The Association of Anosmia With Various Comorbidities in COVID-19 Positive Patients

INTRODUCTION

Anosmia (loss of smell) emerged as a hallmark symptom during the COVID-19 pandemic, often serving as an early clinical indicator of SARS-CoV-2 infection in the absence of other nasal symptoms.^[1] According to retrospective observational studies conducted among patients diagnosed with COVID-19 by RT-PCR, cough, fever, generalised malaise, and myalgia have been established as the most common presenting symptoms of COVID-19.^[2] However, a positive history of anosmia was reported to be a significant symptom by several studies.^[1-4] As per the study conducted among the Indian population, the incidence of anosmia amongst COVID-19 positive patients was documented to be 14.8%.^[5]

However, the specific association between anosmia and common comorbidities, including diabetes mellitus, hypertension, asthma, etc., has received limited attention. These conditions are of particular interest, given their prevalence and potential influence on COVID-19 severity.

This study aims to explore the relationship between anosmia and these comorbidities in COVID-19 patients. Additionally, we examine whether anosmia correlates with disease progression in patients with these underlying conditions.

MATERIAL and METHODS

This retrospective observational study was done at Justice KS Hegde Charitable Hospital. IEC clearance was obtained from the Institutional Ethics Committee (INST.EC/EC/070/2020-21). Data was retrieved from the Medical Records Department, and 1100 patients with comorbidities and those who tested positive for COVID-19 by RT-PCR, from August 1, 2021 to September 30, 2021, were identified in the process, and their details were collected.

Patients who were known cases of anosmia due to previous head injuries or nasal pathologies, those who had already undergone tracheostomy or laryngectomies previously, those with a history of psychiatric disorders, and those who failed to respond to and did not give consent were excluded from the study.

Data collection: A total of 1100 patients with comorbidities and those who tested positive for COVID-19 using RT-PCR were identified, and their details were collected from the medical records department. All patients were contacted to participate in the study, but only 111 out of 1100 patients gave oral consent to participate in the study. Patients who did not give the consent were excluded from the study. These 111 patients, who provided consent to participate in the study, underwent a telephonic interview using a predesigned, structured questionnaire to collect data on demographics, symptomatology, comorbidities, and disease progression. Efforts were made to minimise interviewer bias through standardised training of interviewers.

However, the limitations of telephonic data collection, including recall bias, were acknowledged

Statistical analysis: Collected data were tabulated using MS Excel and analysed using statistical software (SPSS Windows version 20.0). The chi-squared test was used to investigate the association between anosmia due to COVID-19 and various comorbidities, with a p-value of less than 0.05 considered statistically significant.

RESULTS

Among 111 patients, 19 had COVID-19, which was included in the study. The study population consisted of 60.36% males (n = 67) and 39.63% females (n = 44) [Table 1]. Out of these 111 patients, 65.8% (n = 73) reported anosmia.

In this study group, 17% (n=19) patients were known cases of diabetes, 16% (n=18) were known cases of hypertension, 8% (n=9) were known cases of asthma, 3.6% ( n=4) were known cases of heart disease, 1.8% (n=2) were known cases of kidney disease, 0.9% (n=1) had an episode of stroke previously, and 0.9% (n=1) had episodes of seizures previously [Table 1].

Of the 19 diabetic patients, 73.7% of patients experienced anosmia (n=14). Using the chi-square test to investigate the correlation between anosmia in COVID-19 patients and diabetes, the p-value of 0.424 indicates that the correlation is statistically insignificant.

Of the 19 diabetic patients, 73.7% of patients experienced anosmia (n=14). Using the Chi-square test to find the correlation between anosmia of COVID-19 and diabetes, the p-value was 0.424, indicating that it is statistically insignificant.

Of the 18 hypertensive patients, 72.2% experienced anosmia (n=13). Using the Chi-square test find the correlation between anosmia of COVID-19 and diabetes, the p-value was 0.528, indicating that it is statistically insignificant.

Similarly, using the Chi-square test while considering other comorbidities, the p-value was noted to be more than 0.05, indicating that there is no correlation between anosmia and comorbidities

Of the 9 asthmatic patients included in the study, anosmia was experienced by all 9 patients (100%). Using the chi-squared test to investigate the correlation between anosmia in COVID-19 patients and asthma, the p-value was found to be 0.059, indicating a borderline significant correlation [Table 2].

DISCUSSION

The Delta variant of SARS-CoV-2 was first identified in India in October 2020. Due to its increased transmissibility, severity of symptoms, and reduced effectiveness of previously administered treatment modalities,^[6,7] it led to a second wave of the COVID-19 pandemic in the country, resulting in mass-scale morbidity and mortality.^[8] The symptomatology of COVID-19 can be classified into two types: mild, which is predominantly found among the younger age group, affecting females more often than males, and the second type, moderate to severe, which is more commonly seen among the elderly.^[9,10] Patients with known comorbidities are associated with an increased risk of complications associated with COVID-19. Hence, this study was conducted to investigate the correlation between the persistence of COVID-19-related anosmia in patients with known comorbidities who tested positive for COVID-19 by RT-PCR.

During this second wave, anosmia was found to be a commonly occurring symptom, with an incidence rate ranging between 44 and 50%, and was later identified to have a significant association with SARS-CoV-2.^[11] Worldwide, the prevalence of anosmia among patients who tested positive for COVID-19 was found to be 44.1%.^[12] Multiple studies concluded that COVID-19 infection should be suspected in any degree of olfactory impairment, with or without altered taste sensitivity.^[12-14] Sehanobish et al. concluded that anosmia is seen more commonly in younger adults.^[10] At the same time, Yan et al. stated that the patients had a milder presentation of the disease.^[15]

Many theories have been hypothesised to contribute to the mechanism of development of anosmia due to SARS-CoV-2, which includes the role of apoptosis and that of TNF and interleukin 1, which act as toxic inflammatory markers; involvement of the hypothalamus; and olfactory pathway damage caused by the causative virus.^[16] Olfactory receptor cells have a lifespan of approximately 40 to 120 days, after which they undergo apoptosis normally. Additionally, these cells possess the property of self-renewal.^[16] Hence, in the case of controlled apoptosis, patients do not typically notice a significant change in their olfactory capability. However, in cases of large-scale apoptosis mediated by cytokines and immune cells, patients may experience anosmia and present to the outpatient department with a sudden loss of their sense of smell.^[16] It is also noted that patients diagnosed with COVID-19 exhibit increased levels of inflammatory cytokines, such as TNF and Interleukin 1, in the nasal mucosa. These cytokines can cause extensive destruction of the olfactory neuroepithelium, resulting in significant anosmia.^[16] It is believed that the virus enters the CNS through the olfactory bulb and spreads to various areas of the brain, including the hippocampus, where it undergoes trans-neuronal spread followed by transmission to the brainstem, thereby causing inflammation or death of the neurons.^[16,17] Thus, the incidence of anosmia must be seen as an indicator in the early stages of CNS involvement.^[17] In clinical practice, it has been observed that Anosmia in COVID is transient and linked with better outcomes and early recovery.^[18]

While anosmia is seen to have a favourable outcome in patients suffering from an active infection of COVID-19, the presence of comorbidities, especially those involving the cardiovascular system and diabetes is seen to increase the severity of the disease progression.^[19]

A meta-analysis conducted by Wang et al. studied regarding the risk of exacerbation of COVID-19 due to comorbidities, and it was noted that those suffering from diabetes mellitus, hypertension, COPD, and other cardiovascular and cerebrovascular diseases had a significantly higher chance of experiencing a worsening of symptoms, a poor recovery rates, and increased mortality.^[20]

This is the first type of study that was conducted to analyse the association and severity of anosmia of COVID-19 with the presence of various comorbidities, and according to the results concluded in our study only those who have asthma had an increased risk of experiencing anosmia.

Asthma is characterised by chronic inflammation of the airways, which leads to increased dysfunction of the olfactory mechanism in these patients, especially during viral infections. Angiotensin Converting enzyme 2 receptors are found in abundance in various cells of the human body- most importantly in the epithelium of the lower respiratory tract, tissue parenchyma of the lungs, endothelium of blood vessels, renal tubules, and cells of the intestine. It is postulated that the SARS-CoV-2 virus has the peculiar feature of neuro-invasive property that leads to exacerbation of lower respiratory disease, such as asthma, and can even lead to respiratory failure in patients who test positive for COVID-19.^[21]

COVID-19 causes an increased production of cytokines, leading to inflammation of the nasal passages and olfactory epithelium, which in turn can result in anosmia. Asthmatic patients have underlying inflammation of their airways, making them more susceptible to the action of cytokines, and hence there is an increased chance of anosmia among asthmatic patients

However, as COVID-19 is a newly emerging viral infection, this suggests that comorbidities may not be responsible for the progression or increase in severity of COVID-19-relatedCOVID-19 related anosmia.

Limitations of our study include a small sample size and difficulty in generalising to the general population. Information from patients was collected using telephonic interviews, which may introduce recall bias.

But as COVID-19 is a new emerging viral infection, this suggests that comorbidities may not be responsible for progression or an increase in severity of COVID-19-related anosmia.

CONCLUSION

This study shows that there is a higher prevalence of anosmia in COVID-19 among asthmatic patients. However, it has been noted that there is no correlation between anosmia and progression of disease among patients with known comorbidities such as diabetes mellitus, hypertension, or asthma. Future studies are needed to investigate the mechanisms underlying the association between anosmia in COVID-19 patients and comorbidities, as well as their implications for patient care and management.