Nearly three years after contracting a mild case of COVID-19, Cynthia Adinig still has problems with her throat. It often feels tight, she has trouble swallowing, and her voice is hoarse. The 37-year-old must meter her energy. She’s been hospitalized for malnutrition and dehydration because she couldn’t eat or drink enough to meet her body’s demands. The last two-and-a-half years of her life, Adinig said, have been “miserable.”
Explore This IssueMay 2023
Jackie Dishner is another of the 30 million or so Americans who are experiencing post-acute sequelae of SARS-CoV-2 infection, also called long COVID. The Arizona resident lost her sense of smell in June 2020 when she contracted COVID-19, and it’s still not back to normal. Her bowel movements smell like green pepper, she says. Tastes and smells are “muffled” and inconsistent. She tried olfactory training at home using an essential oils kit she purchased online but didn’t notice a significant improvement.
“Somehow, the virus changed how my brain speaks to my mouth and nose,” Dishner said. “I don’t think my sense of taste and smell will ever return to what they were before.”
Dishner is a writer and artist, not a physician or scientist. But her interpretation of her experience lines up with the latest scientific thinking. Long COVID otolaryngologic symptoms “largely seem to be related to some sort of neurological change,” said Diana Kirke, MBBS, MPhil, assistant professor in the department of otolaryngology–head and neck surgery at the Icahn School of Medicine at Mount Sinai in New York City.
Researchers also know that SARSCoV-2, the virus that causes COVID-19, attaches to epithelial cells surrounding olfactory neural cells, and rodent studies have shown that although damaged nasal epithelium can recover and create new neurons, the axons that find their way back to the olfactory bulb don’t target the same area as the original neurons. That disruption may explain why some people experience parosmia and anosmia after COVID-19 infection.
According to the American Academy of Physical Medicine and Rehabilitation and articles in the Journal of the American Medical Association and Nature Reviews Microbiology, at least 10% of individuals who had COVID-19 reported at least one persistent symptom up to six months after initial infection, with approximately 15% continuing to experience symptoms at one year (JAMA. 2022;328:1604–1615; Nat Rev Microbiol. 2023. doi:10.1038/s41579-022-00846-2). Other sources suggest that as many as 30% of COVID- 19 survivors may have long COVID, which the CDC broadly defines as “signs, symptoms, and conditions that continue or develop after initial COVID-19 or SARSCoV-2 infection … [which] are present four weeks or more after the initial phase of infection; may be multisystemic; and may present with a relapsing-remitting pattern and progression or worsening over time, with the possibility of severe and life-threatening events even months or years after infection.”
Otolaryngologists and primary care providers report seeing more patients with smell loss or a distorted sense of smell than ever before. Chronic fatigue and headaches are common; some patients also report tinnitus, hearing loss, “brain fog,” persistent cough, and heart palpitations.
“There are patients who come in after a year or two and ask, ‘How can you help me?’” said Alfred Marc Iloreta, Jr., MD, an assistant professor of otolaryngology and director of skull base surgery at The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai Hospital in New York City.
Otolaryngologists and researchers are still looking for answers to that question. Here is what’s currently known.
Anosmia and hyposmia appear more common in long COVID patients who also report headache, mental clouding, or both, according to a cross-sectional study of patients with olfactory dysfunction (Brain Sci. 2022;12:154). Cognitive impairment and headache were associated with more severe olfactory loss in the cohort of adult patients experiencing persistent smell alterations—a finding the researchers noted is “consistent with neuroinflammatory mechanisms mediating a variety of long COVID symptoms.”
A recent study in Communications Medicine implicated the coronavirus in hearing and balance disorders. It provided putative evidence that the SARS-CoV-2 virus can directly infect the inner ear. —Michael Brenner, MD
The Brain Sciences study and others report a higher rate of olfactory dysfunction in female COVID-19 survivors, though it isn’t yet entirely clear whether this difference has a biological underpinning or is perhaps related to sociological differences.
“We saw a significantly higher predominance of parosmia in female patients, but it may just be because male patients aren’t coming in when they experience a change in smell,” Dr. Iloreta said.
Although a 2021 study of 231 patients with COVID-related olfactory dysfunction found that “a majority of patients sought treatment” for olfactory challenges, anecdotal evidence suggests that many patients aren’t getting medical help for anosmia, parosmia, and phantosmia (Laryngoscope. 2022;132:633–639). Dishner told her primary care physician about her continued olfactory dysfunction, but “he did not have suggestions,” she said.
Patients and physicians alike have been frustrated by the lack of proven, well-tolerated, efficacious medical interventions for smell loss. Pre-pandemic, “the mainstays for treating post-viral smell loss were olfactory training and high-volume steroid irrigations,” said Zara M. Patel, MD, director of endoscopic skull base surgery and a professor of otolaryngology–head and neck surgery at Stanford University Medical Center in Stanford, Calif. Both interventions have since proven helpful for many patients with long COVID olfactory dysfunction.
A 2022 study from Turkey used a randomized controlled trial to test the effectiveness of modified olfactory training in treating COVID-19-related parosmia. One group received modified olfactory training; the others received no rehabilitation therapy. Olfactory improvements were noted in both groups at three, six, and nine months, with larger improvements observed in the treatment group (Laryngoscope. 2022;132:1433–1438).
“Doing olfactory training is worthwhile,” said Eric Holbrook, MD, MS, an associate professor at Harvard Medical School and division chief of rhinology at Massachusetts Eye and Ear in Boston, “but it’s unlikely to restore a sense of smell to a patient whose olfactory dysfunction is a complete loss and has persisted for a year or more. Still, it’s worth a try, as olfactory training is relatively cheap and generally well-tolerated.”
Some studies have suggested that combining olfactory training with budesonide irrigation may improve outcomes (Int Forum Allergy Rhino. 2018;8:977–981). It’s difficult to determine the real-world utility of steroid irrigation in treating long COIVD, however.
“It’s very difficult to conduct proper clinical trials for smell loss because there’s a natural regenerative process that occurs. To compare efficacy of placebo versus treatment, large numbers are needed,” said Dr. Holbrook, noting that most studies to date have been small. “I ask patients with smell loss to use budesonide irrigation only if I see evidence of inflammation in the nasal cavity and olfactory cleft. Otherwise, I have them concentrate on training,” he said.
Small studies also suggest that certain supplements—specifically, omega-3 fish oil and palmitoylethanolamide and luteolin (PEA-LUT)—may help patients regain their sense of smell. Early in the pandemic, Dr. Iloreta participated in a randomized controlled trial of omega-3 fatty acid supplementation for the treatment of COVID-19-related olfactory dysfunction (Trials. 2020;21:942). “We saw a trend toward improvement in the sense of smell in patients who took 2000 milligrams of omega-3 fish oil capsules daily for six weeks,” Dr. Iloreta said. “The findings weren’t statistically significant.”
A small German study, however, found that adding omega-3 supplementation to olfactory training resulted in improved olfactory scores in adult patients with post-viral olfactory dysfunction. Fifty-eight patients (25 men, 33 women) were included in the study, and more improvement in odor thresholds was noted in the group that received both olfactory training and omega-3 supplementation than in the group that underwent only olfactory training (Rhinology. 2022;60:139–144).
Another study compared the effectiveness of olfactory training plus daily oral ultramicronized PEA-LUT supplementation to olfactory training plus placebo and found improvements in olfactory discrimination and identification in 92% of the patients who received the supplement versus 42% of those who received olfactory training and placebo (Curr Neuropharmacol. 2022;20:2001–2012).
“Because supplements and smell retraining are relatively benign and fairly inexpensive with minimal to no side effects, I recommend the combination to a lot of my patients,” Dr. Iloreta said.
A “really exciting new breakthrough in treating long COVID” is platelet-rich plasma (PRP) injections, Dr. Patel said. Her team evaluated the efficacy of intranasal PRP injections to treat COVID-19-related olfactory dysfunction that had persisted at least six months and had not responded to olfactory training or steroid rinses. Enrolled patients received intranasal injections of either PRP or sterile saline into their olfactory clefts every two weeks for six weeks. Three months after the first injection, 57.1% of the PRP group showed clinically significant improvement, compared to just 8.3% of the placebo group. The PRP group also experienced a 3.67- point greater improvement in olfaction (Int Forum Allergy Rhinol. 2022. doi:10.1002/alr.23116).
“These patients had already tried and failed to improve with olfactory training and budesonide irrigations. So, this intervention isn’t simply just another option, but one that has proven efficacy even in the face of other known standard options failing,” Dr. Patel said. She has since offered PRP injections to all patients with smell loss and is “seeing some continued good results,” she said.
Although the CDC does not include tinnitus, hearing loss, or balance problems on its list of long COVID symptoms, which it states is “not a comprehensive list,” evidence suggesting that COVID-19 can cause tinnitus, hearing loss, and vertigo is “mounting,” said Michael Brenner, MD, associate professor in the department of otolaryngology–head and neck surgery at the University of Michigan in Ann Arbor.
“There’s a high likelihood that this virus is capable of causing hearing loss,” he said. “A recent study in Communications Medicine implicated the coronavirus in hearing and balance disorders. It provided putative evidence that the SARSCoV- 2 virus can directly infect the inner ear. The work showed that adult human inner ear tissue expresses the receptors and cofactors required for SARS-CoV-2 viral entry, including angiotensin-converting enzyme 2 (ACE2) receptor, the transmembrane protease serine 2 (TMPRSS2), and FURIN cofactors. In addition, explanted human vestibular tissue can be infected by SARS-CoV-2.”
A 2021 systematic review and meta-analysis published by Cambridge University Press found a 3.1% event rate of hearing loss, 4.5% rate of tinnitus, and 12.2% rate of hearing loss in patients who had COVID-19 (Can J Neurol Sci. 2022;49:184–195).
Kris Bordessa, a writer in Hawaii, developed tinnitus shortly after contracting a presumed case of COVID-19 in December 2021. It has not cleared up. “I’ve had occasional ringing in the ears before, but not this ongoing screaming tinnitus,” Bordessa said. Her doctor is quite sure that the tinnitus—and the occasional “full body buzzing” Bordessa experiences—is a result of COVID-19 infection, but has no solutions to offer.
Because supplements and smell retraining are relatively benign and fairly inexpensive with minimal to no side effects, I recommend the combination to a lot of my patients —Alfred Marc Iloreta Jr., MD
To date, no medical treatments have been found to be particularly efficacious in treating otologic symptoms of long COVID. A case study reported in the American Journal of Otolaryngology noted improved tinnitus after gabapentin treatment. The 49-year-old male patient developed new onset severe tinnitus and mild hearing loss after COVID-19 infection. Conservative treatment, including white noise masking, did not offer relief. The patient’s physician started him on gabapentin 300 mg daily; after two weeks, the dosage was increased to 300 mg twice per day. The patient’s tinnitus symptoms “significantly improved within two weeks” and continued to be tolerable at a onemonth follow-up (Am J Otolaryngol. 2022;43:103208). (Gabapentin has also been suggested as a treatment for persistent COVID-19-related olfactory dysfunction, and a randomized, double- blinded, placebo-controlled trial to assess the efficacy of oral gabapentin for post-COVID-19 olfactory dysfunction is currently enrolling patients (ClinicalTrials.gov Identifier: NCT05184192).)
Initially, the medical community assumed that COVID-19 patients who were intubated during their infection would be most likely to experience persistent laryngeal symptoms after recovery. But while it’s true that many individuals who were intubated or underwent a tracheotomy continue to have airway issues, vocal changes, or dysphagia, some patients with laryngeal symptoms—like Cynthia
Adinig—had only mild cases of COVID-19. Adinig wasn’t even hospitalized during the acute phase of her infection. Yet she still experiences throat tightness, difficulty swallowing, and vocal hoarseness. Other patients with long COVID report globus, a persistent or intermittent sensation of “something” stuck in the throat.
“What we think may be going on is laryngeal hypersensitivity,” Dr. Kirke said. Pre-COVID, she used larynx rehabilitative techniques to treat patients with laryngeal hypersensitivity, so she’s using the same techniques to treat long COVID patients with laryngeal symptoms. “Largely, it seems to be working,” she said.
Dr. Kirke is also conducting a histopathological study on autopsy specimens to better understand laryngeal sequelae of COVID-19. “We haven’t examined a lot of tracheas yet, but in the pilot study we’ve done, we’ve noted significant amounts of inflammation and loss of cilia in the airways,” she said. “COVID-19 tracheas also demonstrated increased intensity of ACE2 and TMPRSS2,” the receptors commonly upregulated in COVID-19. Dr. Kirke has already compared COVID-affected tracheas to non-COVID-affected tracheas, and eventually plans to compare the tracheas of intubated patients who had COVID-19 to the tracheas of intubated patients who did not have COVID-19. If significant differences are noted, they may suggest a novel pathology for COVID-19-related laryngeal symptoms.
Unfortunately, her research will take time, and patients continue to suffer while scientists and physicians work to understand long COVID. “I think what we need to do most is listen carefully to our patients,” Dr. Brenner said. “Some of the more nuanced aspects of long COVID still have not gotten the attention or recognition they deserve. We need to bring a tremendous amount of humility to our practices and listen to what our patients are describing and experiencing. The relative inattention to otolaryngologic manifestations of long COVID can lead to missed opportunities to provide symptomatic relief, as in the case of patients whose perception of malaise or fatigue is amplified by vestibular impairment.”
Jennifer Fink is a freelance medical writer based in Wisconsin.
An Olfactory Implant for Smell Loss?
Cochlear implants bypass damaged areas of the inner ear and deliver sound signals directly to the auditory nerve, allowing some individuals with severe hearing loss to perceive sound. Could a similar system be used to restore olfaction to individuals who have a lost or distorted sense of smell?
Dr. Holbrook thinks so. Each olfactory neuron has a receptor that has an affinity for a specific chemical. Because odors are complex, each odor stimulates a different collection of receptors. Olfactory sensory neurons expressing the same type of odorant receptor target specific glomeruli on the olfactory bulb, and research has confirmed that each glomerulus only contains one receptor type. Scientists working with mice have found that when the rodents are exposed to different odors, different glomeruli patterns are stimulated.
Theoretically, “if you could somehow figure out how to stimulate different patterns on the olfactory bulb, you may be able to bypass damaged nasal epithelium” to induce the perception of odors, Dr. Holbrook said. “You’d have an artificial stimulation but a real perception.”
Dr. Holbrook is currently working with Mark Richardson, MD, PhD, director of functional neurosurgery at Massachusetts General Hospital, to further explore the neuronal pathways of olfaction, and with James Schwob, MD, PhD, the George A. Bates Professor of Histology and professor of developmental, molecular, and chemical biology at Tufts University School of Medicine, on olfactory stem cell treatments for smell loss.