Symptoms associated with a COVID-19 infection among a non-hospitalized cohort in Vienna

Background Most clinical studies report the symptoms experienced by those infected with coronavirus disease 2019 (COVID-19) via patients already hospitalized. Here we analyzed the symptoms experienced outside of a hospital setting. Methods The Vienna Social Fund (FSW; Vienna, Austria), the Public Health Services of the City of Vienna (MA15) and the private company Symptoma collaborated to implement Vienna’s official online COVID-19 symptom checker. Users answered 12 yes/no questions about symptoms to assess their risk for COVID-19. They could also specify their age and sex, and whether they had contact with someone who tested positive for COVID-19. Depending on the assessed risk of COVID-19 positivity, a SARS-CoV‑2 nucleic acid amplification test (NAAT) was performed. In this publication, we analyzed which factors (symptoms, sex or age) are associated with COVID-19 positivity. We also trained a classifier to correctly predict COVID-19 positivity from the collected data. Results Between 2 November 2020 and 18 November 2021, 9133 people experiencing COVID-19-like symptoms were assessed as high risk by the chatbot and were subsequently tested by a NAAT. Symptoms significantly associated with a positive COVID-19 test were malaise, fatigue, headache, cough, fever, dysgeusia and hyposmia. Our classifier could successfully predict COVID-19 positivity with an area under the curve (AUC) of 0.74. Conclusion This study provides reliable COVID-19 symptom statistics based on the general population verified by NAATs. Supplementary Information The online version of this article (10.1007/s00508-022-02028-9) contains supplementary material, which is available to authorized users.


Introduction
The frequency of the symptoms associated with coronavirus disease 2019 (COVID-19) is valuable information for health authorities during the pandemic. Such knowledge has been used in a variety of applications including triage recommendations and diagnostics [1][2][3]; however, most studies reporting on COVID-19 symptom frequencies concern patients in hospital settings [1]. Thus, published symptom frequencies may not reflect those found in the general population. For example, non-hospitalized people experience less severe forms of the disease [1].
To reduce the above sampling bias, some approaches have been implemented to collect COVID-19 self-reported symptoms from the general population. Self-reported symptoms have been collected 344 Symptoms associated with a COVID-19 infection among a non-hospitalized cohort in Vienna K original article via a variety of means, including an official test prioritization questionnaire [4], symptom trackers [5][6][7], a symptom checker [8] and even Twitter [9]; however, only the symptoms collected via an official test prioritization questionnaire are associated with verified tests results. With other methods, test results are only self-reported. Of the data associated with a verified result, while valuable, most have shortcomings. For example, the data released by the Israeli Ministry of Health does not contain dysgeusia or anosmia as it was not known as a relevant symptom at the early stages of the pandemic [4].
In this work, we describe the COVID-19 symptoms reported by a non-hospitalized cohort in Vienna from 2 November 2020 to 18 November 2021. With a dataset spanning over 9000 users, we analyze the association between these symptoms and the COVID-19 NAAT status. Lastly, we build a classifier to predict COVID-19 positivity from those experiencing flu-like symptoms.

Data collection
From November 2020, Vienna's online COVID-19 symptom checker provided inhabitants with an initial COVID-19 risk assessment. Depending on the outcome, possible options for further action included a nucleic acid amplification test (NAAT) using the reverse transcription-polymerase chain reaction (RT-PCR) method [10,11]. The aim was to offer an additional scalable service, complementing the medical telephone health service "1450". The symptom checker is currently available at https:// symptomchecker.fsw.at/.
The Vienna Social Fund (FSW), the Public Health Services of the City of Vienna (MA15), and the private company Symptoma mutually developed the chatbot based on previous results detailing the accuracy of Symptoma's symptom checker with respect to COVID-19 [3,12,13]. During the chatbot conversation, each user was asked the same set of questions and responses were recorded accordingly. A user had to answer a series of 12 yes/no questions about symptoms. These are fever (> 38°C), cough, dyspnea, sneezing, rhinorrhea, sore throat, malaise, fatigue, diarrhea, headache, hyposmia and dysgeusia. In addition, the user could indicate if, in the last 10 days, there was close contact with a duration longer than 15 min with a person who tested positive for COVID-19. Finally, each user was invited to specify their age and sex. We did not record the exact age of users for data protection issues, but only the age group (see Supplementary Table 1). Symptoms, age group and sex information are used by Symptoma's algorithm to rank COVID-19 against over 20,000 other potential causes [3]. If COVID-19 appeared in the 30 top causes, the user was offered a NAAT [10,11]. A NAAT was also offered if the user reported a positive self-test, had returned from abroad, or has a severe medical precondition and reported any symptom.
The statistics reported in this paper are based on the combined information of the chatbot conversations and the results of the NAATs. A total of 120,768 users were screened this way between the 2nd of November 2020 and the 18th of November 2021. A total of 88,861 users (73.6%) were eligible for the NAAT, of which 10,089 (11.4%) were tested. Among users who did a NAAT, 956 (9.5%) did not report any symptoms but only close contact with a person who tested positive for COVID-19. These were excluded from our further analyses. The remaining 9133 (90.5%) users, who were both symptomatic and had performed a NAAT, were used in the further analyses.

Data analysis
All data were anonymized prior to analysis. Only sex, age group, the answers to the questions, and the result of the NAAT were collated. We analyzed for each symptom if there was a significant difference between users who tested positive for COVID-19 (C19+) and users who tested negative for COVID-19 (C19-). The P-values were calculated by a two-tailed Fisher's exact test and corrected for multiple testing by the Benjamini-Hochberg [14] method.
We analyzed for each symptom if there was a significant difference between male and female among those who tested positive, and if there was a significant difference between male and female among those who tested negative. The P-values were calculated by a two-tailed Fisher's exact test and corrected for multiple testing by the Benjamini-Hochberg [14] method for each of the two analyses independently.
In addition, we quantified the association of each symptom pair via a two-tailed Fisher's exact test. Odds ratios (OR) were calculated and P-values were corrected for multiple testing by the Benjamini-Hochberg [14] method.
We also quantified the association of the three-wise combinations of symptoms via a Breslow-Day test. The P-values were corrected for multiple testing by the Benjamini-Hochberg [14] method.
Lastly, we built a logistic regression model to predict C19+ based on the collected data. A total of 8966 users, who provided an age group and specified their sex as either male or female, were included in this analysis. Sex information is encoded to be 1 for the female and 0 for the male. Age categories were encoded as integers and treated as continuous. Performance was assessed based on the concatenation of the 10 test sets obtained from the cross-validation. We analyzed the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC). Confidence intervals (CI) were calculated by bootstrapping with 3000 repetitions. We then repeated this analysis when including interaction terms in the model.
In both C19+ and C19-groups women reported sore throat (P < 0.001), sneezing (P < 0.001) and headache (P < 0.01) more frequently than men. Men reported fever more frequently (P < 0.001). In the C19+ group only, rhinorrhea and dyspnea (P < 0.01) were more frequently present for women than for men. In the C19-group only, men reported diarrhea more frequently (P = 0.02), while women more frequently reported fatigue (P < 0.001) (Supplementary Fig. 1).

Co-occurrence and association of symptoms
The frequency and the association of all pairs of symptoms within the C19+ are indicated in Fig. 2. For 66.7% of the pairs of symptoms, the association was significantly positive. The three highest associations of symptoms within the C19+ group were between dysgeusia and hyposmia (odds ratio, OR = 32.05, P < 0.001), fatigue and malaise (OR = 8.63, P < 0.001), and sneezing and rhinorrhea (OR = 7.02, P < 0.001). Within the C19+ group, 21% reported both dysgeusia and hyposmia, 23% reported both rhinorrhea and sneezing and 66% reported both fatigue and malaise. These associations were also observed within the C19-group (see Supplementary Fig. 2).
Among associations with a OR higher than 1.18, only those between fever and diarrhea (OR = 1.28, P = 0.052), malaise and dysgeusia (OR = 1.22, P = 0.083), and dysgeusia and headache (OR = 1.19, P = 0.063) were not significant. Associations with an OR between 0.86 and 1.16 did not have a significant positive or negative association.
The frequency and the association of all threewise combinations of symptoms within C19+ are indicated in Supplementary Table 2. For 11.9% of the combinations, the OR are significantly different between the strata. Among these combinations, the ones with the highest co-occurrence frequency are the triplets fatigue, malaise and dysgeusia with 21.3%, malaise, headache and dysgeusia with 17.7% and fatigue, headache and dysgeusia with 17.6%. As a reference for these triplets, the expected symptom co-346 Symptoms associated with a COVID-19 infection among a non-hospitalized cohort in Vienna Symptom co-occurrence frequencies for the C19+ group. Frequencies are reported in percentage of the C19+ group that report both symptoms. Log odds ratios (LOR) are represented by the color scale. They show the strength of the association. LOR indicates an association when its value is more than 0, a dissociation if lower than 0. The equivalent results for the C19group are included as Supplementary Fig. 2 frequencies calculated as the product of the individual symptom frequencies are 16.8%, 14.4% and 13.6%, respectively.

Evaluation of a classifier based on symptoms
A classifier was built using the 8966 users who reported symptoms, age, and sex. The ROCs for each test set are shown in Fig. 3. Across the 10 test sets, the logistic regression model predicts with an AUC of 0.74 (95% CI 0.72 to 0.75). The coefficients and the P-values obtained for the logistic regression after training on all the available data are reported in Supplementary Table 3. Possible working points, that being a threshold to which we predict COVID-19 positivity, include a sensitivity of 0.70 and a specificity of 0.65, sensitivity of 0.80 and a specificity of 0.51, or a sensitivity of 0.90 and a specificity of 0.32. We also evaluated the performance when excluding the answer about a contact with a COVID-19 positively tested person. In this setting, the AUC is 0.69 (95% CI 0.68 to 0.70). The ROC curve is included in Supplementary figure 3. Next, we expanded the first model to include all pairwise-interaction terms. It performs significantly better than the model without interaction terms (P < 0.001), with an AUC of 0.76 (95% CI 0.74 to 0.77). The ROC curve for the model with interaction terms is shown in Supplementary Fig. 4
The results also show that the symptoms experienced by C19+ significantly differ, except for dyspnea, to those experienced by C19-. This agrees with other studies that also reported hyposmia, dysgeusia, and fever as significantly increased in C19+ persons [6,21,22]. Further, the large relative difference of hyposmia (+155%) and dysgeusia (+101%) frequencies for C19+ in comparison to C19-users suggests that hyposmia and dysgeusia are specific but not sensitive, i.e. their presence strongly suggests the user is C19+ but no conclusion can be drawn from their absence.
The association of dyspnea with a COVID-19 positivity, not observed in the present analysis, was also not found by Menni et al. [2]. This might be due to a sample bias as dyspnea is often a late symptom of an infection while chatbot users might rather be at an earlier stage of infection [23]. Alternatively, dyspnea can be a distressing symptom and affected individuals might rather call an emergency hotline instead of using a chatbot [24]. Additionally, results show symptoms were reported in different frequencies by men and women, which could be caused by sex-specific differences in the clinical course [25,26].
As shown in previous studies, the high correlation found between dysgeusia and hyposmia indicates that these pairs of symptoms frequently occur together [27]. The same holds true for rhinorrhea and sneezing [28]. The high correlation between fatigue and malaise might be explained by the fact that fatigue is a subjective symptom of malaise [29]. The latter pair of symptoms also has a high co-occurrence frequency, which might be explained by the correlation, and the non-specific nature of these symptoms [29].
The AUC of our predictor (0.74) is in the range of the performance of the symptom-based COVID-19 predictor described in the literature. Other reported AUCs were as 0.68 [21], 0.74 [2] and 0.90 [4]. The considerably higher AUC of the latter predictor is explained by the inclusion of many asymptomatic patients who did not report any contact with a COVID-19 infected person. These patients, as expected, are mostly C19-, thereby inflating performance. Predicting COVID-19 positivity from patients who do not report any symptoms or contact is not considered within our study, which only deals with symptomatic people.
Our study has limitations. First, self-reported symptoms are, by definition, not assessed by a medical professional which leads to inconsistencies. Second, there is selection bias because people with a low risk of being C19+ were not offered a test (see methods). Another selection bias is the potential underrepresentation of subgroups with reduced access to the technology. For example, Nguyen et al. show that the usage of chatbots significantly decreases with age and low education level [30]. Third, users can experience additional symptoms after completing the session. These symptoms were not recorded and included in the present study. This leads us to believe, as discussed previously, that our cohort is focused on the early onset of COVID-19. Lastly, the consideration of the NAAT as a ground truth has been criticized due to its low sensitivity [31].
In addition to the above limitations, our sampling period aligns with Austria's COVID-19 vaccination campaign as well as the emergence of new variants. Both of these factors, namely being vaccinated or being infected with a variant, have the potential to alter the symptoms experienced. For example, it has been reported that vaccinations reduce the number of symptoms experienced [32]. In contrast, the emergence of variant B.1.1.7 (Alpha), was reported to not affect the symptoms experienced [33]. In our study, we did not find any significant changes in the symptom frequencies over time (see Supplementary  Fig. 5).
In conclusion, we have analyzed in depth the COVID-19 symptoms reported by a non-hospitalized cohort in Vienna over the past year. Data were systematically collected and results were automatically associated with a NAAT. To date, no other work features a general European population in combination with systematic data collection. For this reason, we believe that this work provides excellent new insights into the characteristics of COVID-19. Ethical standards This study was exempted from ethics review by the ethics commission of the city of Vienna (MA15-EK/21-037-VK_NZ). All individuals using the chatbot agreed that their data will be used in an anonymized way.
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