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

doi:10.21203/rs.3.rs-3930891/v1

Purpose: 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.

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

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.

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).

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.

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)

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.

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. Data analysis was performed by M Mølhave and J Agergaard. The first draft of the manuscript was written by M Mølhave. 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.

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No competing interests reported.

Supplementarymaterials.docx

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

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Abstract

Figures

Introduction

Materials and methods

Study design and follow-up

Study population and data collection

Statistical analysis

Ethical approval

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1