Post-infection sequelae of COVID-19 and other infectious diseases—a nationwide Danish study with 40-month follow-up

Domain: biology
Published: 2026-03-13
Editorial outcome: major_revision

Abstract
Nationwide follow-up studies of long-term post-acute COVID-19 sequelae compared with
sequelae of other infections have been lacking. Using nationwide registers, we analyzed all
SARS-CoV-2 PCR test results, prescriptions for anti-infective agents, and hospitalizations with
COVID-19 or other infections in Denmark from March 2020 to June 2023, including up to 40-
month follow-up. We used Cox Proportional Hazards models with time-varying exposures to
estimate the rates of first-time mental disorders (n = 5,147,288) and general medical conditions
(n = 4,074,487). Here we show that positive SARS-CoV-2 PCR tests alone were not associated
with clinically relevant increased rates of mental disorders or general medical conditions when
compared with negative SARS-CoV-2 PCR tests, nor when compared to individuals with anti-
infective prescriptions. Rates of general medical conditions after a positive compared with a
negative SARS-CoV-2 PCR test were only elevated for virus types preceding Omicron and for
individuals with less than 3 vaccinations. Compared with the general population, the rates of
mental disorders or general medical conditions were elevated among hospitalized COVID-19
patients, and particularly when ICU treatment was required. However, when comparing patients
hospitalized with COVID-19 to patients hospitalized with non-COVID-19 pulmonary infections
or other infections, the rates of mental disorders or general medical conditions were increased to
the same extent. In conclusion, severe COVID-19 post-infection sequelae are comparable to
sequelae observed after other infections of similar severity.

Introduction
The COVID-19 pandemic resulted in over 700 million people infected with SARS-CoV-2
worldwide.1 Ten to 20% of individuals with COVID-19 have been estimated to experience
sequelae, even after mild illness, and thus, long-COVID is estimated to impact the lives of at
least 65 million individuals.2,3 However, many other infections, such as influenza and
pneumonia, can also lead to post-infection sequelae, and the post-COVID complications have yet
to be compared comprehensively with sequelae after other infectious diseases. Strong
epidemiological evidence regarding COVID-19 sequelae and whether they differ from sequelae
after other infections is of utmost importance for healthcare planning, including resource
allocations, but also for the society through increased understanding of the specificity of
COVID-19 sequelae compared to other infections.

Prior studies investigating different aspects of COVID-19 and the risk of sequelae have reached
conflicting results depending on the time of follow-up, admission status of COVID-19 patients,
and whether the control groups were individuals with negative tests, no positive test, or various
non-COVID-19 infections.4-19 Thus, a largescale study including all of these aspects is needed to
clarify the status on the directions and specificity of these associations. Prior large-scale studies
and meta-analyses, not comparing to other infections with similar severity, found that individuals
with COVID-19 had higher risks of numerous adverse health outcomes, including increased risks
of mental, neurological, respiratory,4,5 hematological,6,7 neurodegenerative,8 cardiovascular,9, 10,
11, 12 kidney and liver disorders,13 and diabetes.14 Studies comparing positive with negative
SARS-CoV-2 PCR tests among non-hospitalized individuals found higher 6-month post-COVID
risks of certain hospital diagnoses, such as venous thromboembolism, although the risk was not
higher for serious complications like ischemic stroke, encephalitis, or psychoses.15 Also, risks of
many sequelae declined 2 years post-COVID among hospitalized and non-hospitalized
individuals compared with individuals with no evidence of a SARS-CoV-2 infection.6
Additionally, the risk of new-onset mental and neurological disorders was not significantly
higher after COVID-19 when comparing with the increased risks observed after other non-
COVID infections.16–18, 19 This emphasizes that different reference groups are important for
clarifying the long-term sequelae and to assess if the findings are specific to COVID-19 in
comparison to other non-COVID infections with similar severity. As SARS-CoV-2 only very
rarely reaches the brain, the immune response after infection might be one of the main drivers for
long-term sequelae, and here the most used measure of general inflammation is C-reactive
protein (CRP), which increases with the severity of infection. Thus, CRP has been suggested as a
potential biomarker indicative of elevated risk for long COVID symptoms,20 however, few
studies have investigated this.21 Moreover, it is unclear how clinically relevant sequelae of
COVID-19 affects individuals not admitted to the hospital with COVID-19 and whether the
sequelae following COVID-19 are comparable to those following other infectious diseases.

In this nationwide cohort study, we utilized nationwide Danish registers to comprehensively
analyze all SARS-CoV-2 PCR tests and all treated infections across the entire population of
Denmark. Our primary objective was to estimate the association between COVID-19 and
subsequent first-time mental disorders and general medical conditions from inpatient, outpatient,
and emergency room visits, among non-hospitalized and hospitalized individuals. Our secondary
objective was to evaluate how these associations compared with those observed after other
infectious diseases. The impact of SARS-CoV-2 on subsequent sequelae were investigated by
comparing 1) individuals with positive SARS-CoV-2 PCR test to individuals with negative and
no SARS-CoV-2 PCR tests, 2) hospital admission with COVID-19 to no admission with
COVID-19, and 3) by comparing COVID-19 with other infections of comparable severity to
examine to what extent post-infection sequelae were specific for COVID-19. To further nuance
the findings, we performed analyses stratified by calendar time to account for differences in virus
variants, lockdown periods, and vaccination status. Lastly, to explore the potential role of CRP in
the development of long COVID, we analyzed the association between peak CRP levels and
COVID-19 sequelae.

Results
The population of Denmark as of March 1, 2020, consisted of 5,806,583 individuals (see
Supplementary Figure 1) for a schematic visualization of the study population). Of these,
910,236 had a prior hospital contact for mental disorders (including mental and behavioral
disorders due to psychoactive substance use, psychotic, mood, and anxiety disorders) and
2,585,417 had a prior hospital contact for general medical conditions (including selected
neurological, respiratory, gastrointestinal, circulatory, kidney, endocrine, hematological,
musculoskeletal, and dermatological disorders, as well as neuropsychiatric symptoms; see
Supplementary Table 1 for number of individuals in the study populations by outcome). When
considering the mental health disorders outcome, the study population consisted of 5,147,288
individuals, and when considering the general medical conditions outcome, the study population
consisted of 4,074,487 individuals. In total, 2,752,053 individuals had a prior hospital contact for
either a mental disorder or a general medical condition (48.9% female, mean age at start (SD)
33.4 (21.2) years) (for cohort characteristics of the study populations of the primary outcomes,
see Supplementary Table 2–4). During the study period, 1,832,328 (54.8%) individuals tested
positive for SARS-CoV-2, 1,222,202 (36.6%) only tested negative for SARS-CoV-2, and
289,176 (8.6%) were not tested for SARS-CoV-2 (see Supplementary Figure 2 for a graphical
representation of the number of individuals in each group over time). In total, 9,409 (0.3%)
individuals were hospitalized with COVID-19, of whom 416 were admitted to ICU
(Supplementary Table 5). During the study period, 266,337 (8.7%) individuals had a hospital
contact for any mental disorder or general medical condition, of which 83,232 previously tested
positive for SARS-CoV-2.

SARS-CoV-2 positive test results and the rate of any first mental disorder
Compared with individuals not tested for SARS-CoV-2, rates of any first mental disorder were
higher after positive SARS-CoV-2 tests (hazard ratio (HR) 1.12, 95% confidence interval (CI)
1.10–1.15, p-value <0.001) and after negative SARS-CoV-2 tests (HR 1.37, 95% CI 1.35–1.40,
p-value <0.001) (Table 1 and Supplementary Table 6). However, with a HR significantly below
one, positive SARS-CoV-2 tests were not associated with higher mental disorder rates compared
with individuals with negative SARS-CoV-2 tests (HR 0.82, 95% CI 0.80–0.83, p-value <0.001).
The rates of mental disorder rates did not depend on the age group (Fig. 1 and Supplementary
Table 7). The mental disorder rates did not significantly increase with the number of SARS-
CoV-2 reinfections (Table 1, Supplementary Table 8). Moreover, there was no significant
association between time since testing and mental disorders (Table 1, Supplementary Table 9).

SARS-CoV-2 positive test results and the rate of any first general medical condition
Compared with individuals not tested, rates of any first general medical condition were higher
after positive SARS-CoV-2 tests (HR 1.90, 95% CI 1.87–1.93, p-value <0.001) and after
negative SARS-CoV-2 tests (HR 1.88, 95% CI 1.86–1.90, p-value <0.001) (Table 1). However,
when compared with negative SARS-CoV-2 tests, positive SARS-CoV-2 tests were not overall
associated with clinically relevant differences (HR 1.01, 95% CI 1.00–1.02, p-value 0.024).
In age-stratified analyses compared with negative SARS-CoV-2 tests, general medical condition
rates were higher for the age groups between 18 and 69 years, lower for the 80+-year-olds (HR
0.88, 95% CI 0.82–0.94, p-value <0.001), and with no significant difference for the <18 and 70-
79-year-olds after positive SARS-CoV-2 tests (Fig. 1 and Supplementary Table 7). Compared
with individuals with negative SARS-CoV- 2 tests, the general medical condition rates increased
with the number of SARS-CoV-2 reinfections (one infection: HR 1.04, 95% CI 1.02–1.05, p-
value <0.001; two or more infections: HR 1.20, 95% CI 1.16–1.24, p-value <0.001) (Table 1 and
Supplementary Table 8). Compared with negative SARS-CoV-2 tests, the rates of general
medical condition after a positive SARS-CoV-2 test were highest 1-month post-COVID-19 (HR
1.10, 95% CI 1.06–1.13, p-value <0.001) and remained significantly elevated until 30 months
post-COVID-19 (Table 1 and Supplementary Table 9).

SARS-CoV-2 positive test results and time-varying effects
Compared with negative SARS-CoV-2 tests, the rates of first mental disorders and general
medical conditions after a positive SARS-CoV-2 test changed over the study period as illustrated
by the time-varying hazard ratios in Fig. 2 (Supplementary Table 10). The time-varying hazard
ratios show that compared to negative SARS-CoV-2 tests, the rates of mental disorders were
consistently lower throughout the study period while the rates of general medical conditions
were initially lower but then elevated through most of 2021 for individuals with positive SARS-
CoV-2 tests.

SARS-CoV-2 positive test results and the rates of specific general medical conditions
Compared with negative SARS-CoV-2 tests, rates after a positive SARS-CoV-2 test were higher
specifically for neuropsychiatric symptoms (HR 1.08, 95% CI 1.06–1.10, p-value <0.001),
musculoskeletal disorders (HR 1.07, 95% CI 1.05–1.10, p-value <0.001), and dermatological
disorders (HR 1.06, 95% CI 1.02–1.10, p-value 0.002) (Supplementary Table 6). The HRs of
incident diagnoses diminished with increasing age (Supplementary Table 7
and Supplementary Figure 3). The HRs for all specific disorders increased by number of
reinfections (Fig. 3, Supplementary Table 8). The HRs for circulatory, endocrine, hematological,
kidney, and respiratory disorders were elevated only during the initial few months following a
positive SARS-CoV-2 test, with little to no significant increases thereafter (Supplementary Table
9). In contrast, the HR for neuropsychiatric symptoms remained significantly higher for positive
compared with negative SARS-CoV-2 tests across most time intervals after testing.

SARS-CoV-2 positive test results compared with prescriptions for anti-infective agents
regarding rates of long-term sequelae
Redeeming a prescription for any anti-infective agent was associated with higher rates of mental
disorders (HR 1.41, 95% CI 1.38–1.44, p-value <0.001) and general medical conditions (HR
1.65, 95% CI 1.62–1.67, p-value <0.001) compared to no prescription among individuals with
negative SARS-CoV-2 tests (Fig. 4 and Supplementary Table 11). Individuals with positive
SARS-CoV-2 tests did not have higher rates of mental disorders (HR 0.63, 95% CI 0.62–0.65, p-
value <0.001) and general medical conditions (HR 0.72, 95% CI 0.70–0.73, p-value <0.001)
compared with individuals with anti-infective prescriptions (and only negative SARS-CoV-2
tests). These findings were consistent across different types of anti-infectives and specific
general medical conditions.

Hospitalization with COVID-19 and rates of long-term mental disorders or general medical
conditions
Compared with non-hospitalized individuals, compromising both those with positive and
negative SARS-CoV-2 tests, hospitalized COVID-19 patients had elevated rates of mental
disorders (HR 1.88, 95% CI 1.75–2.03, p-value <0.001) and general medical conditions (HR
2.53, 95% CI 2.40–2.67, p-value <0.001) (Table 1 and Supplementary Table 12). Compared with
the non-hospitalized individuals, COVID-19 related ICU admission was associated with further
elevated rates of mental disorders (HR 2.49, 95% CI 1.96–3.15, p-value <0.001) and general
medical conditions (HR 5.09, 95% CI 4.34–5.98, p-value <0.001). Compared with the general
population, all age groups showed higher rates of mental disorders and general medical
conditions after COVID-19 admission, and highest among 60–79-year-olds (Fig. 1 and
Supplementary Table 13). A dose-response relationship was observed between the rate of
sequelae and number of admissions, duration of admission (Table 1, Supplementary Table 14–
15).

Hospitalization with COVID-19 and time-varying effects
Compared to non-hospitalized individuals, the rates of mental disorders and general medical
conditions for patients admitted with COVID-19 varied over the study period as illustrated by the
time-varying hazard ratios in Fig 2 (Supplementary Table 16). The effect of hospital admission
with COVID-19 on sequelae were highest around the turn of the years 2020 and 2021.

Hospitalization with COVID-19 and the rates of specific general medical conditions
Compared to the general population, rates of all specific general medical conditions, except
musculoskeletal disorders, were higher among patients admitted with COVID-19 (Fig. 3 and
Supplementary Table 12). The rates of respiratory disorders were particularly elevated (without
ICU: HR 3.09, 95% CI 2.92–3.27, p-value <0.001; with ICU: HR 7.77 (6.77–8.92, p-value
<0.001). The hazard ratios tended to decrease with increasing age (Supplementary Table 13 and
Supplementary Figure 3).

Hospitalization with COVID-19 compared with other infectious diseases regarding rates of
long-term sequelae
Compared with those not hospitalized with infections, hospital admissions with non-COVID-19
infections, particularly pulmonary infections, were associated with higher rates of mental
disorders and general medical conditions (Fig. 4, Supplementary Table 17-18). Individuals
hospitalized with COVID-19 had similar rates of mental disorders as those hospitalized for non-
COVID-19 infections (HR 1.03, 95% CI 0.94–1.13, p-value 0.517) and non-COVID-19
pulmonary infections (HR 0.87, 95% CI 0.79–0.96, p-value 0.005). However, the rates of general
medical conditions were higher for COVID-19 compared with non-COVID-19 infections (HR
1.15, 95% CI 1.09–1.23, p-value <0.001), but lower for COVID-19 compared with non-COVID-
19 pulmonary infections (HR 0.70, 95% CI 0.65–0.75, p-value <0.001) among individuals
hospitalized with infections.

Sensitivity analyses
For more information on sensitivity analyses, see Supplementary Materials.

Number of SARS-CoV-2 tests and the rates of long-term sequelae
To investigate the impact of testing behavior, we further stratified by the number of conducted
tests in the comparison between positive and negative SARS-CoV-2 PCR tests, (Table 2 and
Sensitivity analysis 2). For general medical conditions, the HRs for positive compared with
negative tests remained close to non-significant, and only slightly increased with more tests
conducted. However, testing behavior seemed to have a larger impact on the observed
associations with mental disorders. Here, the HR increased with more tests conducted and to a
non-clinically relevant difference for individuals with ≥15 SARS-CoV-2 tests, where the HR was
0.94 (95% CI 0.91–0.96).

Type of SARS-CoV-2 virus and the rates of long-term sequelae
Compared to individuals with negative SARS-CoV-2 PCR tests, positive tests were not
associated with higher rates of mental disorders for all SARS-CoV-2 variants, while the general
medical condition rates were only elevated for the virus-types preceding Omicron (Original: HR
1.21, 95% CI 1.14–1.28; Alpha: HR 1.17, 95% CI 1.11-1.22, p-value <0.001; Delta: HR 1.09,
95% CI 1.05–1.13, p-value <0.001; Omicron: HR 0.98, 95% CI 0.96-1.01, Omicron subtypes:
HR 1.02, 95% CI 1.01–1.04, p-value 0.001) (Fig. 2, Sensitivity analysis 3-4). Compared with the
general population, the rates of mental disorders and general medical conditions were increased
for all virus-types among individuals admitted to the hospital with COVID-19 (Fig. 2, Sensitivity
analysis 8-9).

Vaccinated vs non-vaccinated and the rates of long-term sequelae
Compared to individuals with negative SARS-CoV-2 PCR tests, positive tests were only
associated with increased rates of general medical conditions among individuals with less than 3
vaccinations (no vaccinations: HR 1.12, 95% CI 1.09–1.14, p-value <0.001, 1 vaccination: HR
1.14, 95% CI 1.08-1.20, p-value <0.001, 2 vaccinations: HR 1.05, 95% CI 1.03–1.07, p-value
<0.001, 3 or more vaccinations: HR 0.99, 95% CI 0.98–1.01, p-value 0.389) (Sensitivity analysis
5). Compared with the general population, the rates of mental disorders and general medical
conditions were increased for patients admitted to hospital with COVID-19 irrespective of
number of vaccinations (Sensitivity analysis 10).

CRP levels and the rates of long-term sequelae
Compared with SARS-CoV-2 negative individuals with peak CRP ≤4 mg/L, peak CRP ≥100
mg/L was associated with higher general medical condition rates among individuals with
positive (HR 1.43, 95% CI 1.35–1.51, p-value <0.001) and negative (HR 1.41, 95% CI 1.36–
1.46) SARS-CoV-2 tests (Supplementary Table 19-20 and Supplementary Figure 4). Among
individuals with positive SARS-CoV-2 tests, there was no significant association between CRP
levels and mental disorder rates and increasing CRP values were only associated with increasing
HR of general medical conditions for the age groups between 40 and 79 years (Supplementary
Table 21–22, Supplementary Figure 5–6). Among individuals hospitalized with COVID-19,
there was no significant association between CRP levels and rates of long-term mental disorders
or general medical conditions (Supplementary Table 23–26, Supplementary Figure 7–8).

Analyses with five years washout period for prior hospital contacts
Post hoc, instead of excluding individuals with hospital contacts for pre-existing disorders at any
point in time before study start, we conducted additional analyses only excluded individuals with
a hospital contact within five years before study start (Sensitivity analysis 7 and 12). This
excludes 659,295 and 1,732,096 individuals with hospital contacts for mental disorders and
general medical conditions, respectively. The results were generally unchanged.

Methods
This study was pre-registered on the Open Science Framework (osf.io/9qgjt). This study was
approved by the Danish Data Protection Agency and the Danish Health and Medicine Authority.
Following the implementation of the General Data Protection Regulation (EU) 2016/679 in
Denmark on 23 May 2018, register-based studies are no longer required to be reported to or
approved by the Danish Data Protection Authority and do not require additional ethical approval
or informed consent.

Study Population
We utilized nationwide registers covering the entire population of Denmark as of March 1, 2020
(5.8 million inhabitants). The registers provided data on each resident, including sex, age,
socioeconomic status, hospital contacts, and prescriptions. Data from the different Danish
registers were linked using the unique personal identification number in the Danish Civil
Registration System, which also enabled linkage to parents.42 Individuals were followed from
March 1, 2020, until the onset of the disorders of interest or censored in case of death,
emigration, or end of follow-up on June 30, 2023. For the primary analysis, we included all
individuals, including those not tested, and considered March 1, 2020, the start of follow-up. For
other analyses, only individuals with a SARS-CoV-2 PCR test were included, with the first test
date as the start of follow-up.

Exposure to SARS-CoV-2
Confirmed COVID-19 was defined by a positive SARS-CoV-2 polymerase chain reaction (PCR)
by nasopharyngeal/tracheal test. Data were available on all SARS-CoV-2 test results performed
in official testing facilities in Denmark from February 2, 2020 through the Microbiology
Database (MiBa).43 Access to health care is free in Denmark, and during the pandemic there was
free and equal access to testing facilities.27 PCR tests were the best method for detecting SARS-
CoV-2,40 and we did not include results from other types of tests such as self-testing, as a
positive self-test required subsequent confirmation with PCR testing.

Assessment of Outcomes
Diagnoses from inpatient, outpatient, or emergency room contacts were collected from the
Danish Psychiatric Central Research Register and the Danish National Patient Register.38,44 The
registers were coded using the International Classification of Diseases, Eighth Revision (ICD-8)
from January 1969 and Tenth Revision (ICD-10) from January 1994. Patients with pre-existing
diagnoses were excluded within each outcome diagnosis. For example, when investigating
kidney disorders, patients with kidney disorders before the start of follow-up were excluded, but
not patients with psychiatric diagnoses such as PTSD (see Supplementary Table 1 for number of
individuals, and Supplementary Table 27 for diagnosis codes).

Primary outcome: Any first-time mental disorder (including mental and behavioral disorders
due to psychoactive substance use, psychotic, mood, and anxiety disorders) or general medical
condition (including selected neurological, respiratory, gastrointestinal, circulatory, kidney,
endocrine, hematological, musculoskeletal, and dermatological disorders, as well as
neuropsychiatric symptoms) (Supplementary Table 27). The pre-specified outcomes were
selected based on our prior work on neurological and psychiatric sequelae of COVID-19,16,18 and
from the prior literature of identified associations.4,5,49–54,6,7,15,19,45–48 The date of the first hospital
contact defined illness onset.

Secondary outcomes: A first diagnosis within the following specific categories: mental,
neurological, respiratory, gastrointestinal, circulatory, kidney, endocrine, hematological,
musculoskeletal, and dermatological disorders, and neuropsychiatric symptoms (Supplementary
Table 27).5,16,18,55–57

Statistical analysis
We performed Cox Proportional Hazards regression, stratified by age and with calendar time as
the underlying time scale to capture the most complex effects during the pandemic, for example
virus variants, lockdowns, and vaccination recommendations. We reported Hazard Ratios (HRs)
with 95% Confidence Intervals (CIs). Statistical analyses were conducted with the survival
package in R, version 4.4.1, with significance level set at a two-sided p-value <0.05 (see
Supplementary Methods Section for more details). The analyses were adjusted for confounders
related to COVID-19 and sequelae, and the confounders were defined at the start of follow-up:
Sex, socioeconomic status (employment status, income quantile, and educational attainment
level),33,58 medical susceptibility to disease (Charlson Comorbidity Index (CCI) (Supplementary
Table 28)),59 parental medical history (parental CCI, and parental psychiatric diagnosis) (see
Supplementary Table 29 for confounder definitions). Missing values were managed by
conducting complete case analyses (missing values 0.2% due to unknown employment status and
income).

The primary analyses compared individuals tested positive for SARS-CoV-2 with individuals
not tested, or tested negative for SARS-CoV-2. We identified the test results in a hierarchal time-
varying manner, where initially everyone was in the no test group and when tested moved to the
negative or positive group. Subsequent negative tests were ignored in the positive group. With
this definition, the same individuals could not be in different groups at the same time.

In the secondary analyses: we investigated how the COVID-19 sequelae were affected by
disease severity, measured by (i) COVID-19-reinfections, (ii) hospital admission, (iii) duration of
hospital admission, (iv) number of admissions, (v) intensive care unit (ICU) admission, and (vi)
peak CRP levels (see Supplementary Table 30 and Supplementary Methods Section for more
details on exposure definitions). CRP was collected from the Register of Laboratory Results for
Research covering the large clinical biochemical and immunological laboratories.60 When
considering SARS-CoV-2 PCR-tests, CRP measurements taken within two weeks (14 days) prior
to the test date were included in the analysis, and in the case of admissions with COVID-19, only
CRP measurements taken within two days before or during the admission were considered. We
assessed the trajectory of the illness by measuring outcomes based on time after infection: <1
month, 1-2 months, 3-5 months, 6-11 months, and more than 12 months. We investigated time-
varying effects by dividing calendar time into 2-month intervals and using stratified analyses to
allow different baseline hazards and different hazard ratios in each interval. We compared
COVID-19 to non-COVID-19 infections separately for hospital and non-hospital-treated
infections (see Supplementary Methods Section for more details on exposure definitions). For
non-hospital-treated infections, SARS-CoV-2 positive tests were compared with, (i) any anti-
infective agent prescription, and (ii) subtypes of anti-infectives (antibacterial, antiviral, and
antimycotic agents) (see Supplementary Table 31 for ATC codes). All individuals with a positive
SARS-CoV-2 test result were assigned to the positive group, regardless of whether they had
prescriptions for anti-infective agents. Prescriptions with anti-infective agents were collected
from the Danish National Prescription Register, which contained information on all redeemed
prescriptions since 1995 grouped by ATC codes.61 For hospital-treated infections, COVID-19-
admissions were compared with: (i) any infection treated in hospital, (ii) any pulmonary
infection treated in hospital, and (iii) subtypes of pulmonary infections (influenza, bacterial
pneumonia, and other pulmonary infections) (see Supplementary Table 32 for diagnosis codes).
Admissions with COVID-19 and non-COVID-19 infections were identified using the Danish
National Patient Register. All individuals admitted to the hospital with COVID-19 were included
in the COVID-19 admission group, regardless of whether they were also admitted for other
infectious diseases.

Sensitivity analysis
In sensitivity analyses, the robustness of results was assessed by repeating the analyses with
various adjustments for confounders: i) no adjustment, ii) stratification for age in 10-year bands,
iii) stratified for age and adjusted for sex, iv ) stratified for age, adjusted for sex, CCI, parental
CCI, parental mental health, employment status, income, the highest level of education. Given
the changes in SARS-CoV-2 contagiousness, testing behavior, and vaccination uptake
throughout the pandemic, we also examined i) the number of conducted tests, ii) dominating
SARS-CoV-2 variants, iii) lockdown periods, iv) vaccination status, and v) immigration status at
the individual level (Supplementary Table 33-34, and Supplementary Figure 9). Vaccination data
was extracted from the Danish Vaccination Register.62 Post hoc, we conducted an additional
sensitivity analysis to investigate how exclusion criterion affected results by only excluding
individuals with a hospital contact for a pre-existing diagnosis 5 years before the start of the
study.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Using the nationwide Danish registers, this large study (3,343,706 individuals) used SARS-CoV- 2 PCR test results and COVID-19 hospitalizations from March 2020 to June 2023, and estimated Hazard ratios of mental, neurological, and general medical conditions, as well as of neuropsychiatric symptoms. The authors found that compared with negative tests, positive SARS-CoV-2 PCR tests were associated with lower risk of mental disorders and minimally higher rates of general medical conditions. This large study is well conducted and an important contribution to the research on long-COVID symptoms but needs major revisions. Please see my comments below:\nComment 1: Methods: exposure to SARS-CoV-2 paragraph; did the study include only tests from the registry MiBa? What about self-testing? Please add a sentence that you did not use self-tests and how this could have influenced the results, for example selection bias.\nComment 2: Study population-flow chart: only those with PCR-test? Only self-test after February 2022 in Norway, the same in Denmark? Low number of participants with PCR-test after omicron? Who are these participants with PCR-test after Omicron? Selection bias.\nComment 3: Too short discussion, half a page… extend the discussion. There are several other studies who have included non-hospitalized and tested for SARS-CoV-2 (Ballering, van Zon et al. 2022, Ellingjord-Dale, Brunvoll et al. 2024, Ellingjord-Dale, Nygaard et al. 2024),\nBallering, A. V., S. K. R. van Zon, T. C. Olde Hartman and J. G. M. Rosmalen (2022). \"Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study.\" Lancet 400(10350): 452-461.\nEllingjord-Dale, M., S. H. Brunvoll and A. Soraas (2024). \"Prospective Memory Assessment before and after Covid-19.\" N Engl J Med 390(9): 863-865.\nEllingjord-Dale, M., A. B. Nygaard, N. C. Støer, R. Bø, N. I. Landrø, S. H. Brunvoll, M. Istre, K. T. Kalleberg, J. A. Dahl, L. Geng, K. Tsilidis, E. Riboli, G. Ursin and A. Søraas (2024). \"Temporal trajectories of long-COVID symptoms in adults with 22 months follow-up in a prospective cohort study in Norway.\" Int J Infect Dis 149: 107263.\nComment 4: Line 204. “hazard ratio of general medical conditions increased with CRP in individuals with positive SARS CoV-2 tests, though not in patients hospitalized with COVID-19”. Please discuss in the discussion section why you did not find any difference? Who was the comparison group? If hospitalized they have already a high CRP?\nComment 5: line 240, please define pre-existing outcome disorders.\nComment 6: line 239-242: 2.5 million people were excluded from the study having pre-existing outcome disorder. Please add a sentence or two on how this large exclusion of people could have affected the results, under- or overestimation? Healthy bias effect as limitation. Selection bias etc.\nComment 7: I could not find any sensitivity-analysis on the 2.5 million excluded from the study?\nPlease, do a sensitivity analysis including these large group of people.\nComment 8: line 241-242- Please rephrase this sentence. Could the authors be more specific than stating that “some effect estimates were not…an unselected population”? “Some” effect estimates? Which ones? In my opinion, this goes for the whole study population and all the effects. By “unselected “I assume you mean the general population in Denmark? Please rephrase.\nComment 9: Conclusion, line 245-46: Unprecise fist sentence-. “Hospitalized COVID-19 individuals have higher rates of sequelae, whereas non-hospitalized COVID-19 individuals do not” Compared to who? Please be more specific.\nComment 10: line 245-246, “Hospitalized COVID-19 individuals have higher rates of sequelae, whereas non-hospitalized COVID-19 individuals do not” Higher rates, should it not be “risk of sequelae” and not “rates” since HR is a risk-estimate? Please be more specific.\nComment 11: line 246-47. “Sequelae are not exclusive to COVID-19 survivors but also occur after other infectious diseases with similar severity”. What do the authors mean “by similar severity”? Hospitalized? Severity according to what? Please me more specific.\nComment 12: line 247-48, “However, the unique data on COVID-19, can help …of infections”. I assume that the authors mean” COVID-19 infection compared to other infections (SARS-CoV-2-negative). Please be more precise.\nComment 13: line 239-241. Excluding pre-existing outcome disorders? How many? What do the authors mean by pre- existing outcome disorders? Please be more specific and define.\nComment 14: Line 260-Methods: “Individuals were followed from March 1, 2020, until the onset of the disorders of interest and censored in case of death, emigration...” I assume that it should say ;…or censored in case of death, emigration..”\nComment 15: line 279-280. Please be more precise in the definition of primary outcomes: what kind of mental disorder, please give examples? The same goes for general medical conditions; please specify.\nComment 16: line 292-93, Statistical analyses. This sentence is confusing “This method has been proven to minimize bias when estimating vaccination effectiveness”. Do the study measure vaccination effectiveness as the main objective? And cox regression is widely used as a survival analysis, time to event, risk analysis etc., so it is a bit misleading to state that it is known for minimizing bias in vaccination effectiveness. Please remove this sentence.\nComment 17: Line 293-94; the authors mention that they reported Hazard rate ratios (HR), shouldn´t it be hazard ratio? The effect estimate should be referred to as hazard ratio throughout the manuscript.\nComment 18: line 296-297 “The analyses were adjusted for the following confounders related to COVID-19 and sequelae at start of follow-up”. Confusing sentence: what are the exposures and what is the outcome in the analyses?\nWhat do the authors mean by confounders related to sequelae at start of follow-up? Are there special confounders for sequelae at start versus at follow-up?\nComment 19: Please reduce the number of tables (27 tables).\nThere are too many sensitivity analyses. Why do the authors need to do all the analyses by SARS-CoV-2 status and admission for COVID-19? Is it possible to only include the comparison btw negative and positive and to compare SARS-CoV-2 status by calendar period, virus variant, lockdown and vaccination? The main comparison is positive vs negative?\nAlso reduce the number of supplementary tables (1-19) Too many on SARS-CoV-2 test and hospitalization. Try to focus on the main objective.\nComment 20: What do the extended data Figures add to the result? Are they necessary? I could not find the referred to in the text.\nComment 21: Methods, line 314-16. Why did not the authors divide the time after infection into more categories after 12 months. Was not the follow-up time 40 months?\nComment 22: Please add in the Methods section whether self-testing was included or not\nComment 23: Sensitivity analyses, line 330-31, adjustments for confounders. Please mention which confounders it was adjusted for in the text and not only referring to the supplementary tables. It is also a bit unclear which specific additional sensitivity analyses that were done for example different SARS-CoV-2 variants etc. Please refer to all the sensitivity analyses (11 analyses) in the text.\nComment 24: Supplementary Figure 1; A bit confusing in the flow chart when it comes to the final study population. I missed a final study population at the end of the flow chart. There are for example exclusions boxes further down in the flow chart without any information on the final study sample after exclusion.\nComment 25: general comment on the headings in the tables and figures is to remove PCR since all tests are PCR-tests and no self-tests are included?\nComment: Supplementary Table 1. Why do you show study population characteristics for people not included in the study?\nIs this a kind of sensitivity analysis?\nComment 26: Table 1. The authors should be more precise in their use of wording, In the heading it should be hazard ratio (HR) instead of relative rates. Further, in the footnotes it should be Hazard ratio instead of hazard rate ratio. In addition, the heading is too long and is therefore difficult to understand. However, the authors should mention the confidence intervals in the title.\nI think that the heading is rather confusing, Relative rates, relative to what? It is difficult to understand by the heading what is the exposure and what is the outcome?\nWhat is presented in Table 1 is the hazard ratios of the association between SARS-CoV-2 test, number of positive SARS-CoV-2 tests, time since test etc. (exposures) and risk of mental disorders or general medical condition. To make Table 1 more accurate, an alternative heading could be “Hazard ratios and 95% confidence intervals of the association between SARS-CoV-2 test, number of positive SARS-CoV-2 tests, time since test, etc. and mental disorders or general medical condition”\nComment 27: Table 1. Please provide info in the footnote how you define the outcome; mental disorder and general medical condition.\nComment 28: Figure 1. See comment for Table 1. The heading is confusing because the order of exposure and outcome is not accurate, the exposure should come before the outcome. Again, a hazard ratio of what? What are the exposures and outcomes?\nComment 29: What is the reference group in Figure 1a? It is really confusing that the outcome comes before the exposures. You should follow the same order/setup as in Table 1 (where the exposures are far left, before the outcomes at the right-hand side of the table. Again, the heading in the figure should follow the following setup. Hazard ratios and 95% confidence intervals of the association between age group, SARS-CoV-2 status, admission to hospital and mental disorders or general medical disorders. This figure should also include a footnote defining the outcomes such as mental disorders and general medical conditions.\nComment 30: Figure 1b, the exposures should be at the left-hand side of the table and the outcome to the right.\nComment 31: Figure 2. The title is too confusing as it is with the headings in the previous tables and figures. Define the exposures and outcome in the heading, see suggestions above for the previous tables/figures. When I look at the figure it is hard to understand what are the exposures and what are the outcomes? What is the reference? It should be indicated by a square in the figure. What is the difference between the x-axis “number of SARS-CoV-2 positive test and the y-axis Number of SARS-CoV-2 infections? These same comments go for Figure 3 and 4 as the comments for the previous comments.\nComment 32: Figure 5 could be added to the supplementary materials. The headings are very unprecise and do not fit the figures.\nGeneral comment to the supplement: Please use Hazard ratios instead of rates which is not very specific in all the headings in all the supplementary tables.", "reviewer_2": "Point by point response to the reviewers\nManuscript #: NCOMMS-24-86598-T\nTitle: COVID-19 post-infection sequelae are comparable to sequelae observed after other\ninfections of similar severity – a nationwide Danish study with 40-month follow-up\nREVIEWER REPORTS\nReviewer #1 (Remarks to the Author):\nUsing the nationwide Danish registers, this large study (3,343,706 individuals) used SARS-CoV- 2\nPCR test results and COVID-19 hospitalizations from March 2020 to June 2023, and estimated\nHazard ratios of mental, neurological, and general medical conditions, as well as of\nneuropsychiatric symptoms. The authors found that compared with negative tests, positive SARS-\nCoV-2 PCR tests were associated with lower risk of mental disorders and minimally higher rates of\ngeneral medical conditions. This large study is well conducted and an important contribution to the\nresearch on long-COVID symptoms but needs major revisions. Please see my comments below:", "reviewer_3": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_4": "Review comments: COVID-19 and all post-infection sequelae on a nationwide scale with 40-months follow-up\nAs indicated in the title, this paper analyses post-infection sequelae on a nation-wide scale with 40-months follow. The paper uses a wide range of Danish health registers spanning the whole population in the period March 2020 – June 2023. Outcomes are mental, neurological and general medical condition as well as neuropsychiatric conditions. The authors follow the Danish population as a cohort starting with all persons being not tested for Sars-CoV-19 where after they can change status to negative and/or positive based on PCR tests. Both those not tested, test-negatives and test-positives are compared. Cox proportional hazard models are used.\nThe authors find that those tested positive for SARS-CoV-2 had lower hazard ratios (HR) of mental disorders while hospitalized Covid-19 patients had a very slight increased hazard ratio (HR 1.01) of all disorders except for a few compared with the general population, but that this elevated HR was not different from that following other infections. The increased HR for test-positives was modified by SARS-CoV-2 variant and vaccination status.\nOverall impression\nThe overall impression of the paper is that this is an extremely comprehensive paper looking at a wide range of symptoms following a test result, either negative or positive. A wide range of factors that can modify or influence outcomes are taken into account, including hospital admission, readmission, vaccination, co-morbidity (?) and virus variants.\nThe paper uses Danish high-quality registers yielding information of a very large number of tested persons and their outcomes. Overall, statistical methods are appropriate.\nThe scale of the study population and the range of the analyses is impressive.\nThe paper presents interesting data and provides novel findings on the subject of long COVID, in particular regarding outcomes after other infections that have been little studied.\nFigures and graphical abstract are well-designed.\nHowever, there are four main issues of concern related to this paper: The paper is extremely comprehensive; Discussion is vague and limited; there is much bias in results that is not dealt with nor discussed; and the large sample size allows the paper to draw conclusions with statistical power that has little biological impact.\nComprehensiveness: The paper aims to identify post-infection sequelae related both to mental health issues, general medical conditions and neurological questions. ‘General medical conditions’ cover most disease groups in the ICD8 and ICD10 diagnosis systems. Thus, the authors wish to identify most sequelae (or differences in occurrence between SARS-CoV-19 test groups), not only in a specified time period (e.g. within one month corresponding to acute Covid or later than that corresponding to Long-Covid), but over a wide time frame from less than 1 month to more than 18 months after test. Not only do the authors estimate HRs between those tested positive and negative, but also between these groups and those not tested. The authors also include number of tests, hospital admissions (no admissions and admissions with and without intensive care), readmissions and length of admissions ad exposures. Other exposures or modifying factors are age, CRP (C-reactive protein), vaccinations, and time period/SARS-CoV-2 strain.\nThe paper is not hypothesis driven, but rather explorative.\nThus, the authors obtain a huge amount of results which is reflected in the volume of supplementary material (81 pages(!)). However, only few of these results are discussed. E.g. the authors describe the study population in detail (supplementary table 2). But these pieces of information are not really used nor discussed in the paper. Any differences between the groups?\nOn the other hand, so many results cannot be realistically discussed in one paper.\nThere is no doubt that the paper shows interesting results. Of those, particularly those concerning comparisons with sequelae after other infections than Covid-19 appear interesting. The natural history of SARS-CoV-2 is not fully described, and there are many remaining questions regarding SARS-CoV-2 sequelae. However, there is also, at present, a large volume of papers published on different aspects of Long-Covid, including nation-wide questionnaire-based papers from Denmark that are not quoted. Overall, such papers deal with aspects of Long-Covid rather than the overall picture.\nThe main impression of this paper is therefore that it would serve as a fine overview paper and starting point for testing of specific hypotheses regarding sequelae of Covid-19, if little was known at this time. The authors rightly point at problems with previous papers that such papers use different comparison groups, different time frames for follow-up, different symptom groupings, etc. Therefore, the authors used the same methodology to look at a range of exposures and outcomes as explained above. But there are also many methodological issues related to this paper, and the question is therefore whether it is too late in the exploration of the natural history of Covid-19 to produce a very high amount of data that are little explained, discussed or put into context.\nDiscussion. This section is very short, just touching upon differences on mental disorders and general medical conditions between those tested for SARS-CoV-2 (positive and negative) and those not tested. But first, the quoted/discussed results are not completely identical to what is written in the abstract nor in the table (in Discussion it says ‘However, positive compared with negative SARS-CoV-2 tests showed no association with mental disorders…’ while in Abstract and Table 1 ‘Compared with negative tests, positive SARS-CoV-2 PCR tests were associated with lower rates of mental disorders (hazard Ratio 0.82, 95% CI 0.80 – 0.83)). And second, this difference is not discussed. Why is it beneficial to mental health to being tested positive to SARS-CoV-2 compared to being tested negative? Third, why should the development of mental disorders be explained by CRP? It is not according to results, but why do the authors believe that CRP would explain mental health disorders? This is not discussed. Also, CRP peaks as indicated in Fig. 3 for SARS-CoV-2 positive are in general below 10 mg/ml, but this is within the normal range (<10 mg/ml). Also, a CRP of 800 as marked as end point for CRP graphs (Figure 3) are unseen in daily practice (question of this is a realistic value). In general, the discussion of own results only cover one page, of which half of the page discusses what the authors did differently from other papers.\nBias: The authors use the national Danish health registers of high quality. However, there are a number of biases associated with this use. The Strengths and limitations section includes a list of possible biases related to this study, but the possible biases and their impact on results are not discussed. Thus, being tested positive for SARS-CoV-2 results in a lower HR for mental health issues than those tested negative. This is hard to understand. Could this be a result of bias? Who are being tested multiple times relative to few times? Also, as the authors rightly point out, all study persons with pre-existing outcome disorders since the start of the registers were excluded, and the study population therefore consisted of very healthy individuals. Why was not paid more attention to this fact in the Discussion, Abstract or elsewhere? This is quite important as the results may not be fully generalizable to the general population because of this bias. In other respects the strength of the paper is that it is population-based and the reader clearly gets the impression that this paper gives a full picture of Covid-19 sequelae in a general population.\nSample size and interpretation: Being population-based over several years, the paper includes an impressively high number of study persons and events. This also gives statistical strength. However, the authors underline this too much when they state (Results and Table 1) that ‘Positive SARS-Cov-2 PCR tests were associated with only slightly higher general medical condition rates compared with negative SARS-Cov-2 PCR tests (HR 1.01, 95% CI 1.00 – 1.02, p-value 0.024)’. This may be significant (how can it be so when the CI includes 1.00?), but an increased HR of 1% (HR 1.01) has no biological nor public health impact. A HR of 1.01 is essentially the same as a HR of 1.00.\nTo sum up – The findings of the paper are so comprehensive, yet subject to bias and little discussed that it is difficult to extract the important findings. An overall paper of all sequelae over al large period of time with many confounders or effect modifiers appears of less use now than some years ago.\nA suggestion would be to divide the paper in a number of papers addressing different aspects of Covid-19 sequelae that are then discussed in more detail plus an overview paper describing the common methodology with a clear delimination of the study population (how large a fraction of the Danish population would not have a pre-existing comorbidity of the given types) and with a discussion of possible bias.\nSpecific comments\nIn its present form, the paper could benefit from improved text structure. It is often challenging to follow the authors' line of thought in each section, and the main points are sometimes unclear. Enhancing the flow of the text would make the content easier to follow and increase the overall readability.\nGiven the impressive size of the paper with supplementary material it is not possible to touch on all parts of the paper including methodology. But the following lists a number of specific points to the paper in its present form in addition the general comments above:\nTitle\n1. Suggest revising the title to make it more informative by clearly stating the paper's main finding.\nAbstract\n1. Lines 37–38. The methods and results related to the comparison of sequelae with other infections should be elaborated upon in the abstract, as this represents one of the primary objectives of the paper.\nIntroduction\n1. Lines 47-48: This statement requires a citation.\n2. Lines 50-51: Is the risk of adverse health outcomes the same for all individuals with COVID-19, regardless of acute illness severity (hospitalized vs. non-hospitalized)? Please elaborate.\n3. Lines 59–60: The statement, \"In older adults, the sequelae resembled those of viral lower respiratory tract illness,\" is unclear. Please specify by providing additional context.\n4. Lines 65-67. “However, the findings of prior studies depended on whether the control group was individuals with negative tests, no positive test, or various non COVID-19 infections”. Needs a citation.\n5. Lines 50-71. This section is informative and well-documented, but the structure could be improved. Adding sentences to clarify the relevance of the information to the paper would enhance readability and overall coherence.\nResults\n1. Consider reporting only the 95% CIs in the results section, as they provide the most relevant measure for assessing statistical significance, making the inclusion of p-values unnecessary.\n2. Line 102. What do the authors mean by “depend on time since testing”?\n3. Lines 114-116. “Temporally, the general medical condition rates were highest 1-month post-COVID-19 (HR 115 1.10, 95% CI 1.06-1.13, p-value <0.001) and remained elevated 18 months post-COVID-19 (HR 116 1.07, 95% CI 1.04-1.10, p-value <0.001)”. Which groups are you comparing? Are the rates higher among those individuals who tested positive compared to those who tested negative?\n4. Lines 120-122. “The HR of general medical conditions was flat for CRP values in the age groups younger than 40 years and increasing in increasing CRP for the age groups between 40 and 79 years”. This sentence is unclear. Please clarify what is meant.\nDiscussion\n1. Lines 209-211. It would be relevant to mention that not all previous studies focused solely on hospital contacts.\n2. Lines 216-218. “Sensitivity analyses revealed that, in the current situation with widespread vaccination and dominant Omicron subtypes, COVID-19 poses a lower risk to humans than previously”. Do the authors mean a lower risk of acute or post-acute symptoms, and does it include all symptoms?\n3. The main section of the discussion focuses mainly on listing the key findings of the paper, which is appropriate. However, the authors do not sufficiently discuss or contextualize their findings in relation to other studies on long COVID, aside from a single Danish study. This comparison with broader research could provide more depth and perspective, and would strengthen the discussion by relating their results to the existing evidence in the literature.\n4. Line 235. Why did the authors choose to exclude sequelae treated in primary care?\n5. Line 247. What other infections? Please give examples.\n6. Lines 247-248. “However, the unique data on COVID-19 can help broaden our understanding of infections and other disorders in general”. This is a valid point however; this aspect is not even mentioned in the general discussion.\nMethods\n1. Did the authors have access to diagnoses registered in the primary care sector? If no, please describe.\n2. Line 296. Please explain why the authors chose to adjust for those specific confounders.\nFigures and tables\n1. Figure 3 contains a lot of information, making it difficult to read. Suggest to select only a few key specific disorders to present. Additionally, expanding the figure caption with more details would improve understanding.\n2. Supplementary Table 20 should be moved to the main paper, as it provides important context and details on the specific diagnoses examined, which are valuable for understanding the study's results.", "reviewer_5": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "Point by point response to the reviewers\nManuscript #: NCOMMS-24-86598-T\nTitle: COVID-19 post-infection sequelae are comparable to sequelae observed after other\ninfections of similar severity – a nationwide Danish study with 40-month follow-up\nREVIEWER REPORTS\nReviewer #1 (Remarks to the Author):\nUsing the nationwide Danish registers"}]

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