Introduction
Anosmia, the loss or change in the sense of smell [1], is a significant health issue with various causes and considerable impact on patients’ lives. It is a well-established consequence of head injury [2], affecting a substantial percentage of individuals who experience traumatic brain injury (TBI) [3]. Reports suggest that approximately 20%–68% of TBI patients exhibit trauma-associated olfactory deficits (OD) [3]. Even patients with mild TBI can experience persistent OD, with prevalence reported in up to 20% of cases [4].
Beyond TBI, other causes of acquired smell loss include upper respiratory infections (such as the common cold or flu) [5], and notably, it is a common symptom of COVID-19, experienced by almost 53% of those affected [1]. Upper airway inflammation, including rhinitis, rhinosinusitis, and nasal polyps, is also a frequent cause of gradual olfactory dysfunction. Neurodegenerative diseases, intracranial/sinonasal tumors, certain drugs, exposure to toxic substances, irradiation, or iatrogenic factors can also lead to anosmia [5].
Globally, a large number of people are affected; recent reports suggest approximately 20.5 million adults over forty in the United States suffer from olfactory dysfunction [6]. Head trauma accounts for about 5%–17% of acquired chemosensory dysfunction cases [7-9].
The significance of olfactory dysfunction is often underestimated, but it has a significant negative impact on patients’ quality of life and ability to accomplish daily activities [2,6]. OD can compromise not only the quality of life but also cognitive and neuropsychiatric functions [6], and can lead to issues like food poisoning, a reduction in appetite, malnutrition, and reduced immunity. Furthermore, olfactory function plays a crucial role in safety. Patients with olfactory impairment are at increased risk for personal injury, such as being unable to detect gas leaks, smoke, or spoiled foods. Studies show that a high percentage of patients with olfactory impairment have experienced hazardous events attributable to their loss of smell. Anosmia has also been associated with diminished satisfaction with life and an increased likelihood of depression [10,11].
Interestingly, anosmia can sometimes serve as an early clinical sign, potentially heralding the progression to dementia in TBI survivors, or serving as an early biomarker for the diagnosis and progression of neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD) [12,13].
The diagnosis of anosmia requires objective olfactory testing, as self-assessment is often unreliable. Management often includes counseling regarding compensatory strategies to avoid safety risks and maximize quality of life [14].
1. Mechanisms of olfactory dysfunction
Post-traumatic OD can be classified as either conductive or neurosensory, depending on the injury location. Conductive deficits occur when odorants cannot reach the olfactory neuroepithelium, often due to physical obstruction like nasal bone fractures, septal deviation, mucosal edema, or hematoma [15]. Neurosensory deficits involve direct damage to the olfactory neuroepithelium or central olfactory pathways, including injury to the olfactory bulb. This can result from shearing of fibers at the cribriform plate or injury to the olfactory bulb itself. The prognosis for neurosensory deficits is generally poor, with many patients not recovering [16,17].
Beyond Physical Damage, Inflammation Plays a Significant Role in Olfactory Dysfunction Associated with Various Conditions
1. Post-traumatic anosmia
Trauma-associated OD are common in TBI patients. Neuroanatomical and kinetic factors make the central olfactory structures, including the olfactory bulb, highly vulnerable to TBI-related damage [13]. Damage to the central components of olfactory pathways, such as the olfactory bulb, can cause post-traumatic olfactory dysfunction [18]. This can result from mechanisms like the shearing or stretching of olfactory nerve fibers at the cribriform plate, which directly affects the connection to the olfactory bulb, or from focal contusion or hemorrhage within the olfactory bulb itself [18]. Neurosensory deficits, in general, involve direct damage to the olfactory neuroepithelium or central olfactory pathways, including the olfactory bulb [19]. The prognosis for neurosensory deficits is often poor, with many patients not recovering. Experimental TBI studies in mice highlight significant inflammatory changes and neuronal dysfunction in the olfactory bulb. TBI in mice causes a rapid and sustained inflammatory response in the olfactory bulb, including elevated levels of pro-inflammatory cytokines, increased numbers of microglia and infiltrating by myeloid cells, and increased interleukin (IL)-1β and IL-6 production [20,21]. This neuroinflammation is accompanied by increased production of reactive oxygen species and upregulation of microglia/macrophages [22,23]. These changes are linked to neuronal dysfunction in the olfactory bulb, including early hyperexcitation and later hypo-neuronal activity, and contribute to OD [21].
2. Chronic rhinosinusitis
Historically, OD in patients with sinusitis were primarily attributed to mechanical obstruction caused by nasal obstruction, respiratory mucosal edema, and decreased airflow to the olfactory cleft [19]. The assumption was that the olfactory mucosa remained histologically normal despite the aggressive inflammatory process in the respiratory regions of the nose. This view considered anosmia secondary to chronic rhinosinusitis (CRS) mainly as a “transport” disorder, where odorant molecules simply couldn’t reach the intact olfactory mucosa [24]. However, clinical studies have shown little correlation between nasal resistance and the degree of olfactory dysfunction, challenging the idea that obstruction is the sole cause [25]. Furthermore, surgical treatment for sinusitis and anosmia often has only limited effects on olfactory sensation despite successful resolution of other symptoms.
More recent studies, particularly a histological examination of olfactory biopsies from patients with chronic sinus disease, provide direct evidence for pathological changes within the olfactory mucosa itself [24]. This indicates that the pathological processes observed in the respiratory regions of the nose can also involve the olfactory mucosa. This suggests that olfactory loss with sinonasal inflammatory disease is a more complex process involving both transport and sensory pathology. Anosmia secondary to sinonasal disease involves direct effects on the olfactory mucosa (sensory disorder) in addition to any gross changes in airflow (transport disorder) [24]. Studies show inflammatory changes in the olfactory mucosa of patients with CRS, including infiltration of lymphocytes, macrophages, and eosinophils [26]. Moderate or severe inflammatory changes in the olfactory mucosa were observed in patients with decreased olfactory function [24]. This inflammation is likely to inhibit olfactory neurogenesis [27].
3. COVID-19
COVID-19, caused by the SARS-CoV-2 virus, is a global pandemic that originated in Wuhan, China, in December 2019 [28]. It is a positive-sense single- stranded RNA virus [29]. One of the most common symptoms reported by patients with COVID-19 infection is olfactory dysfunction or anosmia [30]. The SARS-CoV-2 virus utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and the priming protease (transmembrane protease, serine 2) TMPRSS2 for entry into host cells. ACE2 receptors are found in various organs, including the respiratory cells and the central nervous system (CNS) [31]. The epithelium of the respiratory system is considered the primary site for initial coronavirus attachment [32]. Several mechanisms have been proposed to explain anosmia in COVID-19 patients:
1) Olfactory cleft obstruction
Nasal mucosal swelling and secretions can physically obstruct the olfactory cleft, preventing odor molecules from reaching the olfactory epithelium (OE) [33]. This is a “conductive” loss. However, anosmia can occur suddenly without nasal discharge or congestion, suggesting other mechanisms are involved. High expression of ACE2 receptors has been detected in the olfactory cleft region, and anosmic COVID-19 patients have shown significantly greater volume and area in the olfactory cleft compared to healthy controls [34].
2) Local inflammation in the olfactory epithelium
High levels of ACE2 receptor expression are found on OE cells, particularly sustentacular cells [34,35]. The binding of the virus to these cells triggers the release of cytokines, promoting inflammation in the OE. Increased levels of pro-inflammatory cytokines like tumor necrosis factor (TNF)-α and IL-1β have been reported in OE biopsies from COVID-19 patients [36]. This inflammation in the OE is considered a probable mechanism for the quick recovery observed in many COVID-19-related anosmia cases. Since ACE2 is highly expressed in non-neuronal supporting cells rather than directly on olfactory neurons (ONs), the virus may primarily target these supporting cells, indirectly disrupting ON function.
3) Role of interleukins
IL-6 is thought to play a significant role in anosmia, potentially activating apoptotic pathways or directly inhibiting the sense of smell [37]. Studies have found significant correlations between decreased levels of IL-6 and the time taken for recovery from anosmia in COVID-19 [38]. Viral infections, including influenza, have been associated with increased levels of IL-6, IL-12, IL-15, and TNF-α [39].
4) Changes in olfactory cilia
Olfactory sensory neurons (OSNs) have cilia with receptors that detect odors. Viral infections, including COVID-19, may disrupt the structure and function of these cilia [40]. COVID-19 antigens have been found in ciliated nasal epithelial cells, and transmission electron microscopy showed absorption sites on cilia for viral entry. The Nsp13 protein of SARS-CoV-2 can bind to the centrosome of cilia, potentially disrupting their structure and leading to deciliation [41].
5) Effect on olfactory bulbs
Some studies have investigated the impact of COVID-19 infection on the olfactory bulb as a potential mechanism for anosmia. It is hypothesized that the virus can enter the CNS by traveling along OSNs and crossing the cribriform plate to reach the olfactory bulbs [42]. MRI studies have identified instances of olfactory bulb injury secondary to COVID-19 infection [43].
6) Damage to olfactory stem cells
In cases of persistent anosmia lasting for more than two months, damage to olfactory stem cells is considered a likely cause, delaying the regenerative capacity of the OE. Inflammation in the olfactory system is a critical factor for anosmia, and stem cell apoptosis can occur at sites of inflammation [44].
7) Age
Anosmia occurs less frequently at the extreme ends of age ranges and is most common in the 40- to 50-year age bracket. This difference might be related to age-related changes in sustentacular cells (which have high ACE2 expression) in older individuals and varying levels of nasal ACE2 gene expression with age [47].
8) Disease severity
Patients with moderate to severe COVID-19 infections tend to report less olfactory involvement compared to those with mild infections. It is suggested that patients with mild disease might have a stronger local immune response in the nasal and olfactory mucosa and bulb, leading to a more pronounced otolaryngological symptom pattern. The upper airway has higher ACE2 expression than the lower airway and is thought to be the initial site of infection [48].
9) Sex
Epidemiological data indicates that females are more likely to experience COVID-19-related olfactory dysfunction, although they are less likely to have severe infections. This difference may be linked to variations in ACE2 expression, innate immunity, steroid hormones, and factors related to sex chromosomes. The ACE2 gene is located on the X chromosome. Estrogen in females might reduce ACE2 expression compared to males, potentially resulting in lower viral load and reduced risk of severe disease. Women’s potentially stronger immune responses might lead to a more significant local inflammatory reaction in the OE, contributing to olfactory dysfunction [49].
4. Neurodegenerative diseases
Olfactory dysfunction is an early symptom of many neurodegenerative diseases, particularly PD and AD, and may serve as an early biomarker [50]. In TBI survivors, OD may be an early sign of progression to dementia. The olfactory bulb is intricately connected to downstream olfactory centers, such as the piriform cortex and hippocampus. The hippocampus and entorhinal cortex are brain regions affected in the very early stages of AD [51]. The entorhinal cortex directly receives olfactory information and is part of a connection loop with the hippocampus and cortex, which is a main hub of network dysfunction in AD [52]. Studies in older adults free from dementia found that impaired olfactory identification was associated with lower volumes of the hippocampus and entorhinal cortex [53]. Post-mortem studies linked impaired odor identification with increased density of neurofibrillary tangles in the hippocampus and entorhinal cortex [53]. Olfactory identification impairment was also correlated with higher plasma total tau (t-tau) and neurofilament light chain concentrations, but not with plasma amyloid-beta [54]. This suggests that impaired odor identification may signify neurodegenerative processes and tau pathology in the brain, with negligible effects from amyloid pathology among dementia-free older adults [54]. Furthermore, impaired odor identification was associated with higher volumes of white matter hyperintensities (WMH) and periventricular WMH [55], markers of cerebral microvascular lesions [56]. These findings suggest that olfactory impairment and cognitive impairment may share common neuropathological bases related to neurodegeneration and vascular brain pathology.
Conclusion
Anosmia is a complex clinical symptom with diverse etiologies, including TBI, CRS, viral infections such as COVID-19, and neurodegenerative diseases. Despite differences in initial triggers, these conditions converge on shared neurophysiological mechanisms, particularly neuroinflammation, disruption of olfactory epithelial and bulb integrity, impaired neuronal regeneration, and central olfactory network dysfunction. Inflammatory cytokines, oxidative stress, and structural damage to olfactory pathways are recurring features that underlie olfactory dysfunction across these diseases. Importantly, anosmia not only affects quality of life and safety but may also serve as an early biomarker of neurodegeneration. Understanding these overlapping mechanisms enhances our ability to develop targeted diagnostic tools and therapeutic strategies, emphasizing the need for interdisciplinary research bridging otolaryngology, neurology, and immunology.
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