Headache or Disturbed Smell and Taste During Acute COVID-19 as Predictors of Long COVID at One Year

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Viral pathogenesis studies suggest the potential of central nervous system (CNS) affection in the acute phase of COVID-19 predicting long COVID. This study investigates whether acute COVID-19 symptoms, particularly headache and disturbed smell and taste, predict manifestations of long COVID. Methods : This prospective cohort study included COVID-19 patients hospitalized between March 2020, and May 2021. One year after discharge, patients responded to a symptom questionnaire. Logistic regression analysis was used to determine the odds ratio (OR) for these outcomes. Results : Of 288 eligible patients, 111 responded to the follow-up questionnaire. At 1 year follow-up, disturbed smell and taste during acute COVID-19 did not elevate the risk of long COVID. However, patients with acute headache demonstrated a tendency towards an elevated risk of CNS-related long COVID. Notably, this risk significantly increased in patients reporting dizziness (adjusted OR=4.20; 95% confidence interval (CI) 1.19 - 14.85). Neither disturbed smell and taste nor headache during acute COVID-19 indicated a statistically significant risk of worsening in fatigue, health, or total symptom score at 1-year follow-up. Conclusion : Headache, and not disturbed smell and taste, predicted CNS-related long COVID. Further research is warranted to clarify pathways connecting CNS-related symptoms during acute COVID-19 with long COVID, aiding the efforts of addressing the range of symptoms observed among long COVID patients and developing effective interventions. COVID-19 long COVID cohort study headache disturbed smell and taste neuroinvasion risk factors Figures Figure 1 Figure 2 Introduction Long COVID 2019 is characterized by persistent symptoms more than 12 weeks after initial infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a concerning aftermath of COVID-19. According to estimates, 58% of hospitalized patients experience at least one persistent symptom 120 days after infection,(Chen et al., 2022 ) and 64% and 59% of patients continue to experience long COVID six months and up to one year after initial infection, respectively.(Ma et al., 2022 ) Symptoms of long COVID are diverse and can arise from multiple organ systems,(Ma et al., 2022 ) including symptoms related to theCNS: headache (21%)(Mølhave et al., 2021 ; Pinzon et al., 2020 ) paresthesia (33%)(Pinzon et al., 2020 ) cognitive disorder (35%),(Pinzon et al., 2020 ) and memory loss (11%).(Ma et al., 2022 ) Although the predominant transmission of SARS-CoV-2 is airborne,(Crook et al., 2021 ) the pathophysiological basis of long COVID associated with the CNS may not be readily apparent and remain unknown. Viral travel along the olfactory nerve causing direct viral CNS damage has been suggested as an underlying mechanism(Whitcroft & Hummel, 2020 ) as nasal epithelial cells show relatively high expression of the angiotensin-converting enzyme 2 receptor required for viral entry.(Nalbandian et al., 2021 ) Further, brain imaging studies investigating the pathology of SARS-CoV-2, have shown structural changes in the olfactory bulb and in brain areas associated with the olfactory system among patients with long COVID.(Douaud et al., 2022 ; Najt et al., 2021 ; Tan et al., 2022 ) While the proximity of upper airways to the olfactory bulb and the high prevalence of disturbed smell and taste as well as headache (54%, 49%, and 48% respectively)(Wu et al., 2022 ) during acute COVID-19, offer possible connections to subsequent CNS-related long COVID. The potential roles of hematogenous spread of SARS-CoV-2 or critical illness for developing CNS-related symptoms cannot be ignored,(Nalbandian et al., 2021 ) and a recent study involving hamsters also suggests a potential interplay between both neuroinvasive abilities and inflammatory processes.(de Melo et al., 2023 ) This study aims to explore this potential link between acute COVID-19 symptoms during hospitalization and subsequent long COVID. The present study investigates whether patients with disturbed smell and taste as well as headache during acute COVID-19 are at an increased risk of developing CNS-related long COVID. It is our hypothesis that these patients were at an increased risk of developing CNS-related long COVID compared with patients without these symptoms. Materials and methods Study design and follow-up A single center, prospective cohort study on patients hospitalized with COVID-19 was performed at the Department of Infectious Diseases at Aarhus University Hospital (AUH), Denmark between March 1st, 2020, and May 1st, 2021. One year after discharge, patients were contacted via e-mail or letter and asked to complete a 31-item Post COVID Symptom Questionnaire (PCQ) in which each symptom experienced during four weeks prior to answering the questionnaire and not present before acute COVID-19 was rated on a Likert scale of 0 to 4: 0: None; 1: A little; 2: Some; 3: A lot; 4: Very much. Symptoms were considered present if they had received a score of 2 or more. Further, the questionnaire contained the standardized tests of fatigue, Fatigue Assessment Scale (FAS)(Michielsen et al., 2003 ) and health-related quality of life, EQ5D-5L.(Janssen et al., 2018 ) The PCQ score is the sum of scores for its 31 symptoms, and it has previously been more thoroughly described.(Agergaard et al., 2022 ; Agergaard, Gunst, et al., 2023 ) Study population and data collection Patients included had tested positive for SARS-CoV-2 with a polymerase chain reaction (PCR) test upon admission, were adults (≥ 18 years of age), and were hospitalized for at least 12 hours. Reasons for exclusion can be seen in Fig. 1. During hospitalization, patient data regarding age, sex, ethnicity, BMI, smoking status, and comorbidities were registered. Symptoms reported on day one, three, and five of hospitalization with acute COVID-19 were also registered in the patients’ file and entered in a secured REDCap database.(Harris et al., 2009 , 2019 ) Before patients were invited to participate in this study, written consents were obtained. Statistical analysis As disturbed taste reported by COVID-19 patients can be attributed to disturbed retronasal olfaction (flavor) rather than impaired gustation(Whitcroft & Hummel, 2020 ), the reporting of disturbed smell and taste were listed together in our data analysis. We compared patients registered with either disturbed smell and taste or headache with those registered without these symptoms during acute COVID-19. As an exploratory approach, we performed all analyses again where all missing data from hospitalization were treated as not present, as negative findings were not always registered in patients’ files and patients were not systematically interviewed during admission. Logistical regression analysis was conducted to determine the OR with 95% CI for differences in demographics and in symptoms at 1 year follow-up between patients who reported disturbed smell and taste as well as headache during acute COVID-19 compared to patients who did not report these symptoms. Risks of reporting symptoms (i.e., scoring 2 or more in one or more symptoms) were presented in the following symptom groups: neurological; upper airway; cardiopulmonary; gastrointestinal; cutaneous; musculoskeletal; general symptoms; and any symptom. If a symptom group presented with an OR of > 2, ORs for individual symptoms within the group were examined. Risks were presented as unadjusted OR and adjusted OR for common confounders: age, sex, and BMI. Risk evaluation of patients reporting cutaneous symptoms was omitted due to the limited size of the sample. Long COVID severity was assessed using PCQ score which was validated previously.(Agergaard et al., 2022 ) Additionally, the FAS score, and EQ5D-5L Index were used as secondary outcomes. Long COVID was classified as severe if the PCQ score exceeded the cohort’s median score (≥ 35 points), FAS ≥ 35 (indicating severe fatigue),(Hendriks et al., 2018 ) and if EQ5D-5L Index was below 0.86, which refers to the median index among Danish individuals who share a comparable age to the median age of responders in this cohort(Jan et al., 2009 ). Logistical regression analysis was used to calculate the OR for scoring above the severe threshold among patients who reported disturbed smell and taste or headache during acute COVID-19 versus patients with none of these symptoms. Data were analyzed using Stata MP Version 17.0. A P-value of < 0.05 was considered statistically significant. Ethical approval Register- and questionnaire-based studies do not require ethics approval (Danish Committee Act, Section 14, Subsection 2, the Central Denmark Region Committee on Health Research Ethics reference 1-10-72-181-20). Data collection and the interview study were approved by the Data Protection Authorities in Central Denmark Region (references 1-16-02-4-21). Results Between March 1 st , 2020, and May 1 st , 2021, 533 patients were admitted to the Department of Infectious Diseases at AUH, Denmark. A total of 107 patients died: 76 patients during admission and 31 patients during follow-up. Additionally, 138 patients were excluded: 15 patients due to a dementia diagnosis, 10 patients were lost to follow-up due to travels, 20 patients did not consent to participate in our study, and 93 patients did not return a signed consent form. The remaining 288 eligible patients were invited to participate in our follow-up questionnaire at 1-year follow-up after discharge via email or letter, of which 111 patients responded (Figure 1). Follow-up questionnaires were collected between 6 th of August, 2021 and 6 th of April, 2022; which was median 369 (interquartile range (IQR): 352-524) days or 53 (IQR: 50-74) weeks after symptom onset. Among responders, the median duration from symptom onset to admission was 8 (IQR: 5-10) days, median duration of hospitalization was 5 (IQR: 3-10) days. During hospitalization, 83% of patients required supplemental oxygen and 16% of patients were transferred to the intensive care unit (ICU). Compared with non-responders, responders had a significantly higher age (65 versus 57 years, P=<0.001), were significantly more likely to be Caucasian (P=<0.001), and a significant higher proportion required supplemental oxygen (P=0.048) and were transferred to the ICU (P=0.002) (Table 1). Table 1. Demographic characteristics of hospitalized COVID-19 patients (responders versus non-responders) at 1-year follow-up. Responders (n=111) Non-responders (n=177) P-value Age, years a 65 (56-75) 57 (48-71) <0.001 Sex 0.240 Female 48 (43) 73 (41) Male 63 (57) 104 (59) Race and Ethnicity <0.001 Caucasian 104 (94) 96 (54) Other 7 (6) 81 (46) BMI a 27.7 (25-33) 29.0 (26-33) 0.300 Smoking status a 0.280 Never-smoker 58 (54) 105 (59) Previous smoker 49 (45) 58 (33) Active smoker 1 (1) 14 (8) ≥1 comorbidities 81 (73) 135 (76) 0.340 Symptom onset to hospital admission, days 8 (5-10) 7 (3-10) 0.140 Hospital admission, days 5 (3-10) 5 (3-9) 0.095 ICU admission 18 (16) 20 (11) 0.002 Required supplemental oxygen 92 (83) 132 (75) 0.048 Data are median (IQR) or n(%). a Age at follow-up, BMI, smoking status, and comorbidities at hospital admission. Of the responders at 1 year follow-up, 60% and 54% had experienced headache as well as disturbed smell and taste during acute COVID-19, respectively. At follow-up, 92% of the responders had at least one persisting symptom. The most frequently reported symptoms present at follow-up were dyspnea during activity (51%), fatigue (47%), and difficulties maintaining sleep (47%) (Table 2). Table 2. Prevalence of symptoms among responders (n=111) during acute COVID-19 and at 1-year follow-up Acute COVID-19 1 year follow-up a (n/N b (%)) (n/N b (%)) CNS-related symptoms Headache 60/100 (60) 27/110 (25) Dizziness 39/79 (49) 23/111 (21) Concentration difficulties - 36/110 (33) Short-term memory problems - 34/111 (31) Long-term memory problems - 37/111 (33) Paresthesia - 22/100 (22) Upper airway symptoms Nasal congestion 7/39 (18) 29/108 (27) Sore throat 18/64 (28) 10/106 (9) Disturbed smell 25/60 (42) 24/109 (22) Disturbed taste 36/69 (52) 20/109 (18) Disturbed smell and taste 37/69 (54) 26/109 (24) Cardiopulmonary symptoms Dyspnea during rest - 31/110 (28) Dyspnea during activity 96/107 (90) 56/111 (51) Cough 103/107 (96) 26/107 (24) Productive cough 39/101 (39) 24/108 (22) Chest pain 22/92 (23) 15/103 (15) Palpitations - 13/103 (13) Gastrointestinal symptoms Reduced appetite - 17/108 (16) Nausea 47/95 (50) 8/104 (8) Stomachache 14/86 (16) 9/105 (9) Diarrhea 48/96 (50) 8/104 (8) Altered bowel habits - 17/106 (16) Cutaneous symptoms Skin rash - 12/104 (12) Skin itching - 22/108 (20) Musculoskeletal symptoms Joint pain - 39/109 (36) Joint swelling - 23/108 (21) Myalgia 56/84 (67) 41/109 (38) Muscle exhaustion - 28/103 (27) General symptoms Fever episode - 9/103 (9) Fatigue 81/93 (87) 51/107 (47) Increased sleep duration - 50/108 (46) Difficulties falling asleep - 33/108 (31) Difficulties maintaining sleep - 51/108 (47) Any symptom 107 (100) 103/111 (92) - : Symptoms only included in questionnaire at 1-year follow-up. a Symptoms were recorded as present at follow-up if symptom score ≥2 (some, a lot, or very much). b Data are number of patients reporting symptoms or not at follow-up (n), divided by total number of patients reporting the specified symptom or not during acute COVID-19 (N). The effect of disturbed smell and taste during acute COVID-19 Patients who experienced disturbed smell and taste during acute COVID-19 had similar demographic characteristics compared to patients who did not have disturbed smell and taste (Table 3). Table 3. Risk of disturbed smell and taste as well as headache among responders during acute COVID-19. Disturbed smell and taste Headache Yes (n/N a ) No (n/N a ) OR (95% CI) Yes (n/N a ) No (n/N a ) OR (95% CI) Age≥60 years 22/37 19/29 0.77 (0.28 – 2.12) 33/60 34/40 0.22 (0.079 – 0.59) Male 21/37 18/32 1.02 (0.39 – 2.65) 31/60 26/40 0.58 (0.25 – 1.31) Non-Caucasian 3/37 2/32 1.32 (0.21 – 8.46) 5/60 1/40 3.55 (0.40 – 31.55) BMI≥25 27/35 19/28 1.60 (0.52 – 4.89) 45/57 25/39 2.10 (0.84 – 5.23) Previous or active smoker 14/37 13/29 0.75 (0.28 – 2.01) 24/59 20/38 0.62 (0.27 – 1.40) ≥1 comorbidity b 31/37 22/32 2.35 (0.74 – 7.42) 43/59 35/40 0.38 (0.13 – 1.15) ≥7 days from symptom onset to admission 21/29 12/29 1.03 (0.35 – 3.06) 40/60 22/40 1.64 (0.72 – 3.72) ≥7 days of hospital admission 27/37 11/37 0.60 (0.22 – 1.64) 16/40 21/60 0.81 (0.35 – 1.84) ICU admission 3/37 3/32 0.85 (0.16 – 4.55) 8/60 5/40 1.08 (0.33 – 3.56) Requiring supplemental oxygen 31/37 26/31 0.99 (0.27 – 3.63) 45/59 38/40 0.17 (0.036 – 0.79) a Data are: number of patients reporting yes to symptoms (n), divided by total number of patients reporting the specified symptom or not during acute COVID-19 (N). Among patients who reported disturbed smell and taste during acute COVID-19, we found no statistically significant higher risk among any symptom group at 1 year follow-up compared to patients without acute disturbed smell and taste during COVID-19 (Table 4 and Supplementary Table 1). Table 4. Risk of CNS-related long COVID symptoms at 1 year among responders who reported (A) disturbed smell and taste and (B) headache during acute COVID-19. CNS-related symptoms at 1-year follow-up a Yes (n/N b ) No (n/N b ) Unadjusted OR (95% CI) Adjusted OR c (95% CI) (A) Disturbed smell and taste during acute COVID-19 Headache 10/37 7/32 1.16 (0.38 - 3.56) 1.04 (0.29 - 3.74) Dizziness 8/37 10/32 0.52 (0.18 - 1.57) 0.60 (0.18 - 2.01) Concentration difficulties 14/37 9/32 1.35 (0.48 - 3.79) 1.07 (0.32 - 3.56) Short-term memory problems 11/37 8/32 1.11 (0.38 - 3.26) 0.79 (0.24 - 2.65) Long-term memory problems 10/37 12/32 0.61 (0.21 - 1.72) 0.53 (0.17 - 1.65) Paresthesia 7/34 4/31 1.56 (0.40 - 5.98) 1.62 (0.39 - 6.75) (B) Headache during acute COVID-19 Headache 19/59 6/40 2.69 (0.97 - 7.50) 1.97 (0.63 - 6.24) Dizziness 18/60 4/40 3.86 (1.20 - 12.45) 4.20 (1.19 - 14.85) Concentration difficulties 22/59 10/40 1.78 (0.73 - 4.34) 1.01 (0.37 - 2.79) Short-term memory problems 21/60 9/40 1.85 (0.74 - 4.62) 1.20 (0.43 - 3.32) Long-term memory problems 21/60 12/40 1.26 (0.53 - 2.97) 0.89 (0.34 - 2.33) Paresthesia 12/52 7/37 1.29 (0.45 - 3.66) 1.51 (0.48 - 4.74) The unadjusted effect of disturbed smell and taste during acute COVID-19 on health scores are shown in Figure 2A. The adjusted OR of a severe PCQ score OR 0.82 (95% CI: 0.22-3.01), for a severe FAS score OR 0.93 (95% CI: 0.25-3.45), and for a EQ5D-5L Index below 0.86 OR 0.57 (95% CI: 0.19-1.67) (Figure 2A). Fig. 2 Risk of severe symptoms or health scores at 1-year follow-up for responders who had (a) disturbed smell and taste as well as (b) headache during acute COVID-19 PCQ score was the sum of the 31 individual symptom scores and classified as severe if the score exceeded the cohort’s median score (≥35 points) FAS was classified as severe if the score exceeded ≥35 points (indicating severe fatigue)[19] EQ5D-5L Index was classified as severe if the index was below 0.86, which refers to the median index among Danish individuals who share a comparable age to the median age of responders in this cohort[20] The effect of headache during acute COVID-19 Patients who experienced headache during acute COVID-19 were less likely to be 60 years or older (OR 0.22, 95% CI 0.079 - 0.59, p = 0.003) and less likely to have had Oxygen therapy during hospitalization (OR 0.17, 95% CI 0.036 - 0.79, p = 0.024) compared with patients who did not report acute headache (Table 3). Among patients who reported headache during acute COVID-19, we found a tendency towards an elevated adjusted OR of reporting neurological symptoms. In terms of individual CNS-related symptoms, these patients had a significantly increased risk of reporting dizziness (adjusted OR 4.20, 95% CI 1.19 - 14.85, p = <0.001) (Table 4 and Supplementary Table 1). The unadjusted effect of acute headache on health scores are shown in Figure 2B. For patients who had acute headache with COVID-19, the adjusted OR of a severe PCQ score OR 0.85 (95% CI 0.30 - 2.46), for a severe FAS score OR 0.51 (95% CI 0.17 - 1.56), and for a EQ5D-5L Index below 0.86 OR 1.66 (95% CI 0.65 - 4.21) (Figure 2B). Due to the lack of systematic interviews with patients at admission, we conducted additional analyses assuming that patients who had no registration in their patient file of acute headache or acute disturbed smell and taste at any time during admission did not have these symptoms. Results of these analyses did not change interpretation of the results. Discussion In this prospective cohort study involving hospitalized COVID-19 patients, we aimed to investigate the interplay between acute COVID-19 symptoms and their potential role in predicting long COVID outcomes. We found no association between acute disturbed smell and taste and subsequent CNS-related long COVID. However, we found evidence of a trend towards higher adjusted OR of reporting CNS-related long COVID at 1 year follow-up among patients reporting headache compared to no headache during acute COVID-19, a risk that was significantly increased in regard to dizziness. At follow-up 1 year after hospitalization, nearly all responders reported at least one symptom. Dyspnea during activity, fatigue, and difficulties maintaining sleep were the most frequently reported symptoms among responders. These findings align with broader meta-analyses,(Chen et al., 2022; Ma et al., 2022) underlining the persistence and prevalence of these symptoms among individuals with long COVID. The evaluation of long COVID severity using the PCQ questionnaire revealed no significant difference between patients who experienced acute disturbed smell and taste compared to those who did not, nor between patients with and without acute headache. These results contradict previous notions of symptom severity among hospitalized patients with acute COVID-19 as a predictor of long COVID outcomes.(Davis et al., 2023a; Maglietta et al., 2022) The elevated risks observed among patients with acute headache in our study suggest a potential involvement of pathological processes initiated during acute COVID-19, which may persist into CNS-related long COVID. The importance of these processes and SARS-CoV-2 neurotropism gains support through recent research demonstrating neuroinflammation induced by COVID-19, leading to encephalitis and elevated levels of cytokines, glial markers, and neuronal damage markers in the cerebral spinal fluid (CSF).(Pilotto et al., 2021) However, these findings in the CSF are not found consistently in the literature.(Kanberg et al., 2023) Signs of neuroinflammation has not only been observed in the CNS but also in the peripheral nervous system.(Agergaard, Yamin Ali Khan, et al., 2023; Hejbøl et al., 2022) On the other hand, longitudinal brain imaging studies have shown damages in cortical areas associated with the olfactory system before versus after acute COVID-19, suggesting a specific impact on those regions.(Douaud et al., 2022) Another study investigating metabolism rates of the brain among long COVID patients found hypometabolism in regions associated with disturbed smell, cognitive impairment, pain, and insomnia.(Guedj et al., 2021) Notably, in the context of documented cases of neuromuscular pathology, with indications of abnormal transmission at the neuromuscular junctions among long COVID patients, the observation of a link between acute headaches and subsequent neurological symptoms adds an interesting dimension to our findings.(Agergaard, Yamin Ali Khan, et al., 2023) Recent research has also demonstrated that various SARS-CoV-2 variants exhibit neuroinvasive capabilities by utilizing the olfactory pathway while also inciting localized inflammation in nervous tissues.(de Melo et al., 2023) Notably, even though olfactory bulb infection was a common occurrence in the studied hamsters, it was observed that neuroinvasion and the loss of smell were independent phenomena. These findings align with our research, where we observed that acute disturbed smell and taste were not reliable predictors of CNS-related long-COVID at follow-up. Recently, suggestions of a common pathogenesis in patients with other post-viral conditions have emerged, where potential pathogenic mechanisms, including those previously discussed such as neuroinflammation and direct viral brain damage, may overlap.(Choutka et al., 2022) Although post-viral conditions have also been described among mild cases(Damsgaard et al., 2016), the risk of experiencing post-acute symptoms after infections with SARS-CoV-2 and other pathogens is associated with the severity of the initial infection(Choutka et al., 2022; Davis et al., 2023b; Maglietta et al., 2022) as well as being a young adult(Ørum et al., 2021). These findings may hold a significant role for understanding and addressing the diverse range of symptoms observed among long COVID patients. Collectively, our findings, along with existing literature, hint at the possibility that both neuroinvasion and local inflammation may be initiated during the acute phase of COVID-19, potentially establishing a link between acute symptoms and persistent COVID-19 manifestations. Further research is warranted to comprehensively clarify the pathways connecting acute symptoms with long-term implications of COVID-19. Strengths As our cohort consisted of hospitalized patients only, we were able to collect detailed and accurate assessment of patient information and exposure variables in real time, which were not possible in patients who present symptoms of long COVID as outpatients.(Agergaard et al., 2022) Limitations This study had several limitations, some of which might have affected our results. First, some of the information of acute symptoms was missing due to the circumstance that data from hospitalization was collected through journal entries and not through systematic patient interviews. Second, a significant loss to follow-up was observed, with two-thirds of eligible patients not responding to the questionnaire, particularly among non-Caucasian patients, indicating potential linguistic barriers. Responders had a higher proportion of patients receiving Oxygen therapy and ICU admission during acute COVID-19. As the severity of acute COVID-19 is associated with an increased risk of developing post-acute symptoms,(Dirican & Bal, 2022) the absence of these patients has the potential to introduce bias and lead to an overestimation of the prevalence and severity of long COVID in this study. We believe that part of the loss to follow-up can be explained by healthy patients not being as motivated to participate in research as sick patients. This can be seen in the fact that 92% of responders reported experiencing at least one symptom at follow-up which is substantially higher than what has previously been estimated.(Ma et al., 2022) Conclusion In our prospective cohort study focusing on long COVID patients, we identified an elevated risk of CNS-related symptoms one year after discharge among patients who had reported acute headache. However, we observed that acute disturbed smell and taste were not reliable predictors of CNS-related long COVID, consistent with the possibility that neuroinvasion and disturbed smell and taste are independent phenomena. We suggest further studies with larger cohorts investigating the importance of headache in the acute phase are warranted for understanding the pathophysiological process and long-term prognosis. Declarations Acknowledgements MULTICOV Consortium members Statements & Declarations Funding/support This work was supported by Central Denmark Region Research Foundation [A3770] and the MULTICOV consortium are funded by the Novo Nordisk foundation [NNF21OC0066984]. Conflicts of interest and competing interests None to declare. Compliance with Ethical Standards Data collection and the interview study were approved by the Data Protection Authorities in Central Denmark Region (reference 1-16-02-4-21). Consent The current study involves research with human participants. Informed consent to participate was collected from all participants. Data availability statement: The data produced and analyzed in the present study are not accessible, as the release of such information would compromise the individual privacy of participants. Author contributions All authors contributed to the design and concept of the study. Data collection was performed by M Mølhave, J Damsgaard, and J Agergaard. 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EJNMMI 48(9):2823–2833. 10.1007/s00259-021-05215-4 Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, McLeod L, Delacqua G, Delacqua F, Kirby J, Duda SN, REDCap Consortium (2019) The REDCap consortium: Building an international community of software platform partners. J Biomed Inf 95:103208. 10.1016/j.jbi.2019.103208 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf 42(2):377–381. 10.1016/j.jbi.2008.08.010 Hejbøl EK, Harbo T, Agergaard J, Madsen LB, Pedersen TH, Østergaard LJ, Andersen H, Schrøder HD, Tankisi H (2022) Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology. Eur Neurol 29(9):2832–2841. 10.1111/ene.15435 Hendriks C, Drent M, Elfferich M, De Vries J (2018) The Fatigue Assessment Scale: Quality and availability in sarcoidosis and other diseases. Curr Opin Pulm Med 24(5):495–503. 10.1097/MCP.0000000000000496 Jan S, Michael D, Claire G, Kjeld Møller P, Henrik B-H (2009) Danish EQ-5D population norms. Scand J 37(5). 10.1177/1403494809105286 Janssen MF, Bonsel GJ, Luo N (2018) Is EQ-5D-5L Better Than EQ-5D-3L? A Head-to-Head Comparison of Descriptive Systems and Value Sets from Seven Countries. PharmacoEconomics 36(6):675–697. 10.1007/s40273-018-0623-8 Kanberg N, Grahn A, Stentoft E, Bremell D, Yilmaz A, Studahl M, Nilsson S, Schöll M, Gostner JM, Blennow K, Zetterberg H, Padmanabhan N, Cohen R, Misaghian S, Romero D, Campbell C, Mathew A, Wang M, Sigal G, Stengelin M, Edén A, Gisslén M (2023) COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications. J Infect Dis jiad395. 10.1093/infdis/jiad395 Ma Y, Deng J, Liu Q, Du M, Liu M, Liu J (2022) Long-Term Consequences of COVID-19 at 6 Months and Above: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health 19(11):6865. 10.3390/ijerph19116865 Maglietta G, Diodati F, Puntoni M, Lazzarelli S, Marcomini B, Patrizi L, Caminiti C (2022) Prognostic Factors for Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis. J Clin Med 11(6):1541. 10.3390/jcm11061541 Michielsen HJ, De Vries J, Van Heck GL (2003) Psychometric qualities of a brief self-rated fatigue measure: The Fatigue Assessment Scale. J Psychosom Res 54(4):345–352. 10.1016/s0022-3999(02)00392-6 Mølhave M, Leth S, Gunst JD, Jensen-Fangel S, Østergaard L, Wejse C, Agergaard J (2021) Long-Term Symptoms among Hospitalized COVID-19 Patients 48 Weeks after Discharge-A Prospective Cohort Study. J Clin Med 10(22):5298. 10.3390/jcm10225298 Najt P, Richards HL, Fortune DG (2021) Brain imaging in patients with COVID-19: A systematic review. BBI - Health 16:100290. 10.1016/j.bbih.2021.100290 Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, Cook JR, Nordvig AS, Shalev D, Sehrawat TS, Ahluwalia N, Bikdeli B, Dietz D, Der-Nigoghossian C, Liyanage-Don N, Rosner GF, Bernstein EJ, Mohan S, Beckley AA, Seres DS, Choueiri TK, Uriel N, Ausiello JC, Accili D, Freedberg DE, Baldwin M, Schwartz A, Brodie D, Garcia CK, Elkind MSV, Connors JM, Bilezikian JP, Landry DW, Wan EY (2021) Post-acute COVID-19 syndrome. Nat Med 27(4):601–615. 10.1038/s41591-021-01283-z Ørum M, Storgaard M, Denton PW, Mogensen TH, Højbjerg CK, Pedersen M, Gunst JD (2021) Predicting Cognitive Rehabilitation Needs in Patients with Central Nervous System Infections Using Montreal Cognitive Assessment. CCM 3(6), 1350–1357. 10.1007/s42399-021-00883-7 Pilotto A, Masciocchi S, Volonghi I, De Giuli V, Caprioli F, Mariotto S, Ferrari S, Bozzetti S, Imarisio A, Risi B, Premi E, Benussi A, Focà E, Castelli F, Zanusso G, Monaco S, Stefanelli P, Gasparotti R, Zekeridou A, McKeon A, Ashton NJ, BlennoW K, Zetterberg H, Padovani A (2021) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Encephalitis Is a Cytokine Release Syndrome: Evidences From Cerebrospinal Fluid Analyses. Clin Infect Dis 73(9):e3019–e3026. 10.1093/cid/ciaa1933 Pinzon RT, Wijaya VO, Buana RB, Al Jody A, Nunsio PN (2020) Neurologic Characteristics in Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis. Front Neurol 29:11:565. 10.3389/fneur.2020.00565 Tan CJ-W, Tan BKJ, Tan XY, Liu HT, Teo CB, See A, Xu S, Toh ST, Kheok SW, Charn TC, Teo N W Y (2022) Neuroradiological Basis of COVID-19 Olfactory Dysfunction: A Systematic Review and Meta-Analysis. Laryngoscope 132(6):1260–1274. 10.1002/lary.30078 Whitcroft KL, Hummel T (2020) Olfactory Dysfunction in COVID-19: Diagnosis and Management. JAMA 323(24):2512–2514. 10.1001/jama.2020.8391 Wu D, Wang VY, Chen Y-H, Ku C-H, Wang P-C (2022) The prevalence of olfactory and gustatory dysfunction in covid-19—A systematic review. Auris Nasus Larynx 49(2):165–175. 10.1016/j.anl.2021.07.007 Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3930891","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271172789,"identity":"19a38a38-f782-42be-8e05-4293503f2912","order_by":0,"name":"Jane Agergaard","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACxgYogx9E8BwgRYtkA7Fa4MDgALFamNvPHnzw45dNvvHt0wkMb84Q47CevGTD3r40y23ncjcwzrlBjJaGHDMJ3p7DBmZneDcw83wgRkv/G/Off3v+Gxj3EK1lRo4ZM8+PAwYGPCAtRDlsxhtjadmGZAMJoMMOziHG+4b9OYYf3/yxM+Dv4d344M0xYrQ0gKxqg3AOEKGBgUEeTP4hSu0oGAWjYBSMVAAA8gU6ySFy8mYAAAAASUVORK5CYII=","orcid":"","institution":"Aarhus University","correspondingAuthor":true,"prefix":"","firstName":"Jane","middleName":"","lastName":"Agergaard","suffix":""}],"badges":[],"createdAt":"2024-02-05 12:29:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3930891/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3930891/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50819032,"identity":"0e8b270a-1c24-407b-a060-cb6eb07b83d1","added_by":"auto","created_at":"2024-02-07 20:24:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12773,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the cohort: patients admitted to Dept. of Infectious Diseases, AUH, Denmark between March 1\u003csup\u003est\u003c/sup\u003e, 2020 and May 1\u003csup\u003est\u003c/sup\u003e, 2021\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-3930891/v1/a08877f55a0c9fa15e451cb0.png"},{"id":50819691,"identity":"db4d3c6a-6ba7-432c-b82d-0585922dae37","added_by":"auto","created_at":"2024-02-07 20:32:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52686,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of severe symptoms or health scores at 1-year follow-up for responders who had (a) disturbed smell and taste as well as (b) headache during acute COVID-19\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-3930891/v1/5d114ebf59bab9871cfe1358.png"},{"id":53588352,"identity":"1ebf4f9f-54e9-44b4-98b7-58e1c59fc996","added_by":"auto","created_at":"2024-03-27 19:23:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":325848,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3930891/v1/10c0bb07-60e0-4d98-a519-e5aba343b612.pdf"},{"id":50819034,"identity":"8176bf2e-4f8c-45bb-8ae5-b903448fda81","added_by":"auto","created_at":"2024-02-07 20:24:23","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":31746,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-3930891/v1/0f6479fc43bb8ae6c21ce689.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Headache or Disturbed Smell and Taste During Acute COVID-19 as Predictors of Long COVID at One Year","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLong COVID 2019 is characterized by persistent symptoms more than 12 weeks after initial infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a concerning aftermath of COVID-19. According to estimates, 58% of hospitalized patients experience at least one persistent symptom 120 days after infection,(Chen et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) and 64% and 59% of patients continue to experience long COVID six months and up to one year after initial infection, respectively.(Ma et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) Symptoms of long COVID are diverse and can arise from multiple organ systems,(Ma et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) including symptoms related to theCNS: headache (21%)(M\u0026oslash;lhave et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Pinzon et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) paresthesia (33%)(Pinzon et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) cognitive disorder (35%),(Pinzon et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) and memory loss (11%).(Ma et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAlthough the predominant transmission of SARS-CoV-2 is airborne,(Crook et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) the pathophysiological basis of long COVID associated with the CNS may not be readily apparent and remain unknown. Viral travel along the olfactory nerve causing direct viral CNS damage has been suggested as an underlying mechanism(Whitcroft \u0026amp; Hummel, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) as nasal epithelial cells show relatively high expression of the angiotensin-converting enzyme 2 receptor required for viral entry.(Nalbandian et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) Further, brain imaging studies investigating the pathology of SARS-CoV-2, have shown structural changes in the olfactory bulb and in brain areas associated with the olfactory system among patients with long COVID.(Douaud et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Najt et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Tan et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) While the proximity of upper airways to the olfactory bulb and the high prevalence of disturbed smell and taste as well as headache (54%, 49%, and 48% respectively)(Wu et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) during acute COVID-19, offer possible connections to subsequent CNS-related long COVID. The potential roles of hematogenous spread of SARS-CoV-2 or critical illness for developing CNS-related symptoms cannot be ignored,(Nalbandian et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) and a recent study involving hamsters also suggests a potential interplay between both neuroinvasive abilities and inflammatory processes.(de Melo et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThis study aims to explore this potential link between acute COVID-19 symptoms during hospitalization and subsequent long COVID. The present study investigates whether patients with disturbed smell and taste as well as headache during acute COVID-19 are at an increased risk of developing CNS-related long COVID. It is our hypothesis that these patients were at an increased risk of developing CNS-related long COVID compared with patients without these symptoms.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and follow-up\u003c/h2\u003e \u003cp\u003eA single center, prospective cohort study on patients hospitalized with COVID-19 was performed at the Department of Infectious Diseases at Aarhus University Hospital (AUH), Denmark between March 1st, 2020, and May 1st, 2021. One year after discharge, patients were contacted via e-mail or letter and asked to complete a 31-item Post COVID Symptom Questionnaire (PCQ) in which each symptom experienced during four weeks prior to answering the questionnaire and not present before acute COVID-19 was rated on a Likert scale of 0 to 4: 0: None; 1: A little; 2: Some; 3: A lot; 4: Very much. Symptoms were considered present if they had received a score of 2 or more. Further, the questionnaire contained the standardized tests of fatigue, Fatigue Assessment Scale (FAS)(Michielsen et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2003\u003c/span\u003e) and health-related quality of life, EQ5D-5L.(Janssen et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) The PCQ score is the sum of scores for its 31 symptoms, and it has previously been more thoroughly described.(Agergaard et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Agergaard, Gunst, et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2023\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and data collection\u003c/h2\u003e \u003cp\u003ePatients included had tested positive for SARS-CoV-2 with a polymerase chain reaction (PCR) test upon admission, were adults (\u0026ge;\u0026thinsp;18 years of age), and were hospitalized for at least 12 hours. Reasons for exclusion can be seen in Fig.\u0026nbsp;1. During hospitalization, patient data regarding age, sex, ethnicity, BMI, smoking status, and comorbidities were registered. Symptoms reported on day one, three, and five of hospitalization with acute COVID-19 were also registered in the patients\u0026rsquo; file and entered in a secured REDCap database.(Harris et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2009\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) Before patients were invited to participate in this study, written consents were obtained.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAs disturbed taste reported by COVID-19 patients can be attributed to disturbed retronasal olfaction (flavor) rather than impaired gustation(Whitcroft \u0026amp; Hummel, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), the reporting of disturbed smell and taste were listed together in our data analysis.\u003c/p\u003e \u003cp\u003eWe compared patients registered with either disturbed smell and taste or headache with those registered without these symptoms during acute COVID-19. As an exploratory approach, we performed all analyses again where all missing data from hospitalization were treated as not present, as negative findings were not always registered in patients\u0026rsquo; files and patients were not systematically interviewed during admission.\u003c/p\u003e \u003cp\u003eLogistical regression analysis was conducted to determine the OR with 95% CI for differences in demographics and in symptoms at 1 year follow-up between patients who reported disturbed smell and taste as well as headache during acute COVID-19 compared to patients who did not report these symptoms. Risks of reporting symptoms (i.e., scoring 2 or more in one or more symptoms) were presented in the following symptom groups: neurological; upper airway; cardiopulmonary; gastrointestinal; cutaneous; musculoskeletal; general symptoms; and any symptom. If a symptom group presented with an OR of \u0026gt;\u0026thinsp;2, ORs for individual symptoms within the group were examined. Risks were presented as unadjusted OR and adjusted OR for common confounders: age, sex, and BMI. Risk evaluation of patients reporting cutaneous symptoms was omitted due to the limited size of the sample.\u003c/p\u003e \u003cp\u003eLong COVID severity was assessed using PCQ score which was validated previously.(Agergaard et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) Additionally, the FAS score, and EQ5D-5L Index were used as secondary outcomes. Long COVID was classified as severe if the PCQ score exceeded the cohort\u0026rsquo;s median score (\u0026ge;\u0026thinsp;35 points), FAS\u0026thinsp;\u0026ge;\u0026thinsp;35 (indicating severe fatigue),(Hendriks et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) and if EQ5D-5L Index was below 0.86, which refers to the median index among Danish individuals who share a comparable age to the median age of responders in this cohort(Jan et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Logistical regression analysis was used to calculate the OR for scoring above the severe threshold among patients who reported disturbed smell and taste or headache during acute COVID-19 versus patients with none of these symptoms.\u003c/p\u003e \u003cp\u003eData were analyzed using Stata MP Version 17.0. A P-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eEthical approval\u003c/h2\u003e\n\u003cp\u003eRegister- and questionnaire-based studies do not require ethics approval (Danish Committee Act, Section 14, Subsection 2, the Central Denmark Region Committee on Health Research Ethics reference 1-10-72-181-20). Data collection and the interview study were approved by the Data Protection Authorities in Central Denmark Region (references 1-16-02-4-21).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween March 1\u003csup\u003est\u003c/sup\u003e, 2020, and May 1\u003csup\u003est\u003c/sup\u003e, 2021, 533 patients were admitted to the Department of Infectious Diseases at AUH, Denmark. A total of 107 patients died: 76 patients during admission and 31 patients during follow-up. Additionally, 138 patients were excluded: 15 patients due to a dementia diagnosis, 10 patients were lost to follow-up due to travels, 20 patients did not consent to participate in our study, and 93 patients did not return a signed consent form. The remaining 288 eligible patients were invited to participate in our follow-up questionnaire at 1-year follow-up after discharge via email or letter, of which 111 patients responded (Figure 1).\u003c/p\u003e\n\u003cp\u003eFollow-up questionnaires were collected between 6\u003csup\u003eth\u003c/sup\u003e of August, 2021 and 6\u003csup\u003eth\u003c/sup\u003e of April, 2022; which was median 369 (interquartile range (IQR): 352-524) days or 53 (IQR: 50-74) weeks after symptom onset. Among responders, the median duration from symptom onset to admission was 8 (IQR: 5-10) days, median duration of hospitalization was 5 (IQR: 3-10) days. During hospitalization, 83% of patients required supplemental oxygen and 16% of patients were transferred to the intensive care unit (ICU).\u003c/p\u003e\n\u003cp\u003eCompared with non-responders, responders had a significantly higher age (65 versus 57 years, P=\u0026lt;0.001), were significantly more likely to be Caucasian (P=\u0026lt;0.001), and a significant higher proportion required supplemental oxygen (P=0.048) and were transferred to the ICU (P=0.002) (Table 1).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"642\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"4\"\u003e\n \u003cp\u003eTable 1. Demographic characteristics of hospitalized COVID-19 patients (responders versus non-responders) at 1-year follow-up.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003eResponders (n=111)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003eNon-responders (n=177)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eAge, years\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e65 (56-75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e57 (48-71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eSex\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.240\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e48 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e73 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e63 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e104 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eRace and Ethnicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Caucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e104 (94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e96 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e7 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e81 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eBMI\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e27.7 (25-33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e29.0 (26-33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eSmoking status\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.280\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Never-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e58 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e105 (59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Previous smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e49 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e58 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Active smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e1 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e14 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003e\u0026ge;1 comorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e81 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e135 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.340\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eSymptom onset to hospital admission, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e8 (5-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e7 (3-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eHospital admission, days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e5 (3-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e5 (3-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.095\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eICU admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e18 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e20 (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"45.638629283489095%\"\u003e\n \u003cp\u003eRequired supplemental oxygen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.24922118380062%\"\u003e\n \u003cp\u003e92 (83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.83177570093458%\"\u003e\n \u003cp\u003e132 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.280373831775702%\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are median (IQR) or n(%).\u003cbr\u003e\u003csup\u003ea\u003c/sup\u003e Age at follow-up, BMI, smoking status, and comorbidities at hospital admission.\u003c/p\u003e\n\u003cp\u003eOf the responders at 1 year follow-up, 60% and 54% had experienced headache as well as disturbed smell and taste during acute COVID-19, respectively. At follow-up, 92% of the responders had at least one persisting symptom. The most frequently reported symptoms present at follow-up were dyspnea during activity (51%), fatigue (47%), and difficulties maintaining sleep (47%) (Table 2).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"634\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"3\"\u003e\n \u003cp\u003eTable 2. Prevalence of symptoms among responders (n=111) during acute COVID-19 and at 1-year follow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003eAcute COVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e1 year follow-up\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.11267605633803%\"\u003e\n \u003cp\u003e(n/N\u003csup\u003eb\u003c/sup\u003e (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"47.88732394366197%\"\u003e\n \u003cp\u003e(n/N\u003csup\u003eb\u003c/sup\u003e (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eCNS-related symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e60/100 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e27/110 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e39/79 (49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e23/111 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eConcentration difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e36/110 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eShort-term memory problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e34/111 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eLong-term memory problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e37/111 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eParesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e22/100 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eUpper airway symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eNasal congestion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e7/39 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e29/108 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eSore throat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e18/64 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e10/106 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDisturbed smell\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e25/60 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e24/109 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDisturbed taste\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e36/69 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e20/109 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDisturbed smell and taste\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e37/69 (54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e26/109 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eCardiopulmonary symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDyspnea during rest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e31/110 (28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDyspnea during activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e96/107 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e56/111 (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e103/107 (96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e26/107 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eProductive cough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e39/101 (39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e24/108 (22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eChest pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e22/92 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e15/103 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003ePalpitations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e13/103 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eGastrointestinal symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eReduced appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e17/108 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e47/95 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e8/104 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eStomachache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e14/86 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e9/105 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e48/96 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e8/104 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eAltered bowel habits\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e17/106 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eCutaneous symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eSkin rash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e12/104 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eSkin itching\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e22/108 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eMusculoskeletal symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eJoint pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e39/109 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eJoint swelling\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e23/108 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eMyalgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e56/84 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e41/109 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eMuscle exhaustion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e28/103 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eGeneral symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eFever episode\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e9/103 (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e81/93 (87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e51/107 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eIncreased sleep duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e50/108 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDifficulties falling asleep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e33/108 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eDifficulties maintaining sleep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e51/108 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.91338582677165%\"\u003e\n \u003cp\u003eAny symptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.960629921259844%\"\u003e\n \u003cp\u003e107 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.125984251968504%\"\u003e\n \u003cp\u003e103/111 (92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e- : Symptoms only included in questionnaire at 1-year follow-up.\u003cbr\u003e\u003csup\u003ea\u003c/sup\u003e Symptoms were recorded as present at follow-up if symptom score \u0026ge;2 (some, a lot, or very much).\u003cbr\u003e\u003csup\u003eb\u003c/sup\u003e Data are number of patients reporting symptoms or not at follow-up (n), divided by total number of patients reporting the specified symptom or not during acute COVID-19 (N).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe effect of disturbed smell and taste during acute COVID-19\u003c/em\u003e\u003cbr\u003e\u0026nbsp;Patients who experienced disturbed smell and taste during acute COVID-19 had similar demographic characteristics compared to patients who did not have disturbed smell and taste (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"686\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"97.8134110787172%\" colspan=\"8\"\u003e\n \u003cp\u003eTable 3. Risk of disturbed smell and taste as well as headache among responders during acute COVID-19.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.186588921282799%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"42.12827988338192%\" colspan=\"3\"\u003e\n \u003cp\u003eDisturbed smell and taste\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.39941690962099%\" colspan=\"5\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003eYes (n/N\u003csup\u003ea\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003eNo (n/N\u003csup\u003ea\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003eYes (n/N\u003csup\u003ea\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003eNo (n/N\u003csup\u003ea\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003eAge\u0026ge;60 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e22/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e19/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e0.77 (0.28 \u0026ndash; 2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e33/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e34/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e0.22 (0.079 \u0026ndash; 0.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e21/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e18/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e1.02 (0.39 \u0026ndash; 2.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e31/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e26/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e0.58 (0.25 \u0026ndash; 1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003eNon-Caucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e3/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e2/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e1.32 (0.21 \u0026ndash; 8.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e5/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e1/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e3.55 (0.40 \u0026ndash; 31.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003eBMI\u0026ge;25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e27/35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e19/28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e1.60 (0.52 \u0026ndash; 4.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e45/57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e25/39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e2.10 (0.84 \u0026ndash; 5.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003ePrevious or active smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e14/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e13/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e0.75 (0.28 \u0026ndash; 2.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e24/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e20/38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e0.62 (0.27 \u0026ndash; 1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003e\u0026ge;1 comorbidity\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e31/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e22/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e2.35 (0.74 \u0026ndash; 7.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e43/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e35/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e0.38 (0.13 \u0026ndash; 1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003e\u0026ge;7 days from symptom onset to admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e21/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e12/29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e1.03 (0.35 \u0026ndash; 3.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e40/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e22/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e1.64 (0.72 \u0026ndash; 3.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.472303206997086%\"\u003e\n \u003cp\u003e\u0026ge;7 days of hospital admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.807580174927114%\"\u003e\n \u003cp\u003e27/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e11/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\"\u003e\n \u003cp\u003e0.60 (0.22 \u0026ndash; 1.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\" colspan=\"2\"\u003e\n \u003cp\u003e16/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.078717201166182%\"\u003e\n \u003cp\u003e21/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.24198250728863%\" colspan=\"2\"\u003e\n \u003cp\u003e0.81 (0.35 \u0026ndash; 1.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.496350364963504%\"\u003e\n \u003cp\u003eICU admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824817518248175%\"\u003e\n \u003cp\u003e3/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.094890510948906%\"\u003e\n \u003cp\u003e3/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.27007299270073%\"\u003e\n \u003cp\u003e0.85 (0.16 \u0026ndash; 4.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.364963503649635%\"\u003e\n \u003cp\u003e8/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.678832116788321%\" colspan=\"2\"\u003e\n \u003cp\u003e5/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.27007299270073%\" colspan=\"2\"\u003e\n \u003cp\u003e1.08 (0.33 \u0026ndash; 3.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.496350364963504%\"\u003e\n \u003cp\u003eRequiring supplemental oxygen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824817518248175%\"\u003e\n \u003cp\u003e31/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.094890510948906%\"\u003e\n \u003cp\u003e26/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.27007299270073%\"\u003e\n \u003cp\u003e0.99 (0.27 \u0026ndash; 3.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.364963503649635%\"\u003e\n \u003cp\u003e45/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.678832116788321%\" colspan=\"2\"\u003e\n \u003cp\u003e38/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.27007299270073%\" colspan=\"2\"\u003e\n \u003cp\u003e0.17 (0.036 \u0026ndash; 0.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Data are: number of patients reporting yes to symptoms (n), divided by total number of patients reporting the specified symptom or not during acute COVID-19 (N).\u003c/p\u003e\n\u003cp\u003eAmong patients who reported disturbed smell and taste during acute COVID-19, we found no statistically significant higher risk among any symptom group at 1 year follow-up compared to patients without acute disturbed smell and taste during COVID-19 (Table 4 and Supplementary Table 1).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\"\u003e\n \u003cp\u003eTable 4. Risk of CNS-related long COVID symptoms\u0026nbsp;at 1 year\u0026nbsp;among responders who reported (A) disturbed smell and taste and (B) headache during acute COVID-19.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.460342146189735%\"\u003e\n \u003cp\u003eCNS-related symptoms at 1-year follow-up\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.9548989113530326%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003eYes (n/N\u003csup\u003eb\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003eNo (n/N\u003csup\u003eb\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003eUnadjusted OR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003eAdjusted OR\u003csup\u003ec\u003c/sup\u003e (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\"\u003e\n \u003cp\u003e(A) Disturbed smell and taste during acute COVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e10/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e7/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.16 (0.38 - 3.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e1.04 (0.29 - 3.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e8/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e10/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e0.52 (0.18 - 1.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e0.60 (0.18 - 2.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eConcentration difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e14/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e9/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.35 (0.48 - 3.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e1.07 (0.32 - 3.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eShort-term memory problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e11/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e8/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.11 (0.38 - 3.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e0.79 (0.24 - 2.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eLong-term memory problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e10/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e12/32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e0.61 (0.21 - 1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e0.53 (0.17 - 1.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eParesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e7/34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e4/31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.56 (0.40 - 5.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e1.62 (0.39 - 6.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"6\"\u003e\n \u003cp\u003e(B) Headache\u0026nbsp;during acute COVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e19/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e6/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e2.69 (0.97 - 7.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e1.97 (0.63 - 6.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e18/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e4/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e3.86 (1.20 - 12.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e4.20 (1.19 - 14.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eConcentration difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e22/59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e10/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.78 (0.73 - 4.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e1.01 (0.37 - 2.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eShort-term memory problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e21/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e9/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.85 (0.74 - 4.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e1.20 (0.43 - 3.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eLong-term memory problems\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e21/60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e12/40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.26 (0.53 - 2.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e0.89 (0.34 - 2.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.41524105754277%\" colspan=\"2\"\u003e\n \u003cp\u003eParesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.19751166407465%\"\u003e\n \u003cp\u003e12/52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.81959564541213%\"\u003e\n \u003cp\u003e7/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.48367029548989%\"\u003e\n \u003cp\u003e1.29 (0.45 - 3.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.08398133748056%\"\u003e\n \u003cp\u003e1.51 (0.48 - 4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;The unadjusted effect of disturbed smell and taste during acute COVID-19 on health scores are shown in Figure 2A. The adjusted OR of a severe PCQ score OR 0.82 (95% CI: 0.22-3.01), for a severe FAS score OR 0.93 (95% CI: 0.25-3.45), and for a EQ5D-5L Index below 0.86 OR 0.57 (95% CI: 0.19-1.67) (Figure 2A).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. 2\u003c/strong\u003e Risk of severe symptoms or health scores at 1-year follow-up for responders who had (a) disturbed smell and taste as well as (b) headache during acute COVID-19\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePCQ score was the sum of the 31 individual symptom scores and classified as severe if the score exceeded the cohort\u0026rsquo;s median score (\u0026ge;35 points)\u003cbr\u003e\u0026nbsp;FAS was classified as severe if the score exceeded \u0026ge;35 points (indicating severe fatigue)[19]\u003cbr\u003e\u0026nbsp;EQ5D-5L Index was classified as severe if the index was below 0.86, which refers to the median index among Danish individuals who share a comparable age to the median age of responders in this cohort[20]\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThe effect of headache during acute COVID-19\u003c/em\u003e\u003cbr\u003e\u0026nbsp;Patients who experienced headache during acute COVID-19 were less likely to be 60 years or older (OR 0.22, 95% CI 0.079 - 0.59, p = 0.003) and less likely to have had Oxygen therapy during hospitalization (OR 0.17, 95% CI 0.036 - 0.79, p = 0.024) compared with patients who did not report acute headache (Table 3).\u003c/p\u003e\n\u003cp\u003eAmong patients who reported headache during acute COVID-19, we found a tendency towards an elevated adjusted OR of reporting neurological symptoms. In terms of individual CNS-related symptoms, these patients had a significantly increased risk of reporting dizziness (adjusted OR 4.20, 95% CI 1.19 - 14.85, \u003cem\u003ep\u003c/em\u003e = \u0026lt;0.001) (Table 4 and Supplementary Table 1).\u003c/p\u003e\n\u003cp\u003eThe unadjusted effect of acute headache on health scores are shown in Figure 2B. For patients who had acute headache with COVID-19, the adjusted OR of a severe PCQ score OR 0.85 (95% CI 0.30 - 2.46), for a severe FAS score OR 0.51 (95% CI 0.17 - 1.56), and for a EQ5D-5L Index below 0.86 OR 1.66 (95% CI 0.65 - 4.21) (Figure 2B).\u003c/p\u003e\n\u003cp\u003eDue to the lack of systematic interviews with patients at admission, we conducted additional analyses assuming that patients who had no registration in their patient file of acute headache or acute disturbed smell and taste at any time during admission did not have these symptoms. Results of these analyses did not change interpretation of the results.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this prospective cohort study involving hospitalized COVID-19 patients, we aimed to investigate the interplay between acute COVID-19 symptoms and their potential role in predicting long COVID outcomes. We found no association between acute disturbed smell and taste and subsequent CNS-related long COVID. However, we found evidence of a trend towards higher adjusted OR of reporting CNS-related long COVID at 1 year follow-up among patients reporting headache compared to no headache during acute COVID-19, a risk that was significantly increased in regard to dizziness.\u003c/p\u003e\n\u003cp\u003eAt follow-up 1 year after hospitalization, nearly all responders reported at least one symptom. Dyspnea during activity, fatigue, and difficulties maintaining sleep were the most frequently reported symptoms among responders. These findings align with broader meta-analyses,(Chen et al., 2022; Ma et al., 2022)\u0026nbsp;underlining the persistence and prevalence of these symptoms among individuals with long COVID.\u003cbr\u003e\u0026nbsp;The evaluation of long COVID severity using the PCQ questionnaire revealed no significant difference between patients who experienced acute disturbed smell and taste compared to those who did not, nor between patients with and without acute headache. These results contradict previous notions of symptom severity among hospitalized patients with acute COVID-19 as a predictor of long COVID outcomes.(Davis et al., 2023a; Maglietta et al., 2022)\u003c/p\u003e\n\u003cp\u003eThe elevated risks observed among patients with acute headache in our study suggest a potential involvement of pathological processes initiated during acute COVID-19, which may persist into CNS-related long COVID. The importance of these processes and SARS-CoV-2 neurotropism gains support through recent research demonstrating neuroinflammation induced by COVID-19, leading to encephalitis and elevated levels of cytokines, glial markers, and neuronal damage markers in the cerebral spinal fluid (CSF).(Pilotto et al., 2021)\u0026nbsp;However, these findings in the CSF are not found consistently in the literature.(Kanberg et al., 2023)\u0026nbsp;Signs of neuroinflammation has not only been observed in the CNS but also in the peripheral nervous system.(Agergaard, Yamin Ali Khan, et al., 2023; Hejb\u0026oslash;l et al., 2022)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn the other hand, longitudinal brain imaging studies have shown damages in cortical areas associated with the olfactory system before versus after acute COVID-19, suggesting a specific impact on those regions.(Douaud et al., 2022)\u0026nbsp;Another study investigating metabolism rates of the brain among long COVID patients found hypometabolism in regions associated with disturbed smell, cognitive impairment, pain, and insomnia.(Guedj et al., 2021)\u003c/p\u003e\n\u003cp\u003eNotably, in the context of documented cases of neuromuscular pathology, with indications of abnormal transmission at the neuromuscular junctions among long COVID patients, the observation of a link between acute headaches and subsequent neurological symptoms adds an interesting dimension to our findings.(Agergaard, Yamin Ali Khan, et al., 2023)\u003c/p\u003e\n\u003cp\u003eRecent research has also demonstrated that various SARS-CoV-2 variants exhibit neuroinvasive capabilities by utilizing the olfactory pathway while also inciting localized inflammation in nervous tissues.(de Melo et al., 2023)\u0026nbsp;Notably, even though olfactory bulb infection was a common occurrence in the studied hamsters, it was observed that neuroinvasion and the loss of smell were independent phenomena. These findings align with our research, where we observed that acute disturbed smell and taste were not reliable predictors of CNS-related long-COVID at follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecently, suggestions of a common pathogenesis in patients with other post-viral conditions have emerged, where potential pathogenic mechanisms, including those previously discussed such as neuroinflammation and direct viral brain damage, may overlap.(Choutka et al., 2022)\u0026nbsp;Although post-viral conditions have also been described among mild cases(Damsgaard et al., 2016), the risk of experiencing post-acute symptoms after infections with SARS-CoV-2 and other pathogens is associated with the severity of the initial infection(Choutka et al., 2022; Davis et al., 2023b; Maglietta et al., 2022)\u0026nbsp;as well as being a young adult(\u0026Oslash;rum et al., 2021). These findings may hold a significant role for understanding and addressing the diverse range of symptoms observed among long COVID patients.\u003c/p\u003e\n\u003cp\u003eCollectively, our findings, along with existing literature, hint at the possibility that both neuroinvasion and local inflammation may be initiated during the acute phase of COVID-19, potentially establishing a link between acute symptoms and persistent COVID-19 manifestations. Further research is warranted to comprehensively clarify the pathways connecting acute symptoms with long-term implications of COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eAs our cohort consisted of hospitalized patients only, we were able to collect detailed and accurate assessment of patient information and exposure variables in real time, which were not possible in patients who present symptoms of long COVID as outpatients.(Agergaard et al., 2022)\u003cbr\u003e\u003cstrong\u003eLimitations\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThis study had several limitations, some of which might have affected our results. First, some of the information of acute symptoms was missing due to the circumstance that data from hospitalization was collected through journal entries and not through systematic patient interviews. Second, a significant loss to follow-up was observed, with two-thirds of eligible patients not responding to the questionnaire, particularly among non-Caucasian patients, indicating potential linguistic barriers. Responders had a higher proportion of patients receiving Oxygen therapy and ICU admission during acute COVID-19. As the severity of acute COVID-19 is associated with an increased risk of developing post-acute symptoms,(Dirican \u0026amp; Bal, 2022) the absence of these patients has the potential to introduce bias and lead to an overestimation of the prevalence and severity of long COVID in this study. We believe that part of the loss to follow-up can be explained by healthy patients not being as motivated to participate in research as sick patients. This can be seen in the fact that 92% of responders reported experiencing at least one symptom at follow-up which is substantially higher than what has previously been estimated.(Ma et al., 2022)\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn our prospective cohort study focusing on long COVID patients, we identified an elevated risk of CNS-related symptoms one year after discharge among patients who had reported acute headache. However, we observed that acute disturbed smell and taste were not reliable predictors of CNS-related long COVID, consistent with the possibility that neuroinvasion and disturbed smell and taste are independent phenomena. We suggest further studies with larger cohorts investigating the importance of headache in the acute phase are warranted for understanding the pathophysiological process and long-term prognosis.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eMULTICOV Consortium members\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatements \u0026amp; Declarations\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/support\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThis work was supported by Central Denmark Region Research Foundation [A3770] and the MULTICOV consortium are funded by the Novo Nordisk foundation [NNF21OC0066984].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest and competing interests\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eNone to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eData collection and the interview study were approved by the Data Protection Authorities in Central Denmark Region (reference 1-16-02-4-21).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe current study involves research with human participants. Informed consent to participate was collected from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe data produced and analyzed in the present study are not accessible, as the release of such information would compromise the individual privacy of participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eAll authors contributed to the design and concept of the study. Data collection was performed by M M\u0026oslash;lhave, J Damsgaard, and J Agergaard. Data analysis was performed by M M\u0026oslash;lhave and J Agergaard. The first draft of the manuscript was written by M M\u0026oslash;lhave. All authors revised and commented on previous versions of the manuscript, contributed to the interpretation of the results, and approved the final version of the study.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAgergaard J, Gunst JD, Schi\u0026oslash;ttz-Christensen B, \u0026Oslash;stergaard L, Wejse C (2023) Long-term prognosis at 1.5 years after infection with wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron variants. 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Auris Nasus Larynx 49(2):165\u0026ndash;175. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.anl.2021.07.007\u003c/span\u003e\u003cspan address=\"10.1016/j.anl.2021.07.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, long COVID, cohort study, headache, disturbed smell and taste, neuroinvasion, risk factors","lastPublishedDoi":"10.21203/rs.3.rs-3930891/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3930891/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: Long coronavirus disease (COVID) poses a significant health concern for a substantial proportion of COVID-19 patients. Viral pathogenesis studies suggest the potential of central nervous system (CNS) affection in the acute phase of COVID-19 predicting long COVID.\u003c/p\u003e\n\u003cp\u003eThis study investigates whether acute COVID-19 symptoms, particularly headache and disturbed smell and taste, predict manifestations of long COVID.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This prospective cohort study included COVID-19 patients hospitalized between March 2020, and May 2021. One year after discharge, patients responded to a symptom questionnaire. Logistic regression analysis was used to determine the odds ratio (OR) for these outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Of 288 eligible patients, 111 responded to the follow-up questionnaire. At 1 year follow-up, disturbed smell and taste during acute COVID-19 did not elevate the risk of long COVID. However, patients with acute headache demonstrated a tendency towards an elevated risk of CNS-related long COVID. Notably, this risk significantly increased in patients reporting dizziness (adjusted OR=4.20; 95% confidence interval (CI) 1.19 - 14.85). Neither disturbed smell and taste nor headache during acute COVID-19 indicated a statistically significant risk of worsening in fatigue, health, or total symptom score at 1-year follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Headache, and not disturbed smell and taste, predicted CNS-related long COVID. Further research is warranted to clarify pathways connecting CNS-related symptoms during acute COVID-19 with long COVID, aiding the efforts of addressing the range of symptoms observed among long COVID patients and developing effective interventions.\u003c/p\u003e","manuscriptTitle":"Headache or Disturbed Smell and Taste During Acute COVID-19 as Predictors of Long COVID at One Year","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-07 20:24:19","doi":"10.21203/rs.3.rs-3930891/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"220c6fa8-3f31-4464-81c7-8926b8bffaf3","owner":[],"postedDate":"February 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-27T19:14:53+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-07 20:24:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3930891","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3930891","identity":"rs-3930891","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}