key: cord-0914227-87o3xblx authors: Basu, B.; Riya, P. A.; Issac, J.; Parvathy, S.; Nair, B. S.; Tokdar, P.; Kumar, D. S.; Kulkarni, P. R.; Hanumanram, G.; Jagadeesan, M.; Suthakaran, P. K.; Nair, L. D. V.; Vennila, R.; Kannan, R.; Kaimal, B.; Anoop, G. K.; Joseph, I.; Nair, R.; George, S.; James, J.; Pillai, M. R. title: Effective community screening for asymptomatic and symptomatic COVID-19 with a fast and extremely low cost COVID-Anosmia Checker tool date: 2020-11-03 journal: nan DOI: 10.1101/2020.10.28.20221200 sha: ce4198136cf8fcceb348070e20c3e67cdae174a1 doc_id: 914227 cord_uid: 87o3xblx Background: Covid-19 curve can be flattened by adopting mass screening protocols with aggressive testing and isolating infected populations. The current approach largely depends on RT-PCR/rapid antigen tests that require expert personnel resulting in higher costs and reduced testing frequency. Loss of smell is reported as a major symptom of Covid-19, however, a precise olfactory testing tool to identify Covid-19 patient is still lacking. Methods: To quantitatively check for the loss of smell, we developed an odor strip, COVID-Anosmia checker, spotted with gradients of coffee and lemon grass oil. We validated its efficiency in healthy and COVID-19 positive subjects. A trial screening to identify SARS-CoV-2 infected persons was also carried out to check the sensitivity and specificity of our screening tool. Results: It was observed that COVID positive participants were hyposmic instead of being anosmic when they were subjected to smelling higher odor concentration. Our tool identified 97% of symptomatic and 94% of asymptomatic COVID-19 positive subjects after excluding most confounding factors like concurrent chronic sinusitis. Further, it was possible to reliably predict COVID-19 infection by calculating a loss of smell score with 100% specificity. We coupled this tool with a mobile application, which takes the input response from the user, and can readily categorize the user in the appropriate risk groups. Conclusion: Loss of smell can be used as a reliable marker for screening for Covid-19. Our tool can rapidly quantitate anosmia, hyposmia, parosmia, and can be used as a first-line screening tool to trace out Covid-19 infection effectively. M a d h a v a n Introduction: The recent ongoing pandemic of COVID-19 caused by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has posed an enormous challenge to the human race 1, 2 . It is important to note that the SARS-CoV-2 is more infectious than that of SARS-CoV and MERS-CoV since all infected individuals can potentially transmit the virus including those who are asymptomatic [3] [4] [5] [6] . That is why the overall number of deaths from COVID-19 outweighs that from SARS and MERS. Although at what stage and how frequently the asymptomatic individuals potentially transmit the disease remains to be elucidated. As on 24 th October 2020, the number of confirmed COVID-19 cases has risen to 42.4 million with more than 1.14 million deaths worldwide (https://coronavirus.jhu.edu/map.html). It is highly likely that the number of cases would be significantly greater than that reported because very mild or asymptomatic cases are excluded as they go untested. Several serological studies have shown that the number of infected cases is more than ten times higher than the confirmed cases [7] [8] [9] . Thus, it raises the question of the efficiency of the broad screening methods adopted currently to prevent the spread of the disease. Given that the Covid-19 cases can surge as a second wave, it is high time to switch from the highly sensitive PCR based surveillance regime to a sufficiently inexpensive and easy to test regime. Perhaps a test that can be performed at home multiple times a week would better serve the purpose 10, 11 . The common symptoms of COVID-19 are fever, cough, fatigue and less common symptoms are headache and diarrhea 12, 13 . But recent reports suggest that the loss of smell is a prominent symptom of COVID-19 infection [14] [15] [16] [17] [18] [19] [20] which is consistent with the listed symptoms by the Center for Disease Control and Prevention (Atlanta, GA, USA) 21 . The identification of the impairment of sense of smell is particularly important in a country like India and similarly for other low and middle-income countries where mass screening through RT-PCR or antigen test is resource-intensive. Therefore, the approach should be made such that the patients with recent onset of olfactory dysfunction (OD), with or without other symptoms of COVID-19, should undergo self-isolation and, when possible, take confirmatory SARS-CoV-2 testing. However, self-testing of olfactory function is difficult to standardize across locations, cultures and scenarios by asking participants to test themselves with household items like flowers, soap etc. 17 . Clearly quantitative assessment of smell perception (e.g., hyposmia) is not feasible in the case of self-reporting. Moreover, subjective bias is an added disadvantage to this way of assessing smell perception dysfunction. Here, we developed an olfactory assessment tool that can reliably test the participants without having a subjective bias. This tool seeks to assess a combination of parameters that includes the odor threshold (minimum strength of an odor that can be perceived), odor discrimination (differentiation between different odors) and odor identification. Moreover, this tool is also capable of identifying a quantitative reduction in smell (anosmia/hyposmia) as well as qualitative changes in smell (e.g., distortions of smell termed as parosmia, or phantom sensation termed phantosmia). This low-cost strip-based anosmia-screening tool can be used for mass screening of COVID-19 and here, we have validated its potential to be used as a first-line screening tool to trace out COVID-19 infection effectively. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. Sample size estimation was carried out in order to determine the study population. It was estimated that more than 25 participants were needed to have a confidence level of 95% with 20% marginal error. Population proportion by default was chosen as 50%. Participants who completed all the mandatory queries (that addresses odor identification, RT-PCR/Antigen/Antibody test results) were included in the present study. Participants who did not complete all required fields and/or provided incomplete responses in smell perception were excluded from the sample. Here, we categorized the participants into three diagnostic groups: 1) Control participants who had no respiratory illness and were confirmed to be antigen or antibody (both IgM and IgG) negative to SARS-CoV-2 (N= 35; 9 M, 26 F; age range 25-50). These participants had not contacted any COVID-19 positive patients and had . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] and fever clinic outpatients (N= 30; 24M, 6F; age range 20-50) whose COVID-19 RT-PCR status was unknown at the time of olfactory assessment but was followed by RT-PCR test. COVID-Anosmia checker consisted of Part-A and Part-B (Fig. S1A&B) . Part-A consisted of the test strip as depicted (Fig. S1A) . The test strip consists of six black printed regions where positions 1, 3, 4, 5 contain different concentrations of coffee oil (2.0µl, 1.0µl, 2.5µl, and 5.0µl respectively, meant for odor threshold/ quantitative smell assessment). Position-2 was intentionally kept blank (to identify odor discrimination/phantosmia and also acted as p l a c e b o ), and Position-6 contained lemongrass oil (5.0µl, for odor discrimination/quantitative smell assessment). This combination is ideal for assessing the quantitative reduction and qualitative changes in smell. Coffee oil and lemongrass oil is used since these two odors are very common to households and consistent with the previous self-reporting based study 22 . The concentration of gradient and the pattern of spotting were standardized after a series of tests on normal healthy individuals. 1μl of coffee oil was the minimum volume that could be detected by any healthy individual. The spotted strip (odorized/non-odorized) was then wrapped with two layers of lamination to trap and stabilize the odor. The test strip with a combination of odor remained unknown to the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint subject being tested. The test subject had to cut each position separately along the dotted lines as depicted, smell the cut ends immediately and report the smell and intensity before proceeding to the next position (Fig.S1A) . The scoring sheet (Part-B) provided along with each paper strip sought to gather a few details of the participants after getting oral consent for their participation in the study (Fig. S1B) . Section-1 includes the personal information and travel history of the test subject. In Section-2 the test subjects had to score Yes/No and mention the perceived odor in the dedicated column after smelling the COVID-Anosmia checker strip. Section-3 covers the symptoms if any, experienced by the test subjects and the date of onset of that particular symptom. Further an android based mobile application was developed to replace Part-B for easy decision making. Currently, the application is downloadable (https://neologix.ae/covid-anosmia-checker-app.html) to any android based smartphone and can be combined with test strips (Part-A) for selftesting or community screening. Participant's responses while identifying coffee and lemongrass oil varied depending upon their prior experience with that odor. For example, in this study, several participants identified the coffee smell as "chocolate" and lemongrass oil as "orange" or "phenyl flavor". Hence the smell identification is considered as 'normal' when the subject either mentions the correct smell or any near perception. If the response is "no smell" or "undetectable" or "cannot identify" then it is considered as 'anosmia'. The strip is made up of absorbent paper and if the response is "paper smell" then it is regarded as 'anosmia' for the odorized spots and 'normal' for the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint non-odorized spot (Position-2). Any smell response other than previously mentioned is considered as a distortion of smell or 'parosmia' for odorized spots and 'phantosmia' for the non-odorized spot. Data were analyzed using IBM SPSS 20.0, Microsoft Excel, and visualized using R Studio ggplot2 package. Descriptive statistics (numbers with percentages) were performed for categorical variables. Chi-squared tests were performed on categorical data as part of the secondary analysis. Multinomial regression analyses were performed on the categorical variables to assess the association between the COVID-19 test status and the sense of smell perception for all the six positions of the Anosmia checker. Logistic regression analysis was performed on the data collected from the fever clinic and suspected COVID cluster to find out the association between any osmia events to COVID-19 test positivity. We agree to make available materials, data and associated protocols used in this study upon request. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. e p a t i e n t s a n d n o n i n f e c t e d p a r t i c i p a n t s : Initially, we confirmed the performance of the test strip on 35 normal healthy individuals who were negative for COVID-19 by Antigen/Antibody testing ( Fig. 1) . All the odorized spots (1, 3, 4, 5, and 6) were identified 'exactly or similarly' by 68-94% of the participants. The odorized spots were arranged in such a way that as the concentration of the odorized oil increased, the percentage of correct smell responses from the participants also increased (1.0µl coffee-71.4%, 2.0µl coffee-88.6%, 5.0µl coffee-68.6%, 5.0µl lemongrass oil-94.3%, Fig. 2A ). We observed a minor anosmia or parosmia response amongst healthy control participants who reported it as "non-identifiable" or "pleasant smell but cannot specify". Parallelly, we Fig. 2A) . Thus, it implies that other than complete loss of smell (anosmia) there are events of reduced smell or hyposmia that otherwise cannot be reliably detected by directly smelling household items. This is evident from the fact . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Phantosmia or phantom sensation of smell is relatively uncommon symptom seen in trivial illness affecting nasal epithelium as well as in many illnesses affecting central nervous system [23] [24] [25] [26] . It is also reported to be present in healthy individuals 27, 28 Interpretation of the data showed that almost 95% of the COVID-19 positive patients showed some degree of olfactory dysfunction ranging from partial to complete loss of smell (Fig. 2B) . The remaining 5% of the COVID-19 positive subjects showed normal smell perception indicating the possibility of the recovery from the disease. Symptom analysis showed that only 30% of Covid-19 positive patients reported fever, 27% dry cough, and 13% had body pain. However, comparatively lower proportion of the patients reported breathing difficulty (3%) and diarrhea (2%) (Fig. 2B) . The loss of smell (95%) turned out to be the most common symptom amongst the positive patients which is consistent with the previous findings [14] [15] [16] [17] . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint Moreover, we have taken into account both symptomatic as well as asymptomatic COVID-19 patients. Amongst the symptomatic patients, 97% of them showed smell perception dysfunction (Fig. 2C) . On the other hand, when the socalled 'asymptomatic' patients were tested, majority of them were found to have olfactory dysfunction (94%, Fig. 2C ). In the current study the proportion of asymptomatic subject was only 34% of the total patient-participants. That is attributed to the fact that majority of patients with clinical symptoms only were admitted to the hospital (Fig. S3B) . Practically, we expect to find an increased percentage of asymptomatic subjects compared to symptomatic patients in a community screening. Next, we wanted to verify whether the COVID-Anosmia checker could be used to predict the COVID-19 test positivity. We explored the association between the loss of smell and SARS-CoV-2 infection. We ran the anosmia test in a small set of population (N=58; age range 20-50) who were suspected to have COVID-19 or were primary contacts (Fig. 1) . This group was a representative of a small community to check the efficiency of the COVID-Anosmia checker to initially screen and identify possible COVID-19 infection. Logistic regression analysis showed that a single altered response (anosmia/ parosmia/ hyposmia) in the smell test increased the likelihood of being tested positive for Covid-19 by 3.8 times (OR 3.8, 95%CI 1.5-9.4, p=0.004, Table. 2). Out of six spots in the COVID-Anosmia checker five of them are odorized and consistent altered smell response for all the five spots increases the probability to be tested positive for COVID-19. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint In the community study, we categorized the participants (N=58) into three risk groups based on their smell response. Altered smell response for each of the five odorized spots was counted as score 1 into the 'Sum of Osmia' score. A 'Sum of Osmia' score was considered as 'low risk group' if the value is 0-2; 'medium risk group' for values 3-4 and 'high risk group' for value of 5. (Fig. 3A) . Out of 58 participants, we found that 26, 15, and 17 of them were at high-risk, medium-risk, and low-risk category respectively. 17 (65%) of the high-risk group, 4 (26%) of the medium-risk group were found to be COVID-19 positive through RT-PCR testing whereas none of the low-risk group participants turned positive indicating a 100% specificity. We have found that it would be difficult for a person who is not familiar with the test to make an unbiased interpretation of the Part-B scoring sheet. To overcome this issue, we developed a mobile application replacing the Part-B scoring sheet (Fig. S2 ). The inputs for the application were statistically derived from the community screening as discussed earlier (Fig. 3B, Table. 2). The person undergoing the test will have to enter the information as shown (Fig. S2) . Based on the detection of the odorized spots, the application will give the output with the 'Sum of Osmia' score as "Low-Risk" (0-2), "Medium-Risk" (3) (4) or "High-Risk" (5). If a person is self-testing with the COVID-Anosmia checker and gets an output as "Medium Risk" or "High Risk" then there is a high probability for that person to be COVID-19 positive and should self-quarantine to reduce the spread (Fig. 3C) . Whereas, in community screening of suspected COVID-19 clusters or at airport/border entry points only . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 3 persons with "Medium-Risk" or "High-Risk" need to be subjected to confirmatory COVID-19 tests thereby significantly reducing the test numbers and cost (Fig. 3C) . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint To counter the shrinking economy, countries throughout the world have no other option but to lift the lockdown in a graded manner. Various countries including India have started lifting the lockdown once the dynamics of the virus and its case fatality rate were understood 29, 30 . This poses a threat to the health sectors as the second wave of infection is being reported in several parts of the world including the UK, France, Spain, etc. (https://coronavirus.jhu.edu/data/new-cases). These circumstances are making it even more critical to self-test and self-isolate than ever before to limit the spread of SARS-CoV-2 virus. So far there is no available test kit to self-test reliably for SARS-CoV-2 infection. As loss of smell is a recently recognized symptom of COVID-19 21 , developing a smell test kit was the need of the hour. Here, we developed a low-cost olfactory assessment tool and validated it amongst the COVID-19 positive and negative participants. We found that quantitative assessment of smell perception is equally crucial as reduced smell or hyposmia may be underestimated while self-testing with available household items. It is important to note that when participants reported reduced smell or hyposmia, in each case their COVID-19 test report turned out to be positive although such number is less in our cohort study. Finally, we have shown that the COVID-Anosmia checker can be used to predict the SARS-CoV-2 infection. Currently, we rely heavily on thermal screening alone to look for symptomatic individuals that entail around 14% of the COVID-19 infected individuals and are significantly missing the rest (Fig. S3A) . Based on our findings we suggest a radical change in COVID-19 screening protocol in public places such as border entry points, schools, restaurants, and airports. It would be ideal to screen out large communities with olfactory dysfunction using the COVID-Anosmia checker along with thermal . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint screening and further, the smaller high or medium-risk group can be subjected to confirmatory COVID-19 testing platforms (Fig. 3C) . This protocol will be extremely useful for low and middle-income countries since it can significantly reduce the proportion of patients that needs to be subjected to costly RT-PCR based confirmation. A model for community screening is depicted in Fig. 3C Further, coupling the COVID-Anosmia checker with the mobile application helped in easy unbiased categorization of the risk groups. Currently, the application can be downloaded onto any android smartphone and used as standalone software. The current android version has the potential to be further integrated with any health systems software to generate a database to track and quarantine the high-risk group. Based on our above findings we stress the usefulness of the COVID-Anosmia checker as a low-cost, fast and accurate quantitative primary mass-screening tool, combined with confirmatory platforms or for self-checking and isolation. It can also be effectively used in difficult to reach geographical locations. This approach could significantly reduce cost, time and enhance detection and tracing of symptomatic and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 6 asymptomatic COVID-19 patients thereby immensely helping in management and control of COVID-19 spread. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint 3 as 1 to 6. Each absorbent paper is spotted onto the middle of the dotted line with different volumes of odorant oils owing to create a gradient of odors. The second position is left blank. (B) The form associated with the paper strip contains the details to be filled by the subjects. and 'asymptomatic' subjects included in the study. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted November 3, 2020. ; https://doi.org/10.1101/2020.10.28.20221200 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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