A decline or loss of capacity to smell is known as olfactory dysfunction or anosmia. It has a significant impact on a person’s quality of life and safety due to the inability to detect warning aromas from food and the surroundings, limits eating due to diminished hunger, reduces social engagement, and is linked to apathy and depression.^1,2 Common causes of anosmia are chronic rhinosinusitis, neurodegenerative disease, aging, and viral infection (Fig. 1). Anosmia caused by chronic rhinosinusitis are induced by inflammatory products that damage olfactory receptors, preventing the transmission of synaptic impulses caused by odorants to cilia receptors. Anosmia in neurological diseases such as Parkinson’s or Alzheimer’s disease is caused by damage to the anterior olfactory nucleus in the brain, whereas anosmia by post-infectious, post-traumatic, or post-surgical caused damage to the olfactory epithelium.³ It is also one of the Coronavirus Disease 19 (COVID-19) side effects that has affected millions of people, drawing more attention to this illness these days.

Figure 1. Photobiomodulation is an emerging therapy for the treatment of olfactory dysfunction.

The pathogenesis of anosmia caused by COVID-19 is still unknown; however, possible mechanisms are olfactory cleft obstruction, local inflammation of the olfactory epithelium, early apoptosis of olfactory cells, changes in olfactory cilia and odor transmission, damage to microglial cells, effect on olfactory bulbs, epithelial olfactory injury, and damage to olfactory neurons and stem cells via angiotensin-converting enzyme 2, the functional receptor for the COVID-19 virus.^4-7

There is currently a high need for an alternative treatment strategy for anosmia caused by COVID-19 due to the limited options for people severely affected by the virus who have comorbidities such as cardiovascular disease, metabolic conditions, diabetes, and chronic lung disease.⁸ The treatment of COVID-19-related olfactory dysfunction differs greatly. No specific treatment is required for cases that improve spontaneously; however, if the impairment lasts longer than two weeks, some therapeutic modality should be considered.⁹

Olfactory dysfunction can be caused by a variety of factors, and determining the etiology is critical for effective treatment. There are several treatment options on the market to help alleviate and treat olfactory dysfunction. One of the treatments available is topical corticosteroid, which could be used as a monotherapy or adjunct treatment to treat olfactory loss irrespective of the etiology.^10-12 In contrast, systemic corticosteroids reduce inflammatory mediators and can influence gene expression.^13,14 However, due to the possibility of immunosuppression, it is not recommended in mild to moderate COVID-19 cases.^13,15 Intranasal calcium buffers, on the other hand, are buffers containing calcium ions that inhibit olfactory signaling. However, the effects of these buffers are transient and short-lived.¹⁶ Other treatments include alpha-lipoic acid, vitamin A, omega-3 fatty acids, and intranasal insulin therapy for their neuroregenerative and anti-oxidant properties. Results vary but have not been tested in larger trials.^17-19

Photobiomodulation (PBM), also known as low-level laser (light) therapy, is irradiating tissue using red or near-infrared (NIR) light (600-1,100 nm) from low-powered lasers or light-emitting diodes to modulate cellular function for tissue repair and healing. The photoreceptor cytochrome c oxidase in the mitochondria absorbs photons, which causes inhibitory nitric oxide (NO) to dissociate from the enzyme, resulting in an increase in electron transport, mitochondrial membrane potential, adenosine triphosphate synthesis, and reactive oxygen species (ROS).²⁰ Increased ROS activates different signaling pathways such as cyclic adenosine monophosphate, NO and Ca²⁺ that leads to activation of transcription factors and increase in gene expression related to protein synthesis, cell migration and proliferation, anti-inflammatory signaling, anti-apoptotic proteins, antioxidant enzymes.²¹ Because light may permeate through skin and surrounding tissues to reach the underlying target tissue, it is often non-invasive and has a wide range of clinical application. PBM is commonly used in wound healing because it speeds up the healing process by releasing and producing NO, which regulates the growth factors needed for wound healing.^22-25 PBM also used in inflammation reduction as it can decreased chemical inflammatory mediators, such as prostaglandin E2, leucocytes, and tumor necrosis factor-α (TNF-α).^26-28 Furthermore, PBM affects inflammation by regulating pro-inflammatory cytokines like interleukin (IL)-1, IL-6, IL-8, and TNF-α while increasing IL-10, an anti-inflammatory cytokine.²⁹ Neurological illnesses, ischemic stroke, and peripheral damage have all been demonstrated to benefit from PBM.^30-35 It improves memory, mood, and cognitive function by increasing regional cerebral blood flow and tissue oxygenation.^33,36

PBM is an emerging alternative treatment for anosmia although, it has been around for a long time to be safe, effective and non-invasive treatment for inflammation, wound and cellular healing as it promotes tissue repair and reduce inflammation and pain.^23,29,37,38 PBM efficiently elevates NO by increasing inducible nitric oxide synthase production, which is important for the immunological response of the host and is induced in the case of pathogen-caused inflammation or infection.^39,40 NO can also interact with reactive oxygen and nitrogen intermediates to generate a variety of antimicrobial molecular species, including COVID-19, which can disrupt RNA replication.^41,42 Furthermore, NO enhances blood flow to tissues, resulting in an increase in oxygen, which facilitates the delivery of activated immune cells to the inflamed region.^43-45 PBM contains antiviral and anti-inflammatory properties that could give an alternative treatment for COVID-19-infected patients with compromised immune systems.

Despite the therapeutic benefits of PBM in the treatment of wide variety of diseases, only two studies on the use of PBM to treat olfactory dysfunction in COVID-19 patients have been published, leaving information on the treatment of anosmia caused by COVID-19 limited.

de Souza et al.⁴⁶ described a female patient infected with COVID-19 who developed ageusia and anosmia during the infection. To treat the patient’s anosmia and ageusia, ten sessions of PBM therapy were administered. For the treatment of anosmia, the patient received intranasal PBM at a wavelength of 808 nm for 5 minutes with a total energy of 30 J. The treatment of ageusia was performed with a total energy of 72 J using 680 nm and 808 nm applied for 2 minutes on the back of the tongue and the skin surface of the cheeks with the mouth partially open to permit the light to reach the sides of the tongues and the inner mucosa of the cheeks. The patient’s sense of smell and taste improved with each session, and by the tenth, she assessed her taste and smell as a ten, indicating that her olfactory and gustatory abilities were normal.

Soares et al.⁴⁷ conducted a multicenter case series using intranasal PBM therapy in COVID-19-related olfactory dysfunction in Brazil. The intranasal PBM lasted 3 minutes and used a 660 nm wavelength with a total energy of 18 J. Intranasal PBM protocols with varying laser session and time intervals were used on 14 patients divided into three groups. The olfaction of the patients was assessed using a visual analog scale ranging from 0 (normal smell) to 10 (complete absence of smell or anosmia). Following the PBM session, all patients reported improved olfaction (Table 1).

Table 1 . Clinical studies of photobiomodulation effects on anosmia caused by COVID-19

Case	Treatment parameters	Target	Results	Reference
Anosmia	Laser (InGaAlP, 660 nm, 18 J, 3 min), 10 sessions, 2x/week and with a 48-hr interval, 5 sessions, 2x/week and with a 48-hr interval, 10 sessions, with a 24-hr interval	Intranasal	Although each patient's findings varied, the majority claimed enhanced olfaction after completing the laser session	Soares et al., 202147
Anosmia and ageusia	Laser (GaAlAs & InGaAlP, 808 nm, 30 J, 5 min)	Intranasal, back of the tongue and cheek	Every session improved smell and taste function, which returned to normal after 10 sessions	de Souza et al., 202246

InGaAlP, aluminium gallium indium phosphide; GaAlAs, gallium aluminium arsenide.

The use of red or NIR light to treat anosmia caused by a viral infection yielded promising results. All patients who received PBM therapy had reversed olfaction after the sessions were completed, and no adverse side effects were reported. Although the effects of PBM therapy on olfactory dysfunction caused by viral infection have been studied, a larger sample size is required to determine and establish its efficacy.

None.

No potential conflict of interest relevant to this article was reported.