key: cord-0912184-q5g12zp7
authors: Salmon, Dominique; Bartier, Sophie; Hautefort, Charlotte; Nguyen, Yann; Nevoux, Jérôme; Hamel, Anne-Laure; Camhi, Yohan; Canouï-Poitrine, Florence; Verillaud, Benjamin; Slama, Dorsaf; Haim-Boukobza, Stephanie; Sourdeau, Elise; Cantin, Delphine; Corré, Alain; Bryn, Agnes; Etienne, Nicolas; Rozenberg, Flore; Layese, Richard; Papon, Jean-François; Bequignon, Emilie
title: Self-reported loss of smell without nasal obstruction to identify COVID-19. The multicenter CORANOSMIA cohort study
date: 2020-07-07
journal: J Infect
DOI: 10.1016/j.jinf.2020.07.005
sha: 760a70060b35d57c5c26aab654889d1899322213
doc_id: 912184
cord_uid: q5g12zp7

OBJECTIVES: To determine the frequency of SARS-CoV-2 positive samples in a subset of patients consulting for primarily isolated acute (<7 days) loss of smell and to assess the diagnostic accuracy of olfactory/gustatory dysfunction for COVID-19 diagnosis in the overall population tested for COVID-19 in the same period. METHODS: Prospective multicentric cohort study in four olfactory ENT units and a screening center for COVID-19. RESULTS: i) Among a subset of 55 patients consulting for primarily loss of smell, we found that 51 (92.7%) had a COVID-19 positive test (median viral load of 28.8 cycle threshold). Loss of smell was mostly total (anosmia), rarely associated with nasal obstruction but associated with a taste disorder in 80%. Olfactory dysfunction occurred suddenly, either as first complaint. The majority of patients (72.9%) partially recovered the sense of smell within 15 days. ii) In a population of 1824 patients tested for COVID-19, the positive predictive value and the specificity of loss of smell and/or taste were 78.5% and 90.3% respectively (sensitivity (40.8%), negative predictive value (63.6%)). CONCLUSIONS: Self-reported loss of smell had a high predictive positive value to identify COVID-19. Making this sign well known publicly could help to adopt isolation measures and inform potential contacts.

Since December 2019, SARS-COV-2 has rapidly spread to become a world pandemic with alarming mortality and morbidity [1] . SARS-COV-2 infection, COVID-19, is a new human disease presenting as a spectrum of symptoms. Some are characteristic of influenza-like disease (i.e. cough, headaches, myalgia, asthenia and eventually dyspnea) whereas other symptoms such as olfactory or taste dysfunction were evidenced along with the development of the pandemic [2] . In the presence of suggestive symptoms, the definite diagnosis of COVID-19 mostly relies on positive real-time polymerase chain reaction (RT-PCR) on nasopharyngeal samples. RT-PCR also allows measuring viral load which could be linked to the disease severity and treatment outcome [3] . However, due to the limited diagnostic test available, all patients suspected of COVID-19 are unlikely to be tested for the presence of the virus and the positive predictive value of each symptom is thus of importance in clinical practice. Self-reported olfactory impairment and gustatory dysfunction have recently been reported, in many patients with COVID-19 and may be an important predictor of clinical outcome [4, 5] . The few cohort studies dealing with these questions have reported a variable prevalence of loss of smell in patients with confirmed COVID-19 (from 5% to 85% according to studies and settings) [4] [5] [6] [7] . These studies being either retrospective [5, 7] or specifically conducted on laboratory-confirmed positive COVID-19 patients [4, 6, 7] , the follow-up of anosmic/hyposmic patients, the link between loss of smell and nasal viral load were not described and the positive predictive value of loss of smell for COVID-19 infection rarely studied. Our first objective was to determine the frequency of SARS-CoV-2 positive samples in a subset of patients consulting for primarily isolated acute loss of smell and to document the link between olfactory dysfunction and the viral load in rhinopharyngeal swabs. A secondary objective was to assess the diagnostic accuracy of olfactory/gustatory dysfunction for the diagnosis of COVID-19 (sensitivity, specificity, Positive and Negative Predictive Value) in the overall population tested for COVID-19 in the same period.

First part of the study: COVID-19 status of a subset of patients self-reporting smell loss as a main symptom

We conducted an observational, prospective multicenter cohort study from March 17th to 25th, 2020 in five centers members of the Group of Greater Paris Hospitals (APHP): four ENT clinics and a Paris emergency screening center for COVID-19 based for health professionals and government employees. In order to document the link between olfactory dysfunction and the presence of SARS-CoV-2, we included consecutive patients consulting (or referred by our ENT colleagues) for a recent (less than 7 days) loss of smell, as primary reason for consultation, either isolated or associated with mild symptoms of COVID-19 (such as headaches, low grade fever, myalgia, nose sneezing..) according to previous reports [8] . All patients were tested for SARS-COV-2 by real-time polymerase chain reaction (RT-PCR) assay in nasopharyngeal swabs. Patients were not included if their olfactory symptoms had lasted for more than 7 days (to ensure that testing occurred during the replicative phase of the disease), if symptoms for COVID-19 were typical or predominant over olfactory symptoms (high fever, cough, dyspnea, pneumonia…) or if the SARS-COV-2 RT-PCR assay could not be performed. Presence of another obvious cause of anosmia was also an exclusion criterion.

The following demographic data were collected at baseline: age, gender, weight, height, occupation, and tobacco use. Medical history included: respiratory allergy, chronic disease, asthma, immunosuppression, diabetes, long-term corticosteroid treatment, obesity, rhinologic history (head trauma, chronic rhinosinusitis, olfactory dysfunction history), acute anosmia history (date and onset (sudden or progressive), severity of associated olfactory symptoms (parosmia, phantosmia), taste disorders (ageusia/dysgeusia, sweet, salty, sour, bitter taste recognition), duration and treatment received (nasal irrigation, local or general corticosteroids, antibiotics…); other ENT symptoms. Data specifically covering COVID-19 included history and chronology of symptoms; severity (hospitalization/outpatient management) and treatment; Results for SARS-COV-2 by RT-PCR assay on nasopharyngeal swabs and contact with a confirmed case (by positive RT-PCR) as previously described [9, 10] .

Patients were followed by a phone interview performed by a physician at day 7 (+/-2 days) 

Samples were collected in Copan UTM-RT (universal transport medium-room temperature) nasopharyngeal swabs and were then inactivated in a Biosafety Level (BSL) 2 level laboratory. Five RT-PCR assaysthe Roche, Altona, Elitech assay or the in house: IP2 (Institut Pasteur Paris, unpublished) and Coreman-Drosten-were used, depending on the center's routine practice, to detect SARS-CoV-2 RNA [10] . The Roche assay (Cobas® SARS-CoV-2) is a qualitative assay based on fully automated sample preparation on a high throughput 8800 system (nucleic acid extraction and purification) followed by PCR amplification and detection. Two genes are targeted: the ORF1/a disordered region that is unique to SARS-CoV-2; and the E-gene of a conserved region in the structural protein envelope (pan-Sarbecovirus detection). The Elitech assay (GeneFinder TM COVID-19 PLUS RealAmp Kit) is a one-step reverse transcription RT-PCR. The protocol is based on viral polymerase (RdRp), envelope (E), and nucleoprotease (N) genes by RT-PCR amplification.

Altona assay is based on the E and S genes detection. For all these tests, viral loads are expressed by Cycle Threshold (CT) values to give a semi quantitative assessment of the SARS-COV-2 viral load: the lower the CT value, the higher the viral load.

Second part of the study: diagnostic accuracy of self-reported loss of smell or taste for

For the second part of the study that assessed diagnostic accuracy of self-reported smell loss and/or taste for the diagnosis of COVID-19, all consecutive patients who were tested for SARS-COV-2 by real-time polymerase chain reaction (RT-PCR) during the same period in Paris screening center for COVID-19, were included and systematically assessed during the usual medical symptom's screening, about their potential olfactory and gustatory dysfunction.

Baseline demographic and medical characteristics (symptoms, history of the disease, ENT and general history) of the patients were described by n (%) for categorical data and mean (standard deviation SD) or median (inter-quartile range IQR) for continuous data as appropriate. We determined the proportion of patients with positive SARS-COV-2 RT-PCR status among patients with acute (<7 days) decreased sense of smell. 95% Confidence Intervals are displayed using binomial assumption.

For diagnostic accuracy of self-reported symptoms smell loss and/or taste for COVID-19 diagnostic, sensitivity, specificity, Positive and Negative Predictive Value and their Confidence Intervals were calculated and compared to that of other symptoms (cough, headache, sore throat) based all the population of all patients screened for COVID-19 during the same period in the Paris-based screening center for health professionals and government employees. Diagnostic accuracy of symptoms were also compared according to single or associated symptoms used as diagnostic criterion (only self-reported smell loss, only selfreported taste loss, presence of both, or non-exclusive association (self-reported smell loss and/or taste). Two-by-two comparisons (with other symptoms) were done using MacNemar test and Bonferroni correction, the threshold being p<0.017. Analysis was performed using Stata SE v15.0 (College Station, TX, USA).

Our study subgroup was 55 patients with self-reported acute loss of smell or taste as main symptom (13 patients referred by the four ENT centers and 42 from the COVID-19 screening center). Median age was 34 years (range 22-61), 56.4 % were female and 61.1% were healthcare professionals. Nineteen patients (34.5%) reported a history of allergic rhinitis, mainly seasonal pollen-induced allergic rhinitis. Twelve patients (21.8%) were current smokers and four (7.4%) had a history of head trauma. Nine patients (16.4%) reported a history of intermittent olfactory dysfunction but none had a history of chronic olfactory dysfunction. Two-thirds (6/9, 66%) of the patients with a history of intermittent anosmia had a history of allergic rhinitis or rhino-pharyngitis or sinusitis, higher than in patients without (13/33; 28%; p=0.05). Patient characteristics are summarized in Table 1 . Table 6 ).

Characteristics of baseline olfactory dysfunction and other ENT symptoms are presented in Table 2 and in Figure 1 Finally, eight patients (14.5%) reported odynophagia.

Thirty-nine patients presented mild clinical symptoms of COVID-19 that usually appeared a few days before the onset of the loss of smell (Table 2 ). These included: headaches (69.1%), asthenia (56%), mild cough (40%), myalgia (30.9%), diarrhea (29.1%) and low-grade fever (29.1%). Cutaneous hyperesthesia with a root pathway on various parts of the body was reported by 9.1% of the patients.

Over half of the patients (30 patients, 54.5%) had received an initial treatment for their olfactory dysfunction: nasal irrigation with saline (n=17/30, 56.7%), a local corticosteroid (n=6/30, 20%), or an oral corticosteroid (n=1/30, 3.3%). Olfactory training was prescribed to 18 patients (n=18/30, 60%). One patient received a 5-day treatment of hydroxychloroquine and azithromycin as an anti COVID-19 therapy and a second one received a 10-day treatment of hydroxychloroquine associated with a 5-day treatment of azithromycin.

Among the 55 patients, 50 had a follow-up at Day 7 (+/-2 days) and at Day 15 (+/-3 days). At Day 7, 33/50 (66%) had a beginning of smell recovery, partial for the majority (Table 3) . At Day 15, 48/51 (94.1%) had a beginning of smell recovery but only complete for 13 (27.1%) ( Table 3 ). The only patient who received oral corticosteroid therapy (for 2 days) completely recovered his sense of smell in less than 7 days and did not develop severe COVID-19 form. Table 4 ). The best diagnostic accuracy was obtained with the non-exclusive association of both symptoms: loss of smell and/or loss of taste (Table 5a ). The diagnostic accuracy of self-reported loss of smell and/or taste was much higher than that of cough, headache and sore throat while sensitivity of cough and headache were higher than loss of smell/taste (Table 5b ).

In the context of the French COVID-19 outbreak, among a subset of patients consulting for an acute and recent (< 7 days) loss of smell as main symptom of COVID-19 suspicion, we found that 51/55 (92.7%) had a positive test for SARS-COV2, thus confirming loss of smell as hallmark of COVID-19 disease. Loss of smell occurred mostly suddenly (within hours) and was the initial COVID-19 symptom in one third of the cases and was associated with taste disorders in 80%. Unlike the usual loss of smell during the common cold, only two patients complained of nasal obstruction.

On the overall population seen at the emergency screening center for COVID-19, by comparing patients self-reporting smell or gustative loss and those without such symptoms, we assessed the high predictive positive value of olfactory and/or gustative dysfunctions for COVID-19 diagnosis (78.5 %) as well as its very high specificity (90%) as already observed in a recent shorter series [2] . Concerning SARS-COV-2 viral loads, although only expressed semi-quantitatively as CTs, we noted that they were globally lower in our series than usually reported in severe forms of COVID [3] .

Viral upper respiratory infection is a major cause of olfactory dysfunction [12] . While rhinoviruses are the most common pathogens found, CoVs are also known to induce postviral olfactory dysfunction (PVOD) [13] . PVOD exhibits a seasonal pattern with a spring predominance [14] . Most of the time, PVOD is temporary, and recovers partially or completely in 80% at one year [15] , which corresponds to the time needed for neuroepithelium regeneration. The very short-term follow-up of 2 weeks in our cohort explains the low complete recovery rate (27.1% at Day 15) . Although the pathophysiology of PVOD induced by SARS COV-2 is not well known [16] , three pathophysiological pathways have been suggested. The first is a conductive dysfunction due to mucosal swelling of the olfactory cleft with common cold. In our cohort, only two patients complained of nasal obstruction. The inflammatory process could be localized in the olfactory cleft alone due to the neurologic tropism of this virus and this could explain the absence of nasal obstruction.

Expression of SARS-CoV 2 entry factors (ACE 2 and TMPRSS2) have been proven in nasal epithelial cultured cells grown in liquid air interface, and specifically in olfactory epithelium [17, 18] . Secondly, PVOD can be a sensorineural dysfunction resulting from damage of the olfactory neuroepithelium. Histological analysis in patients with post-infectious olfactory loss shows acute inflammation and chronic neuroepithelial remodeling [19] . Yet, SARS-CoV2 has been shown to have a neurologic tropism and neuroinvasive potential [20] . The virus is known to induce a cytokine storm with release of pro-inflammatory cytokines, including interleukin and activation of the toll-like receptors in the respiratory tract [21] . Moreover, we have previously reported that neuroepithelium is more widely spread in the nasal cavity of younger people which could explain such a prevalence of smell loss in our population of young health professionals [22] . Furthermore, we observed an atypically high frequency of neurogenic signs such as headaches (69.1%) usually described in around 10% of the patients in COVID-19 disease [23] , endonasal burning sensations (10.9%) and cutaneous paresthesia (9.1%), which seems to argue in favor of neuroepithelium damage. The third pathway, less probable form the rapid beginning of recovery in a majority of the patients, involves central dysfunction resulting in damage of the olfactory central nervous system with one hypothesis for PVOD being that pathogens enter the brain directly through the olfactory nerve [24] . or weak viral excretion…) [25] . We minimized the risk by including patients with loss of smell onset of less than 7 days. Among the four patients with a negative RT-PCR out of 55 included in our subset, one had a PCR-confirmed case contact and the three others had a very typical picture of anosmia without nasal obstruction. Thus, we believe that the negative test results in these four patients could be false negatives. To note, false negative results were lower in this study than observed in others, probably because clinical presentation with loss of smell corresponds to a viral localization in nasopharynx.

In conclusion, the present study confirms the high diagnostic value of self-reported loss of smell for SARS-COV-2 infection which appears as an early sign of the disease. And this finding has potential implications at the individual and public health levels in the current COVID-19 outbreak. Our cohort study confirms that i) acute isolated self-reported loss of smell without nasal obstruction is an early red flag of COVID-19 and an additional criterion for identifying COVID-19 infected-patients and does not need further investigation. This symptom could be added to the list of warning symptoms for public to look out for. Making this sign well known publicly could help these patients, highly contagious despite otherwise mild symptoms, to self-isolate and inform potential contacts of potential sources of contamination. ii) The very high predictive value and specificity of self-reported loss of smell and/or taste, among other classical symptoms, could help to make a presumptive diagnosis of COVID-19. At the public health level, this sign could be easily contained in public health guidance for follow-up of the disease along with the fever, cough and breathlessness. Further studies are needed to better understand the physiopathology and define therapeutic approaches that could increase the recovery rate of the patients. 

Availability of data and materials: All data generated or analysed during this study are included in this published article [and its supplementary information files].

Competing of interest: All the authors have read and agreed with the paper's content. No authors have financial or personal conflicts. Neither the work nor any part of its essential substance, tables or figures have been or will be published or submitted to another scientific journal or are being considered for publication elsewhere. 

2019-nCoV: novel coronavirus 2019 APHP: Assistance Publique des Hôpitaux de Paris ARDS: acute respiratory distress syndrome COVID-19: Coronavirus Disease 2019 CT: Cycle Threshold ENT: Ear Nose Throat HCoV: Human coronavirus MERS: Middle East respiratory syndrome OSN: Olfactory sensory neurons PPV: positive predictive value PVOD: post viral olfactory dysfunction RT-PCR: real time polymerase chain reaction SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2 UTM-RT: universal transport medium-room temperature TLR: Toll Like Receptor

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%) 55 [inter-quartile range] or number (percentage %)

Negative Predictive Value

The authors would like to thank Pr Sebastien Gallien, Henri Mondor Hospital, Pr Stéphane Jaurreguiberry and Dr Tran Khai Nhung, Bicêtre Teaching Hospital, Le Kremlin Bicêtre France. We thank all patients who participated in the study and nurses/doctors who performed the nasopharyngeal samples. We thank Felicity Neilson for linguistic revision.