2 RNA in their tears. In a paper by Zhou et al. of 63 confirmed COVID-19 patients in Wuhan, only 1 had conjunctivitis; that patient had a negative conjunctival swab for SARS-CoV-2 RNA. One other patient’s conjunctival swab was positive and 2 were “probable."
- In a case report published in the Annals of Internal Medicine, the first patient in Italy to be diagnosed with COVID-19 also had conjunctivitis in addition to fever and respiratory and gastrointestinal signs. RT-PCR on conjunctival swabs showed SARS-CoV-2 RNA from day 3 of hospitalization until day 21 (1 day after the conjunctivitis resolved), and again at day 27, at which point nasal swabs were negative. Infectious virus was isolated by cell culture from a sample taken on day 3.
- In a story from CNN, a registered nurse in a nursing home in Washington state with a large COVID-19 outbreak reported that red eye was a common early sign in elderly patients who then became sick with COVID-19.
- More recently, a study reported an association between complement activation disorders, including age-related macular degeneration, and severe COVID-19 disease.
Existing data suggest that conjunctivitis is an uncommon event as it relates to COVID-19. However, because conjunctivitis is a common condition overall, and patients with conjunctivitis frequently present to eye clinics or emergency departments, ophthalmologists may be the first providers to evaluate patients infected with COVID-19. Almost all reports of SARS-CoV-2 associated conjunctivitis described to date are of bilateral, mild, follicular conjunctivitis without corneal involvement. However, a patient with unilateral conjunctivitis and a coarse epithelial keratitis was found to be RT-PCR positive on a conjunctival swab. Another patient who developed COVID-19 while on a cruise ship developed a bilateral pseudomembranous conjunctivitis. A third patient hospitalized for COVID-19 in France developed a bilateral hemorrhagic, pseudomembranous conjunctivitis. Based on these studies, it is possible that the ocular secretions of a patient with COVID-19 associated conjunctivitis could contain infectious virus.
Therefore, protecting your mouth and nose by a surgical or an N95 mask, and eyes by goggles or shield, is recommended when caring for patients during the pandemic. In addition, slit-lamp breath shields are recommended for protecting both health care workers and patients from respiratory illness. Free slit-lamp breath shields are being offered by some manufacturers, including Topcon and Zeiss.
Resources
WHO
CDC
Relevant articles
EyeNet magazine
- Of Black Swans, TP, and Health Care, editorial by David W. Parke II, MD, CEO
- COVID-19 and Ophthalmology, editorial by David W. Parke II, MD, CEO
- Reflections During a Crisis, editorial by Ruth D. Williams, MD, Chief Medical Editor
- COVID-19 Moves Telemedicine to the Forefront
- COVID-19 Pandemic: Ocular Tumor Triage and Care
Journal studies and scientific articles
James Chodosh, MD, MPH, is the Edith Ives Cogan Professor of Ophthalmology at Harvard Medical School’s Department of Ophthalmology, a member of Harvard’s PhD program in virology and an expert in cornea and external disease working at the Massachusetts Eye and Ear.
Gary N. Holland, MD, is the Jack H. Skirball Professor of Ocular Inflammatory Diseases, director of the Ocular Inflammatory Disease Center, and a member of the cornea/external disease and uveitis divisions at the Jules Stein Eye Institute, David Geffen School of Medicine at UCLA.
Steven Yeh, MD, is the M. Louise Simpson Associate Professor of Ophthalmology, a member of the uveitis and vitreoretinal surgery divisions at the Emory Eye Center, and a faculty fellow of the Emory Global Health Institute.