key: cord-253410-rdmopd4t authors: Gorzkowski, Victor; Bevilacqua, Sibylle; Charmillon, Alexandre; Jankowski, Roger; Gallet, Patrice; Rumeau, Cécile; Nguyen, Duc Trung title: Evolution of olfactory disorders in COVID‐19 patients date: 2020-07-02 journal: Laryngoscope DOI: 10.1002/lary.28957 sha: doc_id: 253410 cord_uid: rdmopd4t OBJECTIVES: A high frequency and a strong association of olfactory/gustatory impairment with COVID‐19 were reported. Its spontaneous evolution remains unknown. The aim of this study was to investigate the spontaneous evolution of olfactory disorders in COVID‐19 patients. STUDY DESIGN: Cross‐sectional study METHODS: A total of 229 patients with laboratory‐confirmed COVID‐19 from March 1 through 31, 2020 in our institution were included. Among them, 140 patients (mean age, 38.5 years, 89 women) reported sudden olfactory/gustatory disorders during COVID‐19. All patients were interviewed by phone based on a questionnaire with 16 questions at time of survey. The primary end point was olfactory recovery rate at time of survey. RESULTS: The frequency of patients with olfactory disorders was higher before March 20, 2020 than since (70.3% vs 53.9%, respectively) (p=0.016). At time of survey (26 days of the mean time from anosmia onset), 95.71% reported to start an olfactory recovery. The mean time from olfactory loss onset to recovery onset was 11.6 days. Recovery started between the 4(th) and the 15(th) day after olfactory loss onset in 78.4% of patients. Complete olfactory recovery happened for 51.43% of patients. There was a significant relationship between the complete olfactory recovery and a short time from olfactory loss onset to recovery onset (p=0.0004), absence of nasal obstruction (p=0.023), and absence of sore/dry/tingling feeling in the nose (p=0.007) in COVID‐19 patients. CONCLUSION: Knowledge of spontaneous evolution of olfactory disorders allows reassuring patients and planning therapeutic strategies for persistent olfactory dysfunction after having definitely recovered from COVID‐19. Many families of virus have been presented as causative agents of olfactory dysfunction during or after upper respiratory tract infection (URTI). The new coronavirus of current outbreaks (SARS-CoV-2) may also be a causative agent of olfactory impairment. Recently, a high frequency and a strong association of smell and taste impairment to COVID-19 was reported [1] [2] [3] [4] [5] . Olfactory impairment/loss in patients with confirmed COVID-19 was reported in 4.8% of 1099 patients in China 6 , in 19.4% of 320 patients 7 and in 34% of 59 hospitalized patients 8 in Italy, in 68% of 59 patients in United States 3 , and in 85.6% of 417 patients in Europe 1 . The frequency of taste disorders was similar to that of smell disorders. It has been suggested that SARS-CoV-2 causes obstructive inflammation of olfactory clefts 9 , or targets and damages olfactory epithelium support and stem cells leading to olfactory disturbances in COVID-19 patients 10 . On the other hand, some types of coronaviruses have been shown to propagate, after exposure to coronaviruses by inhalation, from the nasal epithelium past the cribriform plate to infect the olfactory bulb and downstream areas like the piriform cortex and the brain stem 11, 12 . We do not know if SARS-CoV-2 is able to reach to the central olfactory system by this way. Sudden olfactory loss without knowing the possibility of its recovery may lead to a very anxious condition and negatively impacts on patients' quality of life, particularly during current COVID-19 pandemic. Knowing the spontaneous evolution of olfactory disorders and its possibility of recovery in COVID-19 patients is very useful to inform and reassure patients. Moreover, it may contribute to understanding the mechanisms of olfactory dysfunctions in this condition from the time of symptom onset to its recovery. Finally, it may help clinicians to plan therapeutic strategies for persistent olfactory dysfunctions after having definitely recovered from COVID-19 (systemic corticosteroid treatment, olfactory training, etc). The aim of this study was to investigate the spontaneous evolution of olfactory disorders in COVID-19 patients. This article is protected by copyright. All rights reserved. A total of 879 adult patients underwent COVID-19 testing between March 1 through 31, 2020 in our tertiary hospital, University Hospital of Nancy (France). These patients were tested at the Infectious Disease Department because of flu symptoms. Most subjects were outpatients and some were hospitalized. Of those, a total of 261 consecutive adult patients were diagnosed COVID-19 positive confirmed by a real-time reverse transcriptase polymerasechain-reaction (RT-PCR) assay from nasopharyngeal swab specimens. A follow-up phone call was done at the time of the survey. Patients with olfactory or gustatory dysfunctions before the pandemic (2 patients), or patients hospitalized in the intensive care unit at time of survey (2 patients), or patients with mental illness or unable to answer the questionnaire by telephone (2 patients) were excluded. Five patients had died from COVID-19 and 21 patients were unreachable despite at least three calls. During the call, patients were asked if they had a sudden olfactory loss during their course of COVID-19. If it was the case, an interview based on a questionnaire with 16 questions was done at the time of the survey. This questionnaire (French and English version in supplementary materials) was tested in ten persons (pilot study) but it was not validated by any previous study. All symptoms were self-reported and no objective measurements of olfactory or gustatory function or nasal obstruction were performed. Verbal consent was obtained from all patients who accepted to participate in this survey. This study was approved by the Institutional Review Board of University Hospital of Nancy, France. These 16 questions had been chosen to characterize the timing of the occurrence of smell impairment and associated symptoms, the time from onset to recovery of olfactory loss. Sense of smell at the time of olfactory loss, and at the time of recovery or at the time of survey if there was no smell recovery were assessed using a subjective Olfaction Numerical Score (ONS) from 0 (no sense of smell) to 10 (normal sense of smell). Scores from 1 to 9 indicated progressively decreasing severity of smell impairment. Other symptoms were not investigated because they were reported in a large number of recent studies. The subjects were not asked to This article is protected by copyright. All rights reserved. rate their olfactory or gustatory function prior to onset of their symptoms. No patient in this study received treatment for olfactory/gustatory loss. Because the olfactory/gustatory loss was announced as a symptom of COVID-19 in the mainstream media on March 20, 2020 in many countries and territories, we took into account the frequencies of olfactory disorders before and since March 20, 2020. Since this day, many patients were considered as COVID-19 positive without laboratory confirmation when they had sudden olfactory disorders. Descriptive statistics for quantitative variables were expressed as mean±standard deviation and for qualitative variables as percentages. Isolate olfactory/gustatory disorders were reported in 5 patients (3.57%). These symptoms The mean time from onset of olfactory dysfunction to survey was 26±7.6 days (range, 13-54 days). Figure 1 shows numbers of patients at the time of survey according to the time from the onset of olfactory disorders to the evaluation in each group. At the time of survey, 134 patients (95.71%) reported to have an onset of olfactory recovery. Table 2 shows relationships between characteristics of olfactory loss and the chance of olfactory recovery as well as the degree of olfactory recovery. The follow-up was slightly longer, but not significantly, in the group with olfactory recovery than for the group without olfactory recovery (22.8±6 vs 26.1±7.6 days, p=0.3). Interestingly, patients without nasal obstruction had more chance to recover their sense of smell than those with this symptom (p=0.017). Regarding the degree of olfactory recovery, the time from smell loss onset to olfactory recovery onset was 10±5.6 days in patients with complete olfactory recovery whereas this time was 13.4±6.4 days in those with incomplete olfactory recovery (p=0.0004). The time from smell loss onset to survey was 26.8±8.2 days in patients with complete olfactory recovery and 25.3±7.1 days in those with incomplete olfactory recovery (p=0.37). Other factors such as nasal congestion or sore/dry/tingling feeling in the nose were significantly related to the degree of olfactory recovery (p=0.023 and p=0.007, respectively). It means that patients without those symptoms had more chance of complete recovery of their sense of smell. Finally, the recovery of olfactory function and taste was neither the same duration nor the same degree (p<0.0001). Table 3 shows spontaneous kinetic of olfactory recovery at each time point of survey. The percentage of complete smell recovery seemed to increase gradually as time goes on. The findings of the present study can be summarized as follows: i)about two thirds reported a sudden olfactory/gustatory impairment; ii)olfactory/gustatory disorders can be isolate or associated to other symptoms; iii)95% of patients recovered (incompletely to completely) their olfactory function at one month; iv)olfactory function was recovered between the 4 th and the 15 th day after the onset of olfactory loss in most patients; v)half of patients completely recovered their olfactory function at 4 weeks; and vi)short time from smell loss to the onset of olfactory recovery, absence of nasal obstruction, and absence of sore/dry/tingling feeling in the nose were significantly related to the chance for complete olfactory recovery. Recently, the olfactory loss outbreak during COVID-19 pandemic draws attention to many 10, 20 . However, many viruses, including coronaviruses such as SARS-CoV 11 or HCoV-OC43 12 , have been shown to be able to infect the olfactory bulb and downstream areas such as the piriform cortex and the brain stem through the nasal epithelial pathway. So, SARS-CoV-2 may not be excluded from this pathway. A post-infectious olfactory impairment is typically associated with the common cold or influenza 21 . On the other hand, there is a close temporal connection between the subsiding of This article is protected by copyright. All rights reserved. the URTI and the development of sudden olfactory disorders 21 . A post-infectious olfactory loss may be incorrectly labeled as idiopathic olfactory loss in some patients because they may be unaware of the URTI episode 22 . Interestingly, isolate olfactory loss without other nasal or general symptoms was observed in 4% of our COVID-19 patients. These cases could be incorrectly labeled as idiopathic if they were out of context of COVID-19 outbreak. Most of patients who suffered from acquired olfactory loss also complained of altered taste, describing food as bland because they often confuse loss of retronasal olfactory function (flavor) with taste. Gustatory dysfunction is often recovered when olfactory function comes back. For this reason, gustatory loss was self-reported in most of COVID-19 patients. However, without objective assessment of specific taste qualities (salty, sour, sweet, bitter or umami/savory) in our study, we did not know if this was truly taste loss or instead a flavor perception change resulting from the olfactory loss. The rates of spontaneous recovery of post-infectious olfactory dysfunction at given points of follow-up varied from 6% within 4 months of follow-up 23 to 67% at 37 months of mean follow-up 24 . However, the true rate of spontaneous recovery of olfactory function is still unknown because of: 1) lack of awareness of this condition among both patients and medical providers; 2) lack of epidemiological studies inventorying the rates of post-infectious olfactory impairment and its spontaneous recovery at short-, middle-and long-term; 3) selection bias as most patients with olfactory loss consulted many months, even many years after smell loss; and 4) methods assessing olfactory loss. In contrast, the evolution of olfactory disorders in most of COVID-19 patients can be followed-up during the outbreak thanks to a database of tested patients. Adding to worries due to other disorders in those patients, the sudden olfactory/gustatory loss is another source of anxiety in this condition. Hence, knowledge of the spontaneous evolution of olfactory disorders during the course of COVID-19 is important to reassure patients. Fortunately, most COVID-19 patients with olfactory loss recovered their sense of smell about 2 to 4 weeks after the onset of this condition. This short time supports findings that the non-This article is protected by copyright. All rights reserved. The limitations of our study are: i) recall bias due to retrospective phone call; ii) lack of objective olfactory assessment because of high risk of COVID-19 exposure to healthcare workers; iii) short follow-up; and iv) unknown prevalence of olfactory disorders in patients with serious conditions. In order to minimize the selection bias by self-selected group using internet or the app such as online surveys, we tried to call all patients from the database of our hospital. However, 10% of our COVID-19 patients did answer their phone. The other main limitation of our study is self-report of all symptoms. It had been shown that olfactory selfratings were not reliable in normosmic subjects 27, 28 but reliable in severe hyposmic or anosmic subjects 28, 29 . Therefore, the results of the present study should be interpreted with caution. In order to assess the olfactory recovery, we used a qualitative assessment ("Has your sense of smell started to recover?") associated to within-subject comparisons using numerical scale (from 0 to 10) to self-rate patients' olfactory abilities for different time points. These two approaches were used to seek the coherence between answers in order to maximize a possible accuracy. However, we cannot know accuracy rates of our patients' self-report. We used the within-subjects design by using numerical scale to assess olfactory function at the moment of olfactory loss and the survey time (e.g. survey time minus onset of olfactory loss) to evaluate the degree of olfactory recovery. This method allows fine-tuning the degree of olfactory. Other limitation is the upper anchor of rating scale that was considered as "normal sense of smell" without taking into account the (objective) individual olfactory status. Unfortunately, the olfactory status of our patients was not assessed (objectively and/or subjectively) before COVID-19. However, we screened and excluded patients with recognized olfactory impairment before COVID-19 (by asking patients during the phone call). Table 2 . Relationships between characteristics of olfactory loss and the chance of olfactory recovery as well as the degree of olfactory recovery OD: olfactory disorders Table 3 . Spontaneous kinetic of olfactory recovery at each time point of survey Accepted Article This article is protected by copyright. All rights reserved. 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