Smell Identification Test (SIT) for Early Diagnosis of COVID-19: Demographic and Symptoms During The First Three Pandemic Waves in Iran

Taherkhani, Safa; Abdollahi Boraei, Seyyed Behnam; Erfanian, Reza; Firoozifar, MohammadReza; Hosseinzadeh Otaghvari, Farnaz; Atashian, Sarvenaz; Zabihidan, Mohammadsadegh

doi:10.30699/ijmm.18.1.57

year 18, Issue 1 (January - February 2024) Iran J Med Microbiol 2024, 18(1): 57-65 | Back to browse issues page

‎ 10.30699/ijmm.18.1.57

Mendeley

Zotero

RefWorks

Taherkhani S, Abdollahi Boraei S B, Erfanian R, Firoozifar M, Hosseinzadeh Otaghvari F, Atashian S et al . Smell Identification Test (SIT) for Early Diagnosis of COVID-19: Demographic and Symptoms During The First Three Pandemic Waves in Iran. Iran J Med Microbiol 2024; 18 (1) :57-65
URL: http://ijmm.ir/article-1-2109-en.html

Smell Identification Test (SIT) for Early Diagnosis of COVID-19: Demographic and Symptoms During The First Three Pandemic Waves in Iran

Safa Taherkhani¹

, Seyyed Behnam Abdollahi Boraei²

, Reza Erfanian³

, MohammadReza Firoozifar³

, Farnaz Hosseinzadeh Otaghvari⁴

, Sarvenaz Atashian⁵

, Mohammadsadegh Zabihidan⁶

1- Department of Biomedical Engineering (Center of Excellence), Amir Kabir University of Technology, Tehran, Iran
2- Biomaterials and Tissue Engineering Research Group, Department of Interdisciplinary Technologies, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran , be.abdollahi@ut.ac.ir
3- Otorhinolaryngology Research Center, Tehran University of Medical Sciences, Tehran, Iran
4- Department of Cell and Molecular Biology, Faculty of Basic Science, University of Maragheh, Maragheh, Iran
5- Biomedical Engineering Department, Science and Research Branch, Islamic Azad University, Tehran, Iran
6- ENT and Head and Neck Surgery Research Center and Department, Rasool Akram Hospital, school of medicine, Iran University of Medical Sciences, Tehran, Iran

Keywords: COVID-19, Olfactory dysfunction, Smell Identification Test

Full-Text [PDF 895 kb] (348 Downloads) | Abstract (HTML) (1362 Views)

Full-Text: (162 Views)

Introduction

Since the end of 2019, SARS-COV-2 (COVID-19) has spread all around the world and become a worldwide problem with a lot of deaths (1). The COVID-19 infection shows some symptoms similar to influenza (headache, cough, fever myalgia, etc.). Also, there are other symptoms (olfactory and taste dysfunction) that were proven to expand during the pandemic (2). In general, the method of diagnosis and differentiation of patients with COVID-19 is a real-time polymerase chain reaction (RT-PCR) test, which is a time-consuming test and should be performed a few days after the onset of COVID-19 symptoms. Because time to diagnosis is so important in a pandemic, it must be possible for the early detection of disease to isolate patients as soon as possible before transmitting the disease to others. Therefore, recognizing and quarantining asymptomatic patients is a crucial and important step in managing the pandemic (3).
From the beginning of the pandemic, there were self-reported olfactory and taste impairments, which can be considered an appropriate and timely prediction of the disease. Studies in this field have observed olfactory dysfunction during the COVID-19 pandemic (4, 5). In March 2020, olfactory and taste symptoms were considered one of the first signs of COVID-19 by the American Academy of Otolaryngology, which suggested preventive quarantine after observing olfactory impairment symptoms to reduce the rate of disease transmission (6). Another study in Italy found that olfactory dysfunction in COVID-19 was more common in younger patients and women. An article states that anosmia and dysgeusia were identified as one of the first symptoms of COVID-19 disease, but this study did not address the relationship between severity, mortality, and pathogenesis (7). How the virus affects the senses of smell and taste is still unknown. Significant advances in cellular and molecular mechanisms of virus effect on olfactory disorders have been made. Recent studies have provided new findings on olfactory epithelial cell types that express virus-associated proteins (8). It seems that ACE2 is expressed in the tongue’s epithelial cells, but perhaps not in the taste buds. Nowadays, ACE2 suppressor drugs are considered stimulants of olfactory and taste impairments (Figure 1) (9). Evidence suggests that there is a cascade of cellular events occurring in the olfactory epithelium that may explain the cause of olfactory dysfunction due to COVID-19.

Figure 1. Shows the mechanisms of ACE2 expression in the tongue (Designed by the authors, 2024).

The most well-known olfactory assay is the University of Pennsylvania smell identification test (UPSIT) is extremely used as a diagnostic tool in research and clinical settings in the USA. UPSIT focuses on the comparative capacity of individuals to identify different odors. Inspired by the UPSIT test, the Iranian smell identification test (ISIT) was developed by Taherkhani, Moztarzadeh (10) in 2015 and is currently used as a reference smell test in Iran (10). Later, it was modified for detecting olfactory malingering in forensics medicine. Using ISIT, it is possible to accurately measure the extent of olfactory loss in people after COVID-19 disease.
In this present research, we study a group of people infected by COVID-19 to specify the relationship between smell dysfunction and the disease. To understand this matter, we compare the results of the smell identification test with other diagnostic tests such as RT-PCR test, ESR, CRP, and lung CT scan. Finally, the results were analyzed to determine the ability of smell dysfunction as a quick, effective, and early marker of screening COVID-19 and the accuracy of ISIT in recognizing COVID-19 patients.

Case Presentation

This is a cross-sectional study. 94 patients with COVID-19 who were admitted to the Amiralam hospital at the peak of the delta variant in Iran were confirmed to participate in this study. They had positive RT-PCR assay results for SARS-CoV-2 nucleic acids or a remarkable absorption of infection signs on their chest CT images. Regarding the demographic characteristics of the study population, the following can be mentioned: The age group of the study was from 18 to 83 including 53.2% male and 46.8% female. Smoking was common in 19.1% of the patients. 2.1% of the participants had an in-hospital job. Regarding the underlying diseases, the following can be mentioned: 23.4% had a history of high blood pressure, 12.8% had diabetes, and 4.3% had a history of heart disease. Nasal congestion and asthma each have occurred in 2.1% of the patients. There was no one with hypothyroidism, Alzheimer's, chronic bronchitis, and a history of head trauma. However, 12.8% of the participants had other underlying diseases.
2.1. Patient Self-reported Symptoms
The first reported symptoms by patients included body pain, fever, cough, olfactory dysfunction, decrease in taste, shortness of breath, headache, and other symptoms.
2.2. Clinical Tests
The initial examinations including body temperature, O₂ saturation, and heart rate were carried out for the patients. Then the complete blood test was performed to monitor the amounts of ESR, CRP, Hg, Lymphocyte, Leucocyte, and Platelet. The olfactory function of the patients was assessed by the Iran Smell Identification Test (ISIT). ISIT is a 24-item smell identification test, for which subjects are asked to scratch and sniff the items and select one of the four alternatives (for example, “banana,” “mint,” “gasoline,” or “cinnamon”). The score of ISIT is determined by the number of correct answers of the subjects. So, it can be a number between zero to 24. A score ≥ 20 is considered a normal range and a score ≤19 is considered an olfactory disorder. The results of clinical tests were statistically analyzed to determine the most accurate and rapid test for COVID-19 detection (Figure 2). Exclusion criteria include people who are unable or unwilling to perform ISIT.

Figure 2. Schematic illustration of materials and methods of the study (Designed by the authors, 2024).
Figure 2. Schematic illustration of materials and methods of the study (Designed by the authors, 2024).

Discussion

3.1. Patients Self-reported symptoms
Table. 1 shows the frequency of common symptoms based on the patient's self-reported. As it can be seen the olfactory dysfunction by 68.1% is the most common symptom in the patients with delta variant. Subsequently, body aches by 57.4%, a decrease in taste by 53.2%, and fever by 51.1% were more frequent than the other symptoms. Cough by 25.5%, shortness of breath by 19.1%, headache by 14.9%, and other symptoms like nausea, weakness, and fatigue at 6.4% are located at the bottom of the list.

Table 1. Patients self-reported symptoms

Symptoms	Total	YES	Percent (%) of positive answers	NO	Percent (%) of negative answers
Olfactory dysfunction	94	64	68/1	30	31/9
Body pain	94	54	57/4	40	42/6
Decrease in taste	94	50	53/2	44	46/8
Fever	94	48	51/1	46	48/9
Cough	94	24	25/5	70	74/5
Shortness of breath	94	18	19/1	76	80/9
Headache	94	14	14/9	80	85/1
Other Symptoms	94	6	6/4	88	93/6

3.2. Clinical Tests
As mentioned above, full clinical tests and examinations were performed for the patients. Then their olfactory function was assessed by the ISIT. The results of the tests are displayed in Table 2. According to these results, 76.6% of the patients have an olfactory disorder which was detected by ISIT. It means that they obtained a score less than 19 on the smell test. 58.5% of the patients show Erythrocyte Sedimentation Rate (ESR) results outside the normal range indicating that an inflammatory condition may be present. C-reactive protein (CRP) a type of protein that is associated with inflammation in the body shows increasing measures in 57.4% of the patients. 37.2% of the patients were found to have a fever and 34% presented SpO₂ less than 95. Results of the blood test also show that the hemoglobin level for 24.5% of the patients was outside the normal range. A rise in the lymphocyte and leucocyte count was observed in 23.4% and 16% of the participants respectively. Patients with platelets outside the normal range are less than 4%. Nobody did not have an abnormal heart rate. Figure 3. Shows the percent (%) outside the normal range for the results of the clinical tests.

Table 2. Results of the clinical tests

Parameters	Total	Average	Standard Deviation	Min	Max	Normal range	Numbers outside the normal range	Percent outside the normal range
ISIT	94	15.29	5.190	3	24	0-24	72	76/6%
ESR	94	28.19	20.74	2.00	79.00	female: <29 Male: <22	55	58/5%
CRP	94	34.03	57.91	1.00	231.00	<3	54	57/4%
Fever	94	37.33	0.525	36.5	38.5	36.8-37.2	35	37/2%
SpO2	94	94.39	3.817	80	98	95-97%	32	34/0%
Hg	94	14.56	2.66	9.00	17.5	female: 12-16 Male: 14-18	23	24/5%
Lymphocyte	94	2.81	1.21	0.18	4.50	0.8-5	22	23/4%
Leucocyte	94	9.96	13.89	0.42	91.00	5-10	15	16/0%
Platelet	94	273.84	61.35	166.0	408.00	150-400	3	3/2%
Heart Rate	94	84.56	7.74	72.00	100	60-100	0	0/0%

Figure 3. Percent (%) outside the normal range for the results of the clinical tests (Designed by the authors, 2024).

3.3. Covid-19 specialized diagnostic tests
As mentioned above, the participants in this study carried out at least one of the Covid-19 specialized diagnostic tests including RT-PCR assay and chest CT scan. We checked their medical records and found out that an RT-PCR assay was performed for 73 patients and a chest CT scan was performed for 66 patients. 45 patients carried out both tests. Table 3 shows the results of COVID-19 specialized diagnostic tests. As can be observed, 68.5% of patients were found to have a positive RT-PCR assay and 62.1% of the patients had a remarkable absorption of infection signs on their chest CT images. A simple comparison of these results with the results of the olfactory test can be seen as the higher accuracy of the olfactory test for the early diagnosis of COVID-19.

Table. 3. Results of COVID-19 specialized diagnostic tests

Tests	Total	The number of patients who have a diagnostic test result	Test Results
Tests	Total		Number of Positive	Percent (%) of Positive	Number of Negative	Percent (%) of Negative
RT-PCR	94	73	50	68/5	23	31/5
Chest CT scan	94	66	41	62/1	25	37/9

This study aimed to evaluate the prevalence of olfactory dysfunctions in COVID-19 patients by self-reported methods and by using the Iran Smell Identification Test (ISIT). We also evaluate the accuracy of ISIT for rapid screening of COVID-19 in comparison with existing diagnosis tests.
Olfactory dysfunction (OD) is one of the common symptoms of COVID-19, but it isn’t a novel phenomenon and there are a lot of viruses that can make OD, including influenza virus, parainfluenza virus, adenovirus, poliovirus, coxsackievirus, herpesvirus and enterovirus (11-13). The COVID-19 virus has been reported to enter the body through the olfactory epithelium at the roof of the nose (14). The task of detecting and transmitting odor information to the brain is performed by sensory neurons in the olfactory epithelium. It should also be noted that a special feature of the basal cells of the olfactory epithelium is that it can regenerate throughout life. It has also been reported that OD, in addition to damaging the olfactory epithelial nerve and extending to the olfactory bulb, may express ACE2 and TMPRSS2 proteins by stem cell neurons (15, 16). Because the expression of these proteins can vary from person to person, the duration of OD varies due to different degrees of damage to the olfactory neurons, and their repair may take several months (Figure 4) (17, 18). Due to the high prevalence of OD in COVID-19 disease, patients need to be consulted about the possibility of recovery. It should also be possible to identify people with a high probability of persistent OD so that appropriate treatment choices can be made. According to the data collected, about 33% of cases recover after a maximum of 14 days, and also 34% did not recover even after 45 days (19).

Figure 4. The normal function of the olfactory epithelium and the damaging procedure of olfactory epithelial nerves (Designed by the authors, 2024).

Our study includes four sections: 1) patient’s self-report, 2) ISIT, 3) clinical tests, and 4) specific diagnostic tests of COVID-19. According to the symptoms self-reported by patients, it was observed that the most common symptom among the patients was related to OD by 68.1%, followed by body pain, decreased taste, fever, and cough. This finding was confirmed by the results of the Iran Smell Identification Test (ISIT) and its comparison with the other clinical tests. Results of this analysis demonstrated that OD by 76.6% of prevalence has a higher rate among the other clinical parameters.
Public health screening for COVID-19 is becoming a routine activity. It has become usual for people to check their body temperature during the pandemic because fever is a key indicator of infection. Scientists, however, propose that taking a temperature is a weak indicator of COVID-19 in older adults and that a pulse oximeter be used instead. The reliability of a pulse oximeter as an indicator of COVID-19 has been the subject of debate in recent months. Recently, the World Health Organization (WHO) listed the use of the pulse oximeter to identify COVID-19 patients who may need to be hospitalized due to low oxygen levels. Based on this study, we find that the value of fever and oxygen saturation of blood are much lower than the olfactory disorders. Therefore, we propose using the Smell Identification Test as a rapid screening for COVID-19. ISIT is a noninvasive, rapid, and easy test and it can be applied for public health screening. ISIT also showed higher accuracy compared with the COVID-19 specialized diagnostic tests including RT-PCR assay and chest CT scan. However, further studies are needed to confirm these findings.
The strength of our study is that it is the method of data collection, the proven olfactory test by the Food and Drug Organization of the Ministry of Health of Iran, a suitable sample size, and the appropriate bio-statistical studies. Also, the weaknesses of the study include: first the sample size and second, the limitation of RT-PCR for the detection of COVID-19 virus, in nasopharyngeal swab samples, which has a less value than the standard, which leads to a high number of false negatives (20).

Conclusion

In summary, in this systematic review study, it was found that there is an acceptable association between lncRNA and SNP with tuberculosis and M. tuberculosis. Therefore, it was found that these regulatory factors play an important role as diagnostic biomarkers and the development of new therapies. However, more studies are needed to discover new lncRNAs and their association with tuberculosis.

Acknowledgment

Declared none.

Conflicts of Interest

All authors – none to declare.

Funding

None declared.

Type of Study: Case report Article | Subject: Microbial Biotechnology
Received: 2023/08/22 | Accepted: 2023/11/18 | ePublished: 2024/03/18

References

1. Paules CI, Marston HD, Fauci AS. Coronavirus Infections-More Than Just the Common Cold. JAMA. 2020;323(8):707-8. [DOI:10.1001/jama.2020.0757] [PMID]

2. Salmon Ceron D, Bartier S, Hautefort C, Nguyen Y, Nevoux J, Hamel AL, et al. Self-reported loss of smell without nasal obstruction to identify COVID-19. The multicenter Coranosmia cohort study. J Infect. 2020;81(4):614-20. [DOI:10.1016/j.jinf.2020.07.005] [PMID] [PMCID]

3. Bhattacharjee AS, Joshi SV, Naik S, Sangle S, Abraham NM. Quantitative assessment of olfactory dysfunction accurately detects asymptomatic COVID-19 carriers. EClinicalMedicine. 2020;28:100575. [DOI:10.1016/j.eclinm.2020.100575] [PMID] [PMCID]

4. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and Ageusia: Common Findings in COVID-19 Patients. Laryngoscope. 2020;130(7):1787. [DOI:10.1002/lary.28692] [PMID] [PMCID]

5. Cristina M, Ana MV, Maxim BF, Sajaysurya G, Julia SE-SM, Alessia V, et al. Loss of smell and taste in combination with other symptoms is a strong predictor of COVID-19 infection. medRxiv. 2020.

6. Kowalski LP, Sanabria A, Ridge JA, Ng WT, de Bree R, Rinaldo A, et al. COVID-19 pandemic: Effects and evidence-based recommendations for otolaryngology and head and neck surgery practice. Head Neck. 2020;42(6):1259-67. [DOI:10.1002/hed.26164] [PMID] [PMCID]

7. Hjelmesæth J, Skaare D. Loss of smell or taste as the only symptom of COVID-19. Tidsskr Nor Laegeforen. 2020;140(7).

8. Bilinska K, Jakubowska P, Von Bartheld CS, Butowt R. Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age. ACS Chem Neurosci. 2020;11(11):1555-62. [DOI:10.1021/acschemneuro.0c00210] [PMID] [PMCID]

9. Bertlich M, Stihl C, Weiss BG, Canis M, Haubner F, Ihler F. Characteristics of impaired chemosensory function in hospitalized COVID-19 Patients. 2020. [DOI:10.2139/ssrn.3576889]

10. Taherkhani S, Moztarzadeh F, Seraj J, Hashemi-Nazari SS, Taherkhani F, Gharehdaghi J, et al. Iran Smell Identification Test (Iran-SIT): a Modified Version of the University of Pennsylvania Smell Identification Test (UPSIT) for Iranian Population. Chemosens Percept. 2015;8(4):183-91. [DOI:10.1007/s12078-015-9192-9]

11. Tian J, Pinto JM, Cui X, Zhang H, Li L, Liu Y, et al. Sendai Virus Induces Persistent Olfactory Dysfunction in a Murine Model of PVOD via Effects on Apoptosis, Cell Proliferation, and Response to Odorants. PLoS One. 2016;11(7):e0159033. [DOI:10.1371/journal.pone.0159033] [PMID] [PMCID]

12. Wang JH, Kwon HJ, Jang YJ. Detection of Parainfluenza Virus 3 in Turbinate Epithelial Cells of Postviral Olfactory Dysfunction Patients. Laryngoscope. 2007;117(8):1445-9. [DOI:10.1097/MLG.0b013e318063e878] [PMID]

13. Suzuki M, Saito K, Min W-P, Vladau C, Toida K, Itoh H, Murakami S. Identification of Viruses in Patients With Postviral Olfactory Dysfunction. Laryngoscope. 2007;117(2):272-7. [DOI:10.1097/01.mlg.0000249922.37381.1e] [PMID] [PMCID]

14. Axel R. The molecular logic of smell. Sci Am. 1995;273(4):154-9. [DOI:10.1038/scientificamerican1095-154] [PMID]

15. Chetrit A, Lechien JR, Ammar A, Chekkoury-Idrissi Y, Distinguin L, Circiu M, et al. Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: Preliminary prospective study. J Infect. 2020;81(5):816-46. [DOI:10.1016/j.jinf.2020.07.028] [PMID] [PMCID]

16. Chen M, Shen W, Rowan NR, Kulaga H, Hillel A, Ramanathan M, Jr., Lane AP. Elevated ACE-2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. Eur Respir J. 2020;56(3):2001948. [DOI:10.1183/13993003.01948-2020] [PMID] [PMCID]

17. Lazarini F, Lledo PM. Is adult neurogenesis essential for olfaction? Trends Neurosci. 2011;34(1):20-30. [DOI:10.1016/j.tins.2010.09.006] [PMID]

18. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020;6(1):1-4. [DOI:10.1038/s41421-020-0147-1] [PMID] [PMCID]

19. Lechien JR, Chiesa-Estomba CM, Beckers E, Mustin V, Ducarme M, Journe F, et al. Prevalence and 6-month recovery of olfactory dysfunction: a multicentre study of 1363 COVID-19 patients. J Intern Med. 2021;290(2):451-61. [DOI:10.1111/joim.13209] [PMID]

20. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020;323(18):1843-4. [DOI:10.1001/jama.2020.3786] [PMID] [PMCID]