Review 2: "Quantitative Assessment of Olfactory Dysfunction Accurately Detects Asymptomatic COVID-19 Carriers"

RR:C19 Evidence Scale rating by reviewer:

• Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

***************************************

Review:

The investigators use an olfactometer – an instrument designed to deliver odorants to human subjects at a fixed concentration – to measure the olfactory ability of healthy people versus those who are currently infected by COVID-19 (as measured by a nasal swab test). The results of this research adds to our knowledge of COVID-19 biology by pointing out that while most subjective reports of smell loss indicate that loss of smell is nearly complete (anosmia; inability to smell), here we learn that for people who are infected but without other symptoms, the smell loss, while detectable, can be partial rather than total. Many studies to date have studied smell loss in COVID-19 patients1-92 but to the best of my knowledge and as I write this review as of Sept 4th 2020, none have used as accurate and as sensitive methods to measure smell as reported here. 

Several features of the research procedures merit should be highlighted. First, the concentration of odorants delivered were measured by photoionization detector which is helpful to rule out the technical explanation that person-to-person differences in the ability to detect an odorant are due to the vicissitudes of odorant concentration, which can arise when cruder methods are used, e.g., scratch-and-sniff. To date and to the best of my knowledge, there are12 studies that use objective tests to assess smell in patients with COVID-19, but here the odorant concentration is measured and controlled by the use of an olfactometer. Another useful aspect of the methods here are that the investigators used ten odorants and so the overall assessment of the patient is more complete than studies using single or fewer odorants. The reason this point is important is that the genotype of human olfactory receptors is exceptionally variable and therefore a person might be unable to detect a particular odor not because they have COVID-19, but because they have a specific blindness that that odorant (specific anosmia). Most of the commonly used odorant tests select odors that are sensed by most people but the small possibility of specific anosmia remains. Using ten odorants as the investigators have done here circumvents this issue. 

The main finding of interest was that whereas the participants who had COVID-19 were mostly unaware that they had smell deficits which reinforces the point that objective tests of olfactory function are needed for COVID-19 surveillance. And two final points require highlighting: the authors provided as supplemental data an informative video explaining the equipment, they used to test the participants and they presented practical information about how the instrument was decontaminated which is salient during the pandemic when sanitation is part of human subject protections. 

There were limitations to this study, the most salient being the lack of test-re-test measures; ideally, we would like to observe how reproducible the results would be for a specific subject when tested again, e.g., in a few hours or within a day. Another issue was the potential to introduce differences in the olfactometer measures that might arise from moving the instrument, e.g., from the laboratory to the quarantine location. More details about the standardization procedures would have strengthened the manuscript.

References

1 Mao, L. et al. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv, 2020.2002.2022.20026500, doi:10.1101/2020.02.22.20026500 (2020).

2 Giacomelli, A. et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clinical Infectious Diseases, doi:10.1093/cid/ciaa330 (2020).

3 Lechien, J. R. et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. European Archives of Oto-Rhino-Laryngology, doi:10.1007/s00405-020-05965-1 (2020).

4 Yan, C. H., Faraji, F., Prajapati, D. P., Boone, C. E. & DeConde, A. S. Association of chemosensory dysfunction and Covid-19 in patients presenting with influenza-like symptoms. International forum of allergy & rhinology n/a, doi:10.1002/alr.22579 (2020).

5 Levinson, R. et al. Anosmia and dysgeusia in patients with mild SARS-CoV-2 infection. medRxiv, 2020.2004.2011.20055483, doi:10.1101/2020.04.11.20055483 (2020).

6 Moein, S. T. et al. Smell dysfunction: a biomarker for COVID-19. International forum of allergy & rhinology n/a, doi:10.1002/alr.22587 (2020).

7 Spinato, G. et al. Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection. JAMA, doi:10.1001/jama.2020.6771 (2020).

8 Vaira, L. A. et al. Objective evaluation of anosmia and ageusia in COVID-19 patients: Single-center experience on 72 cases. Head Neck, doi:10.1002/hed.26204 (2020).

9 Luers, J. C. et al. Olfactory and Gustatory Dysfunction in Coronavirus Disease 19 (COVID-19). Clin Infect Dis, doi:10.1093/cid/ciaa525 (2020).

10 Haehner, A., Draf, J., Draeger, S., de With, K. & Hummel, T. Predictive value of sudden olfactory loss in the diagnosis of COVID-19. medRxiv, 2020.2004.2027.20081356, doi:10.1101/2020.04.27.20081356 (2020).

11 Vaira, L. A. et al. Validation of a self-administered olfactory and gustatory test for the remotely evaluation of COVID-19 patients in home quarantine. Head Neck, doi:10.1002/hed.26228 (2020).

12 Lee, Y., Min, P., Lee, S. & Kim, S. W. Prevalence and Duration of Acute Loss of Smell or Taste in COVID-19 Patients. J Korean Med Sci 35, e174, doi:10.3346/jkms.2020.35.e174 (2020).

13 De Maria, A., Varese, P., Dentone, C., Barisione, E. & Bassetti, M. High prevalence of olfactory and taste disorder during SARS-CoV-2 infection in outpatients. J Med Virol, doi:10.1002/jmv.25995 (2020).

14 Menni, C. et al. Real-time tracking of self-reported symptoms to predict potential COVID-19. Nat Med, doi:10.1038/s41591-020-0916-2 (2020).

15 Iravani, B. et al. Relationship between odor intensity estimates and COVID-19 population prediction in a Swedish sample. medRxiv, 2020.2005.2007.20094516, doi:10.1101/2020.05.07.20094516 (2020).

16 Liu, J. Y., Chen, T. J. & Hwang, S. J. Analysis of Imported Cases of COVID-19 in Taiwan: A Nationwide Study. Int J Environ Res Public Health 17, doi:10.3390/ijerph17093311 (2020).

17 Merza, M. A., Haleem Al Mezori, A. A., Mohammed, H. M. & Abdulah, D. M. COVID-19 outbreak in Iraqi Kurdistan: The first report characterizing epidemiological, clinical, laboratory, and radiological findings of the disease. Diabetes Metab Syndr 14, 547-554, doi:10.1016/j.dsx.2020.04.047 (2020).

18 Paderno, A. et al. Smell and taste alterations in Covid-19: a cross-sectional analysis of different cohorts. International forum of allergy & rhinology, doi:10.1002/alr.22610 (2020).

19 Speth, M. M. et al. Olfactory Dysfunction and Sinonasal Symptomatology in COVID-19: Prevalence, Severity, Timing, and Associated Characteristics. Otolaryngol Head Neck Surg, 194599820929185, doi:10.1177/0194599820929185 (2020).

20 Shoer, S. et al. Who should we test for COVID-19? A triage model built from national symptom surveys. medRxiv, 2020.2005.2018.20105569, doi:10.1101/2020.05.18.20105569 (2020).

21 Vaira, A. L. et al. Olfactory and gustatory function impairment in COVID-19 patients: Italian objective multicenter-study. Head Neck, doi:10.1002/hed.26269 (2020).

22 Beltran-Corbellini, A. et al. Acute-onset smell and taste disorders in the context of COVID-19: a pilot multicentre polymerase chain reaction based case-control study. Eur J Neurol, doi:10.1111/ene.14273 (2020).

23 Boscolo-Rizzo, P. et al. New onset of loss of smell or taste in household contacts of home-isolated SARS-CoV-2-positive subjects. Eur Arch Otorhinolaryngol, doi:10.1007/s00405-020-06066-9 (2020).

24 Parma, V. et al. More than smell. COVID-19 is associated with severe impairment of smell, taste, and chemesthesis. medRxiv, 2020.2005.2004.20090902, doi:10.1101/2020.05.04.20090902 (2020).

25 Tudrej, B. et al. Self-Reported Loss of Smell and Taste in SARS-CoV-2 Patients: Primary Care Data to Guide Future Early Detection Strategies. J Gen Intern Med, doi:10.1007/s11606-020-05933-9 (2020).

26 Dell'Era, V. et al. Smell and taste disorders during COVID-19 outbreak: A cross-sectional study on 355 patients. Head Neck, doi:10.1002/hed.26288 (2020).

27 Hornuss, D. et al. Anosmia in COVID-19 patients. Clin Microbiol Infect, doi:10.1016/j.cmi.2020.05.017 (2020).

28 Lovato, A., Galletti, C., Galletti, B. & de Filippis, C. Clinical characteristics associated with persistent olfactory and taste alterations in COVID-19: A preliminary report on 121 patients. Am J Otolaryngol 41, 102548, doi:10.1016/j.amjoto.2020.102548 (2020).

29 Sayin, I., Yasar, K. K. & Yazici, Z. M. Taste and Smell Impairment in COVID-19: An AAO-HNS Anosmia Reporting Tool-Based Comparative Study. Otolaryngol Head Neck Surg, 194599820931820, doi:10.1177/0194599820931820 (2020).

30 Biadsee, A. et al. Olfactory and Oral Manifestations of COVID-19: Sex-Related Symptoms-A Potential Pathway to Early Diagnosis. Otolaryngol Head Neck Surg, 194599820934380, doi:10.1177/0194599820934380 (2020).

31 Qiu, C. et al. Olfactory and Gustatory Dysfunction as an Early Identifier of COVID-19 in Adults and Children: An International Multicenter Study. Otolaryngol Head Neck Surg, 194599820934376, doi:10.1177/0194599820934376 (2020).

32 Yan, C. H., Faraji, F., Prajapati, D. P., Ostrander, B. T. & DeConde, A. S. Self-reported olfactory loss associates with outpatient clinical course in COVID-19. International forum of allergy & rhinology, doi:10.1002/alr.22592 (2020).

33 Gelardi, M., Trecca, E., Cassano, M. & Ciprandi, G. Smell and taste dysfunction during the COVID-19 outbreak: a preliminary report. Acta Biomed 91, 230-231, doi:10.23750/abm.v91i2.9524 (2020).

34 Klopfenstein, T. et al. Features of anosmia in COVID-19. Med Mal Infect, doi:10.1016/j.medmal.2020.04.006 (2020).

35 Gudbjartsson, D. F. et al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med 382, 2302-2315, doi:10.1056/NEJMoa2006100 (2020).

36 Wee, L. E. et al. The role of self-reported olfactory and gustatory dysfunction as a screening criterion for suspected COVID-19. Eur Arch Otorhinolaryngol, doi:10.1007/s00405-020-05999-5 (2020).

37 Dawson, P. et al. Loss of Taste and Smell as Distinguishing Symptoms of COVID-19. medRxiv, 2020.2005.2013.20101006, doi:10.1101/2020.05.13.20101006 (2020).

38 Noh, J. Y. et al. Asymptomatic infection and atypical manifestations of COVID-19: Comparison of viral shedding duration. J Infect, doi:10.1016/j.jinf.2020.05.035 (2020).

39 Izquierdo-Domínguez, A. et al. Smell and taste dysfunctions in COVID-19 are associated with younger age in ambulatory settings - a multicenter cross-sectional study. J Investig Allergol Clin Immunol, 0, doi:10.18176/jiaci.0595 (2020).

40 Freni, F. et al. Symptomatology in head and neck district in coronavirus disease (COVID-19): A possible neuroinvasive action of SARS-CoV-2. Am J Otolaryngol 41, 102612, doi:10.1016/j.amjoto.2020.102612 (2020).

41 Schmithausen, R. M. et al. Characteristic Temporary Loss of Taste and Olfactory Senses in SARS-CoV-2-positive-Individuals with Mild Symptoms. Pathog Immun 5, 117-120, doi:10.20411/pai.v5i1.374 (2020).

42 Durrani, M., Haq, I. U., Kalsoom, U. & Yousaf, A. Chest X-rays findings in COVID 19 patients at a University Teaching Hospital - A descriptive study. Pak J Med Sci 36, S22-S26, doi:10.12669/pjms.36.COVID19-S4.2778 (2020).

43 Lan, F. Y. et al. COVID-19 symptoms predictive of healthcare workers' SARS-CoV-2 PCR results. PLoS One 15, e0235460, doi:10.1371/journal.pone.0235460 (2020).

44 Mercante, G. et al. Prevalence of Taste and Smell Dysfunction in Coronavirus Disease 2019. JAMA Otolaryngol Head Neck Surg, doi:10.1001/jamaoto.2020.1155 (2020).

45 Lombardi, A. et al. Characteristics of 1,573 healthcare workers who underwent nasopharyngeal swab for SARS-CoV-2 in Milano, Lombardy, Italy. Clin Microbiol Infect, doi:10.1016/j.cmi.2020.06.013 (2020).

46 Altin, F., Cingi, C., Uzun, T. & Bal, C. Olfactory and gustatory abnormalities in COVID-19 cases. Eur Arch Otorhinolaryngol, doi:10.1007/s00405-020-06155-9 (2020).

47 Vacchiano, V. et al. Early neurological manifestations of hospitalized COVID-19 patients. Neurol Sci, doi:10.1007/s10072-020-04525-z (2020).

48 Adorni, F. et al. Self-reported symptoms of SARS-CoV-2 infection in a non-hospitalized population: results from the large Italian web-based EPICOVID19 cross-sectional survey. JMIR Public Health Surveill, doi:10.2196/21866 (2020).

49 Hintschich, C. A. et al. Psychophysical tests reveal impaired olfaction but preserved gustation in COVID-19 patients. International forum of allergy & rhinology, doi:10.1002/alr.22655 (2020).

50 Chiesa-Estomba, C. M. et al. Patterns of smell recovery in 751 patients affected by the COVID-19 outbreak. European Journal of Neurology n/a, doi:10.1111/ene.14440 (2020).

51 Petrocelli, M. et al. Remote psychophysical evaluation of olfactory and gustatory functions in early-stage coronavirus disease 2019 patients: the Bologna experience of 300 cases. The Journal of Laryngology & Otology, 1-12, doi:10.1017/S0022215120001358 (2020).

52 Lechien, J. R. et al. Loss of Smell and Taste in 2013 European Patients With Mild to Moderate COVID-19. Annals of Internal Medicine, doi:10.7326/M20-2428 (2020).

53 Boscolo-Rizzo, P. et al. Evolution of Altered Sense of Smell or Taste in Patients With Mildly Symptomatic COVID-19. JAMA Otolaryngol Head Neck Surg, doi:10.1001/jamaoto.2020.1379 (2020).

54 Sakalli, E. et al. Ear nose throat-related symptoms with a focus on loss of smell and/or taste in COVID-19 patients. Am J Otolaryngol 41, 102622, doi:10.1016/j.amjoto.2020.102622 (2020).

55 Somekh, I., Yakub Hanna, H., Heller, E., Bibi, H. & Somekh, E. Age-Dependent Sensory Impairment in Covid-19 Infection and Its Correlation with Ace2 Expression. Pediatr Infect Dis J, doi:10.1097/INF.0000000000002817 (2020).

56 Jalessi, M. et al. Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19. Neurol Sci, doi:10.1007/s10072-020-04590-4 (2020).

57 GÜner, H. R. et al. COVID-19 experience of the major pandemic response center in the capital: Results of the pandemic's first month in Turkey. Turk J Med Sci, doi:10.3906/sag-2006-164 (2020).

58 Martin-Sanz, E. et al. Prospective study in 355 patients with suspected COVID-19 infection. Value of cough, subjective hyposmia, and hypogeusia. Laryngoscope, doi:10.1002/lary.28999 (2020).

59 Morshed, M. S., Mosabbir, A. A., Chowdhury, P., Ashadullah, S. M. & Hossain, M. S. Clinical manifestations of patients with Coronavirus Disease 2019 (COVID- 19) attending at hospitals in Bangladesh. medRxiv (2020).

60 Boscolo-Rizzo, P. et al. Predominance of an altered sense of smell or taste among long-lasting symptoms in patients with mildly symptomatic COVID-19. Rhinology, doi:10.4193/Rhin20.263 (2020).

61 Foster, K. J., Jauregui, E., Tajudeen, B., Bishehsari, F. & Mahdavinia, M. Smell loss is a prognostic factor for lower severity of COVID-19. Ann Allergy Asthma Immunol, doi:10.1016/j.anai.2020.07.023 (2020).

62 Nakagawara, K. et al. Acute Onset Olfactory/Taste Disorders are Associated with a High Viral Burden in Mild or Asymptomatic SARS-CoV-2 Infections. Int J Infect Dis, doi:10.1016/j.ijid.2020.07.034 (2020).

63 Villarreal, I. M. et al. Olfactory and taste disorders in healthcare workers with COVID-19 infection. Eur Arch Otorhinolaryngol, doi:10.1007/s00405-020-06237-8 (2020).

64 Wagner, T. et al. Augmented Curation of Clinical Notes from a Massive EHR System Reveals Symptoms of Impending COVID-19 Diagnosis. medRxiv, 2020.2004.2019.20067660, doi:10.1101/2020.04.19.20067660 (2020).

65 Fontanet, A. et al. Cluster of COVID-19 in northern France: A retrospective closed cohort study. medRxiv, 2020.2004.2018.20071134, doi:10.1101/2020.04.18.20071134 (2020).

66 Kempker, R. R. et al. Loss of Smell and Taste Among Healthcare Personnel Screened for Coronavirus 2019. Clin Infect Dis, doi:10.1093/cid/ciaa877 (2020).

67 Chen, A. et al. Are Gastrointestinal Symptoms Specific for COVID-19 Infection? A Prospective Case-Control Study from the United States. Gastroenterology, doi:10.1053/j.gastro.2020.05.036 (2020).

68 Gorzkowski, V. et al. Evolution of olfactory disorders in COVID-19 patients. Laryngoscope, doi:10.1002/lary.28957 (2020).

69 Song, J. et al. Self-reported taste and smell disorders in patients with COVID-19: distinct features in China. medRxiv, 2020.2006.2012.20128298, doi:10.1101/2020.06.12.20128298 (2020).

70 D'Ascanio, L. et al. Olfactory Dysfunction in COVID-19 Patients: Prevalence and Prognosis for Recovering Sense of Smell. Otolaryngol Head Neck Surg, 194599820943530, doi:10.1177/0194599820943530 (2020).

71 Moein, S. T., Hashemian, S. M. R., Tabarsi, P. & Doty, R. L. Prevalence and Reversibility of Smell Dysfunction Measured Psychophysically in a Cohort of COVID-19 patients. International forum of allergy & rhinology, doi:10.1002/alr.22680 (2020).

72 Iversen, K. et al. Risk of COVID-19 in health-care workers in Denmark: an observational cohort study. The Lancet Infectious Diseases, doi:10.1016/s1473-3099(20)30589-2 (2020).

73 Cocco, A. et al. Neurological features in SARS-CoV-2-infected patients with smell and taste disorder. J Neurol, doi:10.1007/s00415-020-10135-8 (2020).

74 Vaira, L. A. et al. Do olfactory and gustatory psychophysical scores have prognostic value in COVID-19 patients? A prospective study of 106 patients. J Otolaryngol Head Neck Surg 49, 56, doi:10.1186/s40463-020-00449-y (2020).

75 Klopfenstein, T. et al. New loss of smell and taste: Uncommon symptoms in COVID-19 patients on Nord Franche-Comte cluster, France. Int J Infect Dis, doi:10.1016/j.ijid.2020.08.012 (2020).

76 Vaira, L. A. et al. Smell and taste recovery in coronavirus disease 2019 patients: a 60-day objective and prospective study. The Journal of Laryngology & Otology, 1-14, doi:10.1017/S0022215120001826 (2020).

77 Zens, M., Brammertz, A., Herpich, J., Südkamp, N. & Hinterseer, M. App-based tracking of self-reported COVID-19 symptoms. J Med Internet Res, doi:10.2196/21956 (2020).

78 Cho, R. H. et al. COVID-19 Viral Load in the Severity of and Recovery from Olfactory and Gustatory Dysfunction. Laryngoscope, doi:10.1002/lary.29056 (2020).

79 Salepci, E. et al. Symptomatology of COVID-19 from the otorhinolaryngology perspective: a survey of 223 SARS-CoV-2 RNA-positive patients. Eur Arch Otorhinolaryngol, doi:10.1007/s00405-020-06284-1 (2020).

80 Weng, C. H., Saal, A., Butt, W. W. W. & Chan, P. A. Characteristics and clinical outcomes of COVID-19 in Hispanic/Latino patients in a community setting: A retrospective cohort study. J Med Virol, doi:10.1002/jmv.26196 (2020).

81 Farah Yusuf Mohamud, M., Garad Mohamed, Y., Mohamed Ali, A. & Ali Adam, B. Loss of Taste and Smell are Common Clinical Characteristics of Patients with COVID-19 in Somalia: A Retrospective Double Centre Study. Infect Drug Resist 13, 2631-2635, doi:10.2147/IDR.S263632 (2020).

82 Merkely, B. et al. Novel coronavirus epidemic in the Hungarian population, a cross-sectional nationwide survey to support the exit policy in Hungary. Geroscience 42, 1063-1074, doi:10.1007/s11357-020-00226-9 (2020).

83 Calica Utku, A. et al. Main symptoms in patients presenting in the COVID-19 period. Scott Med J, 36933020949253, doi:10.1177/0036933020949253 (2020).

84 Maechler, F. et al. Epidemiological and clinical characteristics of SARS-CoV-2 infections at a testing site in Berlin, Germany, March and April 2020 - A cross-sectional study. Clin Microbiol Infect, doi:10.1016/j.cmi.2020.08.017 (2020).

85 Chary, E. et al. Prevalence and Recovery From Olfactory and Gustatory Dysfunctions in Covid-19 Infection: A Prospective Multicenter Study. Am J Rhinol Allergy 34, 686-693, doi:10.1177/1945892420930954 (2020).

86 Bergquist, S. H. et al. Non-hospitalized Adults with COVID-19 Differ Noticeably from Hospitalized Adults in Their Demographic, Clinical, and Social Characteristics. SN Compr Clin Med, 1-9, doi:10.1007/s42399-020-00453-3 (2020).

87 Al-Ani, R. M. & Acharya, D. Prevalence of Anosmia and Ageusia in Patients with COVID-19 at a Primary Health Center, Doha, Qatar. Indian J Otolaryngol Head Neck Surg, 1-7, doi:10.1007/s12070-020-02064-9 (2020).

88 Otte, M. S., Eckel, H. N. C., Poluschkin, L., Klussmann, J. P. & Luers, J. C. Olfactory dysfunction in patients after recovering from COVID-19. Acta Otolaryngol, 1-4, doi:10.1080/00016489.2020.1811999 (2020).

89 Lechien, J. R. et al. Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019. J Intern Med 288, 335-344, doi:10.1111/joim.13089 (2020).

90 Van Loon, N., Verbrugghe, M., Cartuyvels, R. & Ramaekers, D. Diagnosis of COVID-19 Based on Symptomatic Analysis of Hospital Healthcare Workers in Belgium: Observational Study in a Large Belgian Tertiary Care Center during Early COVID-19 Outbreak. J Occup Environ Med, doi:10.1097/jom.0000000000002015 (2020).

91 Brandao Neto, D. et al. Chemosensory Dysfunction in COVID-19: Prevalences, Recovery Rates, and Clinical Associations on a Large Brazilian Sample. Otolaryngol Head Neck Surg, 194599820954825, doi:10.1177/0194599820954825 (2020).

92 Trubiano, J. A., Vogrin, S., Kwong, J. C. & Homes, N. Alterations in smell or taste - Classic COVID-19? LID - ciaa655 [pii] LID - 10.1093/cid/ciaa655 [doi] FAU - Trubiano, Jason A.