Natural history of long-COVID in a nationwide, population cohort study

doi:10.21203/rs.3.rs-2496392/v1

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Natural history of long-COVID in a nationwide, population cohort study

https://doi.org/10.21203/rs.3.rs-2496392/v1

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published 13 Jun, 2023

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Previous studies on the natural history of long-COVID have been few and selective. Without comparison groups, disease progression cannot be differentiated from symptoms originating from other causes. The Long-COVID in Scotland Study (Long-CISS) is a Scotland-wide, general population cohort of adults who had laboratory-confirmed SARS-CoV-2 infection matched to adults never infected. Serial, self-completed, online questionnaires collected information on pre-existing health conditions and current health: 26 symptoms and health-related quality of life, six, 12 and 18 months after the index test. Those previously infected also self-reported current recovery status (fully, partially or not recovered). Here we show that, of those with previous symptomatic infection, 35% reported persistent incomplete/no recovery, 12% improvement and 12% deterioration. At six and 12 months, one or more symptom was reported by 71.5% and 70.7% respectively of those previously infected, compared with 53.5% and 56.5% of those never infected. Altered taste, smell and confusion improved over time compared to the never infected group and adjusted for confounders. Conversely, late onset dry and productive cough, and hearing problems were more likely following SARS-CoV-2 infection than among those never infected. Whilst resolution of some symptoms of long-COVID (altered taste/smell and confusion) is reassuring, late onset cough and hearing problems in some individuals merits further investigation.

Health sciences/Signs and symptoms

Health sciences/Risk factors

Long-COVID

population cohort

SARS-CoV-2 infection

Understanding the scale and natural history of long-COVID is essential to planning health and social care. The majority of studies report the prevalence of long-COVID at a single timepoint post-infection,^1-7 with some adjusting for pre-existing symptoms.^8,9 Less is known about changes in long-COVID over time. Studies with serial outcome measurements have been restricted to selected groups (e.g. hospitalised patients,^10-13older patients,¹⁴ or veterans with break-through infections¹⁵) or specific (e.g. mental health) outcomes,¹⁶ or have lacked a comparison group making it difficult to distinguish persistent or late-onset symptoms of long-COVID from symptoms that would have occurred anyway in the absence of SARS-CoV-2 infection.^11-13,17,18

Hospital cohorts have variously reported no change,^10,11,13 improvement,^10,11 and deterioration over time.^10,14In one cohort of 807 people, there was no change in the proportion reporting full recovery between 5 months and one year post discharge.¹³A study of 61 subjects reported no change in quality of life, but improvement in six-minute walking test distance.¹¹ A meta-analysis of seven cohort studies included 2,883 people with repeat measures, in whom the prevalence of depression declined over follow-up and was not significantly different to the comparison group beyond two months.¹⁶

Some studies have highlighted the possibility of late-onset sequelae. In an ambidirectional cohort study, conducted on 1,276 patients, the proportion reporting at least one symptom decreased from 68% at six-month follow-up to 49% at 12 months.¹⁰ However, both breathlessness (26% to 30%) and anxiety/depression (23% to 26%) increased over time. Three-six month follow-up of veterans with break-through SARS-CoV-2 infections (infections despite vaccination) revealed increased risk of new (HR 1·13, 95% CI 1·07-1·20) as well as persistent (HR 1·90, 95% CI 1·77-2·04) symptoms.¹⁵ In a retrospective cohort study using linked electronic health records, 37% of people had at least one of nine long-COVID features three-six months after SARS-CoV-2 infection.¹⁹ Of these, 40% had not had these features in the first three months of follow-up. A hospital cohort of 1,438 patients, 60 years of age or older, reported increased risk of progressive and late onset cognitive decline at 12-months follow-up among severe cases.¹⁴ In an online survey of 3,762 participants who had previous suspected or confirmed SARS-CoV-2 infection, 86% reported re-occurrence of symptoms over time.¹⁷

Therefore, whilst long-COVID may be a stable condition in some, existing evidence suggests that others may experience recovery, relapse, or progression. We use serial questionnaire data from the long-COVID in Scotland Study (Long-CISS)²⁰ to investigate the natural history of long-COVID in an unselected, general population cohort with laboratory-confirmed SARS-CoV-2 infection compared with symptoms in an age-, sex-, and socioeconomically-matched group of people who have never been infected.

Study design and participants

The Long-COVID in Scotland Study (Long-CISS) is an ambidirectional, general population cohort. The National Health Service Scotland notification platform for SARS-CoV-2 PCR results was used to identify eligible participants and invite them via automated SMS text messages. Every adult (>16 years) in Scotland with a positive PCR test from April 2020 was invited along with a comparison group who had had a negative test but never a positive test, matched by age, sex, and deprivation quintile.²⁰ People in the latter group were reallocated to the infected group if, and when, they had a positive test. The study commenced in May 2021 and recruited both retrospectively and prospectively based on existing and new test results respectively. Participants provided electronic consent and study approval was obtained from the West of Scotland Research Ethics Committee (ref. 21/WS/0020) and Public Benefit and Privacy Panel (ref. 2021-0180).

An online questionnaire, self-completed six, 12 and 18 months after the index test (first positive test or, for comparison group, most recent negative test), collected information on pre-existing health conditions and 26 current symptoms and health-related quality of life using the EuroQoL-5D (EQ-5D) score. Respondents who had tested positive also self-assessed their current recovery status (fully, partially or not recovered). The questionnaire data were linked retrospectively to the PCR test, vaccination, hospital admissions (Scottish Morbidity Record; SMR01 and SMR04) and dispensed prescriptions (Prescribing Information System; PIS) databases.

Exclusion and inclusion criteria

Only people who completed a six-month follow-up questionnaire plus at least one subsequent questionnaire (12-month, 18-month or both) were included. We excluded people who had asymptomatic SARS-CoV-2 infection, usually detected during occupational or travel-related screening, and those who reported a positive test not recorded on the database, as we could not corroborate the accuracy and date of tests performed outside Scotland.

Definitions

Linkage to the test database provided date and result of the index PCR test plus age, sex and postcode of residence. The latter was used to derive the Scottish Index of Multiple Deprivation (SIMD) from aggregated data on: income, employment, education, health, access to services, crime and housing.²¹ Severe infection was defined as hospital admission with an International Classification of Diseases v10 (ICD-10) code U07.1 between one day prior to the index test and two weeks after. Vaccination status (0, 1 or ≥2 doses) at the time of the index test was obtained via linkage to the vaccination database. SARS-CoV-2 variants were defined as dominant if they accounted for ³95% of cases genotyped that week (https://sars2.cvr.gla.ac.uk/cog-uk/). Ethnic group was self-reported using the questionnaire. Pre-existing health conditions were ascertained from self-report using the questionnaire, as well as linkage to previous hospitalizations and dispensed prescriptions. Respiratory disease was defined as ICD10 codes J40-J47, J98·2 or J98·3, or bronchodilators, inhaled corticosteroids, cromoglycate, leukotriene or phosphodiesterase type-4 inhibitor (British National Formulary (BNF) 3·1-3·3), or self-report. Coronary heart disease was defined as ICD10 codes I11·0, I13·0, I13·2, I20-I25 (excluding I24·1), I50, T82·2, or Z95·5, or self-report. Depression was defined as ICD10 codes F30-F33, or anti-depressant, hypnotic or anxiolytic use (BNF 4·1;4·3), or self-report. Diabetes was defined as ICD10 codes E10-E14, G590, G632, H280, H360, M142, N083, O240-O243 or self-report.²² Total number of self-reported health conditions was categorised as 0, 1, 2-3, or ³4.

The outcomes measured were changes in self-reported recovery status following symptomatic SARS-CoV-2 infection, and changes in 26 individual symptoms and quality of life score compared with those never infected. Improvement in recovery status was defined as change from no recovery to partial/full recovery, or from partial recovery to full recovery. Deterioration was defined as change from full recovery to partial/no recovery or from partial recovery to no recovery.

Statistical analyses

Participant characteristics were summarized using frequencies/percentages and medians/inter-quartile ranges for categorical and continuous variables and compared using c² and Mann-Whitney U tests respectively. The analyses were first conducted comparing six- and 12-month follow-up, then repeated comparing six and 18 months. Separate binary logistic regression models were used to determine the factors associated with improvement and deterioration in recovery status over time following symptomatic infection; univariately then adjusted for potential confounders (age, sex, deprivation quintile, ethnic group, individual and total number of long-term conditions, vaccination status, and dominant variant).

Change in the prevalence of the 26 individual symptoms was compared in those with previous, symptomatic SARS-CoV-2 infection and those never infected using McNemar’s tests. Separate binary logistic regression models were run for the presence of each symptom at 12 months. The models were adjusted for whether the person had been infected or never infected, whether the symptom was present at six months, as well as the confounders listed above. The models were repeated for each of the symptoms at 18 months.

Median EQ-5D score was calculated at six and 12 months for the infected and never infected groups. A Poisson regression model was run for EQ-5D score at 12 months, adjusting for whether the person had been infected or never infected, the score at six months, and the confounders listed above. All analyses were performed using Stata v16. All statistical tests were two-tailed.

Of the 4,049,590 questionnaires sent out, 345,673 (9%) were completed by 288,173 unique individuals, of whom 257,341 (89%) consented to record linkage, required to obtain their test result. Following linkage, 53,530 were excluded because they reported a previous positive test that was not recorded on the database, 5,687 because they had asymptomatic infections, and 37,343 because they were recruited beyond six months follow-up. Of the remaining 160,781 individuals, 80,332 (50%) had previous symptomatic, laboratory-confirmed SARS-CoV-2 infection and 80,449 (50%) had never had a positive test for SARS-CoV2 infection. Of the 80,332 people who had previous symptomatic infections, 12,947 have so far completed questionnaires at both six- and 12-month follow-up and 4,196 have completed questionnaires at both six- and 18-month follow-up. The corresponding figures for the 80,449 individuals never infected were 11,026 and 1,711 respectively.

Changes in recovery status

Six months following SARS-CoV-2 infection, 6,407 (49.5%) people reported being fully recovered, 5,649 (43.6%) partially and 891 (6.9%) not recovered. At 12-month follow-up, the figures were 6,575 (50.8%), 5,412 (41.8%) and 960 (7.4%) respectively (c² trend, p=0.323). Forty one percent of people reported full recovery at both six- and 12-month follow-up, 35% reported persistent incomplete/no recovery, 12% reported improvement and 12% deterioration (Table 1). Between six and 18 months, the figures were 36%, 36%, 14% and 15% respectively.

Of those who felt partially recovered at six months, 1,179/5,649 (21%) had improved by 12 months and 421/1,934 (22%) by 18 months and, of the 891 people not recovered at six months, 404 (45%) had some degree of improvement by 12 months, and 28 (3%) had fully recovered. Of those who felt partially recovered at six months, 458/5,649 (8%) reported deterioration at 12 months and 189/1,934 (10%) at 18 months. In addition, of 6,407 who reported being fully recovered at six months, 1,039 (16%) reported deterioration by 12 months.

Depression prior to SARS-CoV-2 infection was more common among people who reported deterioration in recovery status between six and 12 months (Table 2). Similar patterns were observed comparing six- and 18-month follow-up (Supplementary Table 1). Among those not fully recovered at six months, improvement at 12 months was less likely among older people and those with depression prior to COVID-19 and more likely among the most affluent, after adjusting for potential confounders (Table 3). Among those who reported full or partial recovery at six months, deterioration at 12 months was less likely among older people and the most affluent and more likely among people with prior depression (Table 3). The associations were not statistically significant comparing six- and 18-month follow-up (Supplementary Table 2).

Changes in symptoms

The percentage who reported at least one of the 26 symptoms did not change between six- and 12-month, and six- and 18-month follow-up, among people with previous symptomatic SARS-CoV-2 infection but increased significantly among those never infected (Table 4).

The prevalence of confusion and altered taste and smell decreased significantly between six and 12 months after SARS-CoV-2 infection contrasting with no significant change in confusion and altered smell, and an increase in altered taste, among those never infected (Table 4). The reductions were significant compared to those never infected after adjusting for potential confounders (Table 5).

Reduced prevalence of altered taste/smell and confusion was specific to those who reported an improvement in their recovery status following SARS-CoV-2 infection (Supplementary Table 4). The prevalence of confusion six months following symptomatic SARS-CoV-2 infection was significantly higher among those with a history of depression or anxiety than those without (1,090/5,839 (18.7%) versus 780/7,108 (11.0%); p<0.001) and improvement in confusion between six- and 12-months was less likely among people with pre-existing depression or anxiety (Table 5).

People with previous symptomatic SARS-CoV-2 infection reported significant increases in the prevalence of both dry and productive cough between six- and 12-month follow-up (Table 4). However, these symptoms were also reported more frequently over time in the never infected group. The increased prevalence of both dry and productive cough remained significantly higher among those previously infected than those never infected, after adjusting for confounders (Table 5). The factors associated with increased prevalence of dry cough were younger age, more pre-existing long-term conditions, and specifically pre-existing depression/anxiety (Table 5). Increased prevalence of productive cough was associated with male sex and pre-existing respiratory disease. Following SARS-CoV-2 infection, late onset cough was specific to those who reported deterioration in their recovery status (Supplementary Table 4).

Increases in the prevalence of hearing problems between six- and 12-month follow-up were reported by both those with previous symptomatic SARS-CoV-2 infection and those never infected (Table 4). After adjustment for confounders, the increased prevalence of hearing problems was significantly higher among those previously infected than those never infected (Table 5). Other factors associated with late onset hearing problems were socioeconomic deprivation, SARS-CoV-2 infection severity, and more pre-existing long-term conditions and specifically depression/anxiety.

Between six- and 18-months follow-up, increased prevalence of dry cough, productive cough and hearing problems were all significant compared to those never infected after adjusting for potential confounders (Supplementary Table 5).

Changes in quality of life

Following symptomatic SARS-CoV-2 infection, median EQ-5D score decreased slightly from 75 (IQR 55-86) at six months to 74 (IQR 53-85) at 12 months (p<0.001). However, it also fell among those never infected, from 80 (IQR 64-90) to 77 (IQR 61-90) (p<0.001). In the fully adjusted Poisson regression model, symptomatic infection was associated with a larger fall in EQ-5D score compared with those never infected (IRR 0·98, 95% CI 0·98-0·98).

This is the first study to report the trajectory of long-COVID in the general population compared to contemporaneous changes in symptoms and quality of life in a comparison group that had never been infected. Beyond six months following SARS-CoV-2 infection, there was no significant overall change in either self-reported recovery status or the percentage of people reporting at least one symptom known to be associated with previous SARS-CoV-2 infection.²⁰ However, 12% of people reported improvements in their recovery status, and 12% reported deterioration. These different trajectories were driven by different symptoms. In some people, altered taste, smell and confusion (‘brain fog’) resolved over time whereas others reported late onset dry or productive cough and hearing problems. These changes were not explained by underlying trends or confounding.

Late onset cough and hearing problems were new findings. Respiratory impairment following COVID-19 is well-recognised. A meta-analysis of 15 studies that followed-up 3,066 patients hospitalised for SARS-CoV-2 infection reported that 56% had residual lung CT abnormalities and 44% had abnormal lung function tests: 35% impaired diffusion, 16% restrictive impairment and 8% obstructive impairment.²³ Systematic reviews had demonstrated that sudden sensorineural hearing loss occurring during acute SARS-CoV-2 infection can persist.²⁴ Proposed mechanisms include a direct effect of viral invasion via ACE2 receptors located in the ear,²⁵ indirect effects via hypoxia, immune-mediated damage or coagulative disorders,²⁶ and ototoxic medications used to treat COVID-19.²⁴

Socioeconomic deprivation and depression are known to be associated with development of long-COVID.^4,19,20 Our findings elaborate by showing both to also be associated with reduced risk of improvement over time and increased risk of deterioration. Biological mechanisms may partly explain these observations. The relationship between depression and inflammation is bidirectional.^27-29 Novel immune therapeutic targets are being investigated for the treatment of depression,³⁰ and there is a well-documented link between acute or chronic psychological stress and immune markers.³¹ The stress resulting from socioeconomic deprivation has been linked to changes in immune response and wider detrimental health effects.^32,33 However, in this study, socioeconomic differences in self-reported recovery status were not corroborated by different changes in specific symptoms over time, other than a weak association with hearing problems. Therefore, it is also plausible that more deprived groups have less capacity to adapt their lives to ongoing health problems or poorer access to support.

In our study 70.7% of people had at least one symptom 12 months following SARS-CoV-2 infection. Estimates from previous longitudinal studies ranged from 28%¹² to 77%.¹⁸

Our 12-month prevalence rates of specific symptoms were comparable to those reported in a random-effects meta-analysis of 18 studies:² fatigue/weakness (28% versus 28%),

dyspnoea (24% versus 18%), arthromyalgia (24% versus 26%), depression (21% versus 23%), and concentration difficulties or confusion (15% versus 18%). However, the high prevalence of these symptoms among people never infected reinforces the importance of a comparison group.

The major strengths of our study included national, non-selective coverage, self-reported plus laboratory-confirmed SARS-CoV-2 infection status, and inclusion of a comparison group, never infected over the same period of the pandemic. Other studies have relied on historic controls or controls sampled earlier in the pandemic.¹⁶ Recovery status, ongoing symptoms and quality of life were not subject to recall bias because participants reported them at the time of completing questionnaires. Follow-up to 18 months is longer than previously reported. Whilst every adult in Scotland with a positive SARS-CoV-2 PCR test was invited to take part in the study, participation was voluntary, so response bias is possible.

In conclusion, whilst long-COVID appeared to be a stable condition in many, both improvement and deterioration occurred in others. Improvements in altered taste, smell and confusion were reassuring. In contrast, the findings of late-onset cough and hearing problems one year following infection, that could not be explained by background trends or confounding, merit further investigation.

Acknowledgements

The study was funded by the Chief Scientist Office (ref COV/LTE/20/06) and Public Health Scotland. This research used data assets made available by National Safe Haven as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029). We are grateful to Public Health Scotland and e-DRIS for providing and linking secondary data and providing a secure analytical environment, Storm-ID for administering invitations and data collection, the Scottish Government for supporting the study launch, and the University of Glasgow, College of Medical, Veterinary and Life Sciences PPIE (Patient and Public Involvement and Engagement) and COVID-19 PPIE groups for their contributions to study design, recruitment, and interpretation of results.

Author Contributions

JPP had the original concept. JPP, DJL, AJW, CEH, CAO’D, DNB, NLM, CB, JTS, TRI and AMcA obtained funding. CEH, JPP, DJL and AMcA obtained approvals. CEH analysed the data. JPP, DJL, AJW, CEH, CAO’D, DNB, NLM, CB, JTS, TRI, AMcA and SB interpreted the results. JPP and CEH produced the first draft. All authors revised the manuscript and approved the final version.

Data Availability

The datasets analysed during the current study are available in the National Services Scotland National Safe Haven, https://www.isdscotland.org/Products-and-Services/eDRIS/Use-of-the-National-Safe-Haven/. This protects the confidentiality of the data and ensures that Information Governance is robust. Applications to access health data in Scotland are submitted to the NHS Scotland Public Benefit and Privacy Panel for Health and Social Care. Information can be found at https://www.informationgovernance.scot.nhs.uk/pbpphsc/

Table 1. Trajectories of recovery status following symptomatic SARS-CoV-2 infection

Recovery status		6 and 12 months N=12,947		6 and 18 months N=4,196
		N	%	N	%
Constant	Overall	9,839	76%	2,998	71%
	Full to full	5,368	55%	1,504	50%
	Partial to partial	4,012	41%	1,324	44%
	No to no	459	4.7%	170	5.7%

Deteriorated	Overall	1,497	12%	587	14%
	Full to partial	996	67%	386	66%
	Full to no	43	2.9%	12	2.0
	Partial to no	458	31%	189	32%
Improved	Overall	1,611	12%	611	15%
	No to partial	404	25%	Not disclosed.	Not disclosed
	No to full	28	1.7%	Not disclosed.	Not disclosed
	Partial to full	1,179	73%	421	69%

Table 2. Characteristics of participants by infection status and recovery status trajectory between 6 and 12 months

	Never infected N=11,026	Previous SARS-CoV-2 infection
		Constant recovery status N=9,839	Deteriorated recovery status N=1,497	Improved recovery status N=1,611	P value*
	Median (IQR)	Median (IQR)	Median (IQR)	Median (IQR)
Age (years)	52 (39-61)	51 (38-60)	50 (37-59)	50 (37-59)	0.117
Sex	N (%)	N (%)	N (%)	N (%)
Female	6,441 (58.4)	6,259 (63.6)	1,015 (67.8)	1,123 (69.7)	<0.001
Male	4,585 (41.6)	3,580 (36.4)	482 (32.2)	488 (30.3)	<0.001
SIMD
1 (most deprived)	2,257 (20.5)	2,040 (20.7)	366 (24.5)	332 (20.6)	0.001
2	2,248 (20.4)	2,016 (20.5)	333 (22.2)	347 (21.5)
3	2,127 (19.3)	1,822 (18.5)	251 (16.8)	316 (19.6)
4	2,164 (19.6)	1,921 (19.5)	298 (19.9)	315 (19.6)
5 (least deprived)	2,230 (20.2)	2,040 (20.7)	249 (16.6)	301 (18.7)
Ethnic group
White	10,200 (92.5)	9,343 (95.0)	1,424 (95.1)	1,537 (95.4)	0.694
South Asian	141 (1.28)	110 (1.12)	20 (1.34)	Not disclosed
Black	48 (0.44)	32 (0.33)	Not disclosed	Not disclosed
Other	176 (1.60)	110 (1.12)	Not disclosed	19 (1.18)
Missing	461 (4.18)	244 (2.48)	35 (2.34)	38 (2.36)
Number of pre-existing health conditions
0	6,870 (62.3)	6,619 (67.3)	969 (64.5)	1,028 (63.8)	0.002
1	1,602 (14.5)	1,427 (14.5)	215 (14.4)	250 (15.5)
2-3	1,938 (17.6)	1,442 (14.7)	231 (15.4)	260 (16.1)
≥4	616 (5.59)	351 (3.57)	82 (5.48)	73 (4.53)
Pre-existing health conditions
Arthritis	1,006 (9.12)	712 (7.24)	146 (9.75)	154 (9.56)	<0.001
Asthma, bronchitis, COPD	2,740 (24.9)	2,217 (22.5)	379 (25.3)	409 (25.4)	0.005
Cancer	269 (2.44)	133 (1.35)	21 (1.40)	24 (1.49)	0.903
CHD	514 (4.66)	358 (3.64)	62 (4.14)	66 (4.10)	0.470
Cystic fibrosis	Not disclosed	Not disclosed	Not disclosed	Not disclosed	0.570
Deep vein thrombosis	57 (0.52)	37 (0.38)	10 (0.67)	Not disclosed	0.091
Depression/anxiety	5,322 (48.3)	4,272 (43.4)	774 (51.7)	793 (49.2)	<0.001
Diabetes	743 (6.74)	535 (5.44)	92 (6.15)	93 (5.77)	0.497
High blood pressure	1,399 (12.7)	1,090 (11.1)	190 (12.7)	196 (12.2)	0.110
HIV	20 (0.18)	Not disclosed	Not disclosed	Not disclosed	0.325
Home oxygen	Not disclosed	Not disclosed	Not disclosed	Not disclosed	0.018
Kidney disease	88 (0.80)	72 (0.73)	12 (0.80)	15 (0.93)	0.685
Liver disease	81 (0.73)	33 (0.34)	10 (0.67)	Not disclosed	0.146
Neurological condition	342 (3.10)	229 (2.33)	35 (2.34)	38 (2.36)	0.997
Overweight	1,271 (11.5)	978 (9.94)	161 (10.8)	188 (11.7)	0.083
Obese	509 (4.62)	336 (3.41)	52 (3.47)	59 (3.66)	0.880
Pulmonary embolism	56 (0.51)	36 (0.37)	Not disclosed	Not disclosed	0.138
Pulmonary fibrosis	18 (0.16)	Not disclosed	Not disclosed	Not disclosed	0.189
Stroke	125 (1.13)	92 (0.94)	17 (1.14)	15 (0.93)	0.754
Vaccinated
No	9,491 (86.1)	6,423 (65.3)	1,012 (67.6)	1,129 (70.1)	0.002
1 dose	536 (4.86)	606 (6.16)	97 (6.48)	90 (5.59)
≥2 doses	999 (9.06)	2,810 (28.6)	388 (25.9)	392 (24.3)
Variant period
Pre VOC	3,840 (34.8)	2,738 (27.8)	407 (27.2)	450 (27.9)	0.004
No dominant (1)	4,824 (43.8)	2,801 (28.5)	484 (32.3)	511 (31.7)
Alpha	1,013 (9.19)	495 (5.03)	72 (4.81)	93 (5.77)
No dominant (2)	230 (2.09)	245 (2.49)	Not disclosed	Not disclosed
Delta	1,102 (9.99)	3,528 (35.9)	496 (33.1)	530 (32.9)
No dominant (3)	17 (0.15)	32 (0.33)	Not disclosed	Not disclosed

*comparison of the three trajectories among those with previous SARS-CoV-2 infection

IQR inter-quartile range; N number; SIMD Scottish Index of Multiple Deprivation; COPD chronic obstructive pulmonary disease; CHD coronary heart disease; HIV human immunodeficiency virus; VOC variant of concern

Table 3. Binary logistic regression of factors associated with improvement and deterioration in recovery status between 6 and 12 months

		Improvement (excluding those fully recovered at 6 months)		Deterioration (excluding those with no recovery at 6 months)
		Referent no change	Referent no change plus deterioration	Referent no change	Referent no change plus improvement
		N=6,082 OR (95% CI)	N=6,540 OR (95% CI)	N=10,877 OR (95% CI)	N=12,056 OR (95% CI)
Age		0.99 (0.99,1.00)	0.99 (0.99,1.00)	0.99 (0.99,1.00)	0.99 (0.99,1.00)
Sex	Female	1.00	1.00	1.00	1.00
Sex	Male	0.99 (0.87,1.13)	0.98 (0.86,1.12)	0.89 (0.79,1.01)	0.91 (0.81,1.03)
Ethnic group	White	1.00	1.00	1.00	1.00
	South Asian	0.94 (0.45,1.95)	0.93 (0.45,1.91)	1.23 (0.76,2.01)	1.30 (0.80,2.11)
	Black	2.22 (0.82,6.04)	2.43 (0.89,6.62)	0.78 (0.27,2.22)	0.74 (0.26,2.07)
	Other	1.52 (0.86,2.68)	1.53 (0.87,2.69)	0.85 (0.49,1.50)	0.86 (0.49,1.51)
	Missing	0.93 (0.64,1.36)	0.97 (0.67,1.40)	0.93 (0.65,1.34)	0.95 (0.66,1.36)
SIMD quintile	1 (most deprived)	1.00	1.00	1.00	1.00
	2	1.16 (0.97,1.38)	1.18 (0.97,1.41)	0.94 (0.80,1.11)	0.93 (0.79,1.09)
	3	1.28 (1.07,1.54)	1.33 (1.11,1.59)	0.79 (0.66,0.94)	0.77 (0.65,0.92)
	4	1.26 (1.06,1.52)	1.29 (1.08,1.55)	0.90 (0.76,1.07)	0.88 (0.75,1.04)
	5 (least deprived)	1.37 (1.14,1.65)	1.44 (1.20,1.73)	0.73 (0.61,0.86)	0.72 (0.60,0.86)
Pre-existing long-term conditions	0	1.00	1.00	1.00	1.00
	1	1.03 (0.87,1.22)	1.05 (0.89,1.25)	0.98 (0.83,1.17)	0.97 (0.82,1.14)
	2-3	0.92 (0.77,1.10)	0.94 (0.78,1.12)	0.99 (0.83,1.18)	0.98 (0.82,1.17)
	≥4	0.98 (0.71,1.36)	0.94 (0.68,1.30)	1.40 (1.03,1.89)	1.40 (1.04,1.89)
Asthma/bronchitis/ COPD	No	1.00	1.00	1.00	1.00
Asthma/bronchitis/ COPD	Yes	0.94 (0.82,1.09)	0.93 (0.80,1.06)	1.10 (0.95,1.26)	1.09 (0.95,1.25)
CHD	No	1.00	1.00	1.00	1.00
CHD	Yes	1.17 (0.86,1.61)	1.16 (0.85,1.58)	1.07 (0.79,1.44)	1.06 (0.79,1.43)
Depression/anxiety	No	1.00	1.00	1.00	1.00
Depression/anxiety	Yes	0.81 (0.71,0.91)	0.78 (0.69,0.88)	1.35 (1.20,1.51)	1.34 (1.19,1.50)
Diabetes	No	1.00	1.00	1.00	1.00
Diabetes	Yes	1.03 (0.79,1.36)	1.04 (0.79,1.36)	1.05 (0.81,1.36)	1.03 (0.80,1.33)
Variant period	preVOC	1.00	1.00	1.00	1.00
	No dominant (1)	1.18 (1.01,1.37)	1.15 (0.99,1.33)	1.17 (1.01,1.35)	1.15 (0.99,1.32)
	Alpha	1.27 (0.97,1.65)	1.29 (0.99,1.68)	0.96 (0.73,1.26)	0.93 (0.71,1.22)
	No dominant (2)	0.77 (0.48,1.25)	0.75 (0.47,1.21)	0.94 (0.63,1.39)	0.95 (0.64,1.40)
	Delta	1.47 (1.13,1.92)	1.46 (1.13,1.90)	0.96 (0.74,1.25)	0.92 (0.71,1.19)
	No dominant (3)	0.63 (0.18,2.21)	0.65 (0.19,2.26)	0.45 (0.10,1.91)	0.44 (0.10,1.89)
Vaccinated	No	1.00	1.00	1.00	1.00
	1 dose	0.79 (0.59,1.07)	0.80 (0.59,1.07)	1.08 (0.82,1.42)	1.12 (0.86,1.47)
	≥2 doses	0.79 (0.60,1.04)	0.78 (0.59,1.03)	0.99 (0.76,1.29)	1.05 (0.81,1.37)
Infection severity	Not hospitalised	1.00	1.00	1.00	1.00
Infection severity	Hospitalised	0.75 (0.59,0.95)	0.74 (0.58,0.94)	1.09 (0.84,1.43)	1.08 (0.83,1.40)

Table 4. Prevalence of symptoms reported at 6 versus 12 months follow-up, and 6 versus 18 months follow-up, among people who had symptomatic SARS-CoV-2 infection and those never infected

	Symptomatic						Never infected
	6 and 12 months N=12,947			6 and 18 months N=4,196			6 and 12 months N=11,026			6 and 18 months N=1,711
	6 months	12 months	p-value*	6 months	18 months	p-value*	6 months	12 months	p-value*	6 months	18 months	p-value*
	N (%)	N (%)		N (%)	N (%)		N (%)	N (%)		N (%)	N (%)
Sensory
Change in taste	1,453 (11.2)	1,125 (8.69)	<0.001	421 (10.0)	322 (7.67)	<0.001	162 (1.47)	200 (1.81)	0.035	16 (0.94)	31 (1.81)	0.024
Change in smell	1,679 (13.0)	1,301 (10.1)	<0.001	483 (11.5)	339 (8.08)	<0.001	116 (1.05)	145 (1.32)	0.062	17 (0.99)	21 (1.23)	0.618
Problems hearing	761 (5.88)	867 (6.70)	0.001	244 (5.82)	303 (7.22)	0.002	373 (3.38)	433 (3.93)	0.013	57 (3.33)	75 (4.38)	0.082
Problems with eyesight	974 (7.52)	986 (7.62)	0.751	333 (7.94)	356 (8.48)	0.283	441 (4.00)	467 (4.24)	0.322	82 (4.79)	84 (4.91)	0.925
Pins and needles	1,468 (11.3)	1,530 (11.8)	0.129	539 (12.9)	579 (13.8)	0.109	739 (6.70)	729 (6.61)	0.775	128 (7.48)	128 (7.48)	1.000
Cardiorespiratory
Chest pain	920 (7.11)	926 (7.15)	0.877	318 (7.58)	327 (7.79)	0.691	289 (2.62)	393 (3.56)	<0.001	63 (3.68)	66 (3.86)	0.838
Palpitations	1,197 (9.25)	1,215 (9.38)	0.632	444 (10.6)	460 (11.0)	0.503	429 (3.89)	443 (4.02)	0.588	75 (4.38)	73 (4.27)	0.920
Breathlessness	2,879 (22.2)	2,830 (21.9)	0.309	1,082 (25.8)	1,058 (25.2)	0.431	863 (7.83)	1,076 (9.76)	<0.001	172 (10.1)	188 (11.0)	0.277
Dry cough	1,559 (12.0)	1,946 (15.0)	<0.001	484 (11.5)	713 (17.0)	<0.001	761 (6.90)	1,127 (10.2)	<0.001	119 (6.95)	187 (10.9)	<0.001
Cough with phlegm	1,408 (10.9)	1,819 (14.1)	<0.001	432 (10.3)	628 (15.0)	<0.001	938 (8.51)	1,382 (12.5)	<0.001	146 (8.53)	200 (11.7)	<0.001
Gastrointestinal
Poor appetite	747 (5.77)	776 (5.99)	0.375	246 (5.86)	246 (5.86)	1.000	480 (4.35)	527 (4.78)	0.088	82 (4.79)	79 (4.62)	0.853
Abdominal pain	930 (7.18)	981 (7.58)	0.149	324 (7.72)	342 (8.15)	0.413	701 (6.36)	745 (6.76)	0.173	117 (6.84)	119 (6.95)	0.936
Sickness/vomiting	812 (6.27)	832 (6.43)	0.569	266 (6.34)	324 (7.72)	0.004	551 (5.00)	578 (5.24)	0.381	96 (5.61)	104 (6.08)	0.570
Diarrhea	1,092 (8.43)	1,138 (8.79)	0.240	385 (9.18)	424 (10.1)	0.094	812 (7.36)	815 (7.39)	0.953	117 (6.84)	119 (6.95)	0.935
Constipation	658 (5.08)	649 (5.01)	0.788	238 (5.67)	225 (5.36)	0.511	434 (3.94)	496 (4.50)	0.017	79 (4.62)	80 (4.68)	1.000
Musculoskeletal
Muscle aches/ weakness	3,387 (26.2)	3,446 (26.6)	0.271	1,231 (29.3)	1,269 (30.2)	0.236	1,723 (15.6)	1,881 (17.1)	<0.001	299 (17.5)	307 (17.9)	0.702
Joint pain	2,798 (21.6)	2,831 (21.9)	0.516	1,020 (24.3)	1,092 (26.0)	0.018	1,784 (16.2)	1,869 (17.0)	0.054	293 (17.1)	336 (19.6)	0.019
Neurological/mental health
Headache	3,250 (25.1)	3,325 (25.7)	0.184	1,141 (27.2)	1,145 (27.3)	0.927	2,131 (19.3)	2,423 (22.0)	<0.001	307 (17.9)	337 (19.7)	0.144
Anxious/depressed	2,588 (20.0)	2,559 (19.8)	0.568	921 (22.0)	904 (21.5)	0.569	1,460 (13.2)	1,566 (14.2)	0.008	232 (13.6)	248 (14.5)	0.337
Confusion	1,870 (14.4)	1,757 (13.6)	0.007	723 (17.2)	637 (15.2)	<0.001	534 (4.84)	532 (4.82)	0.970	101 (5.90)	95 (5.55)	0.646
Sleep problems	3,381 (26.1)	3,437 (26.6)	0.310	1,149 (27.4)	1,198 (28.6)	0.131	1,942 (17.6)	2,130 (19.3)	<0.001	300 (17.5)	293 (17.1)	0.736
Dizzy/blackouts/fits	653 (5.04)	645 (4.98)	0.812	234 (5.58)	233 (5.55)	1.000	330 (2.99)	354 (3.21)	0.308	44 (2.57)	49 (2.86)	0.649
Balance problems	901 (6.96)	980 (7.57)	0.018	317 (7.55)	356 (8.48)	0.058	412 (3.74)	465 (4.22)	0.028	79 (4.62)	95 (5.55)	0.145
Non-specific
Tiredness	6,055 (46.8)	5,987 (46.2)	0.264	2,110 (50.3)	2,145 (51.1)	0.325	3,360 (30.5)	3,541 (32.1)	0.001	505 (29.5)	534 (31.2)	0.193
Weight loss	280 (2.16)	241 (1.86)	0.047	103 (2.45)	87 (2.07)	0.221	132 (1.20)	147 (1.33)	0.344	27 (1.58)	31 (1.81)	0.652
Skin rash	552 (4.26)	578 (4.46)	0.366	167 (3.98)	212 (5.05)	0.006	277 (2.51)	314 (2.85)	0.091	43 (2.51)	52 (3.04)	0.343

At least one symptom now	9,252 (71.5)	9,148 (70.7)	0.060	3,080 (73.4)	3,117 (74.3)	0.243	5,899 (53.5)	6,226 (56.5)	<0.001	895 (52.3)	947 (55.4)	0.026

*McNemar’s test; N number

Table 5. Binary logistic regression models of the factors associated with symptoms at 12 months referent to six months

		Altered taste	Altered smell	Confusion	Hearing problems	Dry cough	Cough with phlegm
		OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)	OR (95% CI)
Covid-19 status	Never infected	1.00	1.00	1.00	1.00	1.00	1.00
Covid-19 status	Symptomatic infection	0.22 (0.14,0.35)	0.20 (0.12,0.34)	0.43 (0.35,0.54)	1.58 (1.35,1.84)	1.41 (1.28,1.56)	1.15 (1.05,1.27)
Age (years)		0.99 (0.99,1.01)	1.00 (0.99,1.01)	1.00 (0.99,1.01)	1.00 (0.99,1.01)	0.99 (0.99,0.99)	0.99 (0.98,0.99)
Sex	Female	1.00	1.00	1.00	1.00	1.00	1.00
Sex	Male	0.91 (0.72,1.15)	0.92 (0.74,1.14)	0.98 (0.81,1.18)	0.92 (0.79,1.07)	0.96 (0.87,1.06)	1.16 (1.05,1.27)
Ethnic group	White	1.00	1.00	1.00	1.00	1.00	1.00
	South Asian	1.35 (0.33,5.62)	0.33 (0.05,1.98)	1.13 (0.54,2.37)	0.23 (0.06,0.93)	0.99 (0.66,1.51)	1.03 (0.69,1.55)
	Black	-	-	2.51 (0.48,13.2)	0.64 (0.16,2.64)	0.63 (0.25,1.56)	0.36 (0.11,1.16)
	Other	1.53 (0.52,4.55)	1.84 (0.73,4.63)	0.69 (0.33,1.48)	1.02 (0.54,1.93)	0.73 (0.47,1.15)	1.02 (0.69,1.50)
	Missing	1.02 (0.53,1.96)	1.51 (0.82,2.79)	1.35 (0.81,2.23)	0.90 (0.59,1.37)	0.74 (0.56,0.99)	0.95 (0.73,1.23)
SIMD quintile	1 (most deprived)	1.00	1.00	1.00	1.00	1.00	1.00
	2	0.84 (0.62,1.14)	0.96 (0.72,1.28)	0.83 (0.65,1.05)	0.93 (0.77,1.14)	1.07 (0.94,1.23)	1.07 (0.94,1.22)
	3	0.82 (0.60,1.12)	0.99 (0.74,1.34)	0.93 (0.72,1.20)	0.82 (0.67,1.02)	1.02 (0.89,1.18)	0.92 (0.80,1.06)
	4	0.99 (0.72,1.35)	1.16 (0.86,1.55)	0.90 (0.69,1.16)	0.86 (0.70,1.07)	0.95 (0.83,1.09)	0.96 (0.84,1.11)
	5 (least deprived)	1.07 (0.77,1.48)	1.02 (0.75,1.38)	1.08 (0.83,1.42)	0.71 (0.57,0.89)	0.85 (0.74,0.98)	0.81 (0.70,0.94)
Pre-existing long-term conditions	0	1.00	1.00	1.00	1.00	1.00	1.00
	1	0.90 (0.66,1.23)	0.85 (0.62,1.15)	1.19 (0.93,1.52)	1.07 (0.86,1.33)	1.45 (1.27,1.65)	1.23 (1.07,1.40)
	2-3	1.16 (0.83,1.62)	0.79 (0.58,1.09)	0.96 (0.76,1.22)	1.69 (1.39,2.04)	1.52 (1.32,1.73)	1.58 (1.38,1.80)
	≥4	0.66 (0.37,1.18)	0.71 (0.40,1.29)	0.87 (0.60,1.26)	2.43 (1.80,3.29)	2.32 (1.87,2.88)	1.98 (1.58,2.47)
Asthma/bronchitis/ COPD	No	1.00	1.00	1.00	1.00	1.00	1.00
Asthma/bronchitis/ COPD	Yes	0.92 (0.72,1.18)	1.05 (0.82,1.34)	0.91 (0.75,1.11)	1.09 (0.92,1.28)	1.10 (0.99,1.23)	1.60 (1.44,1.78)
CHD	No	1.00	1.00	1.00	1.00	1.00	1.00
CHD	Yes	1.12 (0.60,2.11)	1.77 (0.91,3.48)	0.86 (0.55,1.35)	1.34 (1.01,1.79)	1.17 (0.95,1.45)	1.06 (0.85,1.32)
Depression/anxiety	No	1.00	1.00	1.00	1.00	1.00	1.00
Depression/anxiety	Yes	0.97 (0.78,1.20)	1.04 (0.85,1.27)	0.76 (0.63,0.91)	1.39 (1.20,1.61)	1.18 (1.07,1.30	1.19 (1.08,1.31)
Diabetes	No	1.00	1.00	1.00	1.00	1.00	1.00
Diabetes	Yes	0.77 (0.46,1.29)	0.83 (0.49,1.39)	1.07 (0.75,1.53)	0.80 (0.61,1.06)	0.95 (0.79,1.15)	0.93 (0.77,1.13)
Variant period	preVOC	1.00	1.00	1.00	1.00	1.00	1.00
	No dominant (1)	1.30 (0.98,1.71)	1.02 (0.79,1.33)	1.16 (0.94,1.42)	0.89 (0.75,1.05)	0.88 (0.79,0.98)	0.79 (0.71,0.88)
	Alpha	1.10 (0.64,1.88)	1.09 (0.63,1.89)	0.86 (0.61,1.22)	0.80 (0.58,1.10)	0.92 (0.75,1.11)	0.80 (0.66,0.98)
	No dominant (2)	0.96 (0.49,1.86)	0.62 (0.33,1.15)	0.64 (0.34,1.23)	0.83 (0.48,1.45)	1.01 (0.73,1.39)	0.59 (0.41,0.86)
	Delta	1.23 (0.80,1.88)	0.81 (0.55,1.20)	1.27 (0.84,1.92)	0.99 (0.68,1.44)	0.86 (0.68,1.09)	0.63 (0.49,0.81)
	No dominant (3)	3.78 (0.73,19.5)	1.21 (0.32,4.53)	0.89 (0.05,15.0)	0.98 (0.22,4.23)	0.86 (0.33,2.24)	0.85 (0.35,2.10)
Vaccinated	No	1.00	1.00	1.00	1.00	1.00	1.00
	1 dose	0.78 (0.46,1.32)	0.89 (0.54,1.46)	0.98 (0.66,1.48)	0.96 (0.66,1.40)	0.95 (0.75,1.20)	1.01 (0.78,1.30)
	≥2 doses	0.83 (0.53,1.31)	1.11 (0.73,1.67)	1.11 (0.72,1.71)	1.01 (0.69,1.47)	1.13 (0.89,1.44)	1.36 (1.04,1.76)
Infection severity	Not hospitalised	1.00	1.00	1.00	1.00	1.00	1.00
Infection severity	Hospitalised	1.36 (0.79,2.33)	0.87 (0.52,1.48)	0.77 (0.56,1.06)	1.69 (1.23,2.34)	0.98 (0.74,1.29)	1.23 (0.94,1.60)

OR odds ratio; CI confidence interval; SIMD Scottish Index of Multiple Deprivation; COPD chronic obstructive pulmonary disease; CHD coronary heart disease; VOC variant of concern

There is NO Competing Interest.

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Natural history of long-COVID in a nationwide, population cohort study

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