The researchers found that nerve fiber loss and an increase in dendritic or key immune cells on the cornea may help identify long COVID.
Gulfidan Bitirgen, MD, of the Department of Ophthalmology of the Necmettin Erbakan University Meram Medical Faculty Hospital in Konya, Turkey, and colleagues found the link was particularly strong in the study of 40 patients when patients had lost a sense of smell or taste or had dizziness, numbness, or neuropathic pain after they contracted COVID-19.
"The fact that physicians will be able to objectively identify patients with Long COVID will enable us to identify those with a definite problem and also paves the way towards assessing the effect of therapies which may help nerve repair," senior author Rayaz A. Malik, , PhD, with the Department of Medicine, Weill Cornell Medicine Qatar in Doha, Qatar, says.
At least 1 in 10 people who become infected with COVID will develop long COVID, what the researchers in this paper defined as having symptoms that last more than 4 weeks after the acute phase has passed. The symptoms aren't readily explained by an alternative diagnosis.
Previous researchers had suggested nerve fiber damage may play a role in long COVID development.
Bitirgen's team investigated that hypothesis with a real-time, noninvasive, high-resolution imaging laser technique known as corneal confocal microscopy (CCM) to look for nerve damage in the cornea and the density of dendritic cells. These cells have a key role in the primary immune system response.
"COVID has affected so many parts of the body, it's no surprise that it affects the eye,” says Angie Wen, MD, assistant professor of ophthalmology, cornea, cataract and refractive surgery at New York Eye & Ear Infirmary of Mount Sinai in New York City.
Checking the cornea through CCM could serve as another piece of information to support a long COVID diagnosis for people who have had, for instance, pulmonary symptoms and unexplained neuropathic pain.
"But it seems we're unable to draw that conclusion yet from these results," she says.
Malik says, "Our technique is not specific for long COVID, as it detects nerve fiber damage and there are potentially many causes for this. However, if other causes of nerve damage are excluded then we can be fairly confident that it is due to Long COVID.
"Also, I think CCM is particularly useful in a patient with Long COVID symptoms who does not have corneal nerve damage, where we can reassure them that there is no serious underlying problem."
As far as access to the CCM technology, Malik says most large ophthalmic centers worldwide will have the equipment.
"Since we pioneered this technique in diabetic neuropathy over 20 years ago interest has grown exponentially and there are over 300 centers using this technique to assess a range of peripheral neuropathies including diabetic neuropathy, inflammatory neuropathy, HIV neuropathy, chemotherapy-induced neuropathy and central neurodegenerative diseases like multiple sclerosis, Parkinson's and dementia," he says.
However, Wen notes that outside large academic centers, the equipment is not generally readily available and that probably limits its use as a diagnostic tool, "but it is an avenue for research."
More Work Needed
Limitations of the study include the small number of participants and the single-site scope as well a use of a questionnaire to define the severity of neurological symptoms rather than more objective measures.
"Further studies of larger cohorts of patients using additional measures of neuropathy and CCM are required," the authors wrote.
Participants in the study had recovered from confirmed COVID-19 between 1 and 6 months earlier. They completed a 28-item National Institute of Health and Clinical Excellence (NICE) questionnaire to find out if they had symptoms consistent with long COVID.
The questionnaire responses that suggested long COVID correlated strongly with corneal nerve damage.
Neurological symptoms were present at 4 and 12 weeks in 22 out of 40 (55%) and 13 out of 29 (45%) patients, respectively.
Participants' corneas were then scanned using CCM to look for small nerve fiber damage and the density of dendritic cells. These cells have a key role in the primary immune system response by capturing and presenting antigens from invading organisms.
The corneal scans were compared with those of 30 healthy people who hadn't had COVID-19 infection.
The scans indicated that patients with neurological symptoms 4 weeks after they had recovered from acute COVID-19 had greater corneal nerve fiber damage and loss, with higher numbers of dendritic cells, than those who hadn't had COVID-19 infection.
Those without neurological symptoms had comparable numbers of corneal nerve fibers as those who hadn't been infected with COVID-19, but more dendritic cells.
"To the best of our knowledge, this is the first study reporting corneal nerve loss and an increase in [dendritic cell] density in patients who have recovered from COVID-19, especially in subjects with persisting symptoms consistent with long COVID," the authors said.