Long-Term Sequelae of SARS-CoV-2 Infection in Patients with Inflammatory Bowel Diseases Compared to Relatives with SARS-CoV-2 Infection without Inflammatory Bowel Disease and Inflammatory Bowel Disease Patients without SARS-CoV-2: Results of a Retrospective Case-Control Study

Since the beginning of the pandemic in early 2020, COVID-19 has had a profound impact on individuals and societies worldwide. As of July 20, 2024, almost seven million confirmed COVID-19-related deaths have been reported globally, with investigations into excess mortality suggesting that the actual death toll is much higher [1].

A significant number of individuals who contracted COVID-19 continue to experience health problems long after the clearance of the acute infection. These belong to the growing group of people with post-acute sequelae of SARS-CoV-2 infection, commonly known as post-COVID. It is estimated that at least one out of 10 people who contract COVID-19 will experience long-term effects [2, 3].

The lack of clear definition and diagnosis of the post-COVID syndrome coupled with a significant increase in the number of people experienced post-COVID symptoms complicates the comprehensive assessment of the long-term health impact of the COVID-19 pandemic. To mitigate methodological challenges, it is recommended to utilize self-reported health measures when assessing the long-term impact of the COVID-19 pandemic on health and health inequalities [3, 4].

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn’s disease, often experience a variable symptom burden due to their underlying disease alone, which shares many aspects with COVID-19 and post-COVID symptoms. Digestive symptoms are prevalent in COVID-19, both at the early stages of the disease and after its resolution, sometimes lasting for several months [5‒8]. In a population-based study of 516 IBD patients from Denmark, i.e., postinfection sequelae affected 43.7% of COVID-19-infected patients [9]. Fatigue, the most common post-COVID symptom, is also a well-known and challenging symptom in many IBD patients regardless of concurrent viral infection [10]. Previous studies may be hindered by the absence of appropriate control groups, as IBD patients who did not have COVID-19 have not been studied thus far [9, 11]. The aim of this study was to comprehensively investigate COVID and post-COVID symptoms in a well-characterized IBD cohort from eight referral centers along with two control cohorts. For the first time, this study incorporated the use of self-reported health measures.

We conducted a retrospective survey of patients diagnosed with IBD who were aged 18 years or older and previously experienced an infection with SARS-CoV-2 (IBD-COVID cohort). Participants in this survey had to have completed their quarantine period at least 3 months prior to their involvement in the study. As controls, we surveyed two groups: (I) individuals who were household members of the participants and had been infected with SARS-CoV-2 but did not have IBD (CONT-COVID) and (II) unrelated individuals who had IBD but were not knowingly infected with SARS-CoV-2 (IBD-no-COVID). Since the start of the post-COVID-period is not uniformly defined, we asked our patients: “What symptoms or complaints persisted after the quarantine ended?” This allowed us to assess post-COVID complaints. We categorized symptom persistence into three groups (a) less than 1 month, (b) 1 to 3 months, and (c) four to 6 months.

IBD-no-COVID patients were asked to report symptoms that occurred during the last 3 months and compare them to the previous 3 months. This survey was conducted at eight German IBD centers, which included four university hospitals and four specialized IBD practices. This survey took place between April 2022 and January 2023. Participants were either requested to complete paper-based anonymous questionnaires during outpatient’s visits or received an invitation by mail. The questionnaires cover various aspects, including demographic data (age, sex, height, weight, IBD type and activity, medication, smoking status), employment details, vaccination status, health care resource utilization, Charlson comorbidity index (CCI), and Fatigue Assessment Scale (FAS) [12, 13]. The FAS is a 10-item general fatigue questionnaire to measure fatigue in sarcoidosis. FAS turned out to be simple and reliable tool in multiple diseases including post-acute neurological manifestations of COVID-19 but have not been validated for IBD [14, 15]. Five questions reflect physical fatigue and five questions (questions three and questions six to nine) mental fatigue.

The statistical analysis was conducted using SPSS version 28 (IBM Inc., Armonk, NY, USA). Statistical differences between unpaired data (e.g., IBD patients with and without SARS-CoV-2 infection) were assessed using the Mann-Whitney U test for continuous or ordinal data and Fisher’s exact test for nominal data. For paired data, such as patients and household members, statistical differences between were analyzed using the Wilcoxon signed-rank test for continuous and ordinal data or the McNemar test for nominal data. Correlations were assessed using Spearman’s nonparametric correlation. P < 0.05 in two-sided tests was considered statistically significant. We did not apply a correction for multiple comparisons. Items with missing data were excluded from the respective analysis.

A total of 648 patients were included in the study, comprising 319 IBD-COVID patients, 108 CONT-COVID patients, and 221 IBD-no-COVID patients (Fig. 1). The patients did not exhibit significant differences in terms of educational level (not shown). The CCI also showed no differences between IBD-COVID patients and IBD-no-COVID patients (p = 0.210), as well as between IBD-COVID patients and CONT-COVID patients (p = 0.412). In the study, 38.1% of all participants with SARS-CoV-2 infection (the IBD-COVID and CONT-COVID patients) were not vaccinated against SARS-CoV-2 compared to only 7.7% of the IBD-no-COVID patients (p < 0.00001).

IBD patients with and without SARS-CoV-2 infection did not exhibit significant differences in terms of sex (female 58.3% vs. 53.4%, p = 0.397). However, patients with an infection were younger than those without (42 vs. 40 years, p = 0.025) and had lower prevalence of nicotine abuse (active smoker 12.5% vs. 22.6%, p = 0.013). They did not differ in type of IBD type, IBD activity, or medication (all p > 0.05; Table 1).

Compared to their even SARS-CoV-2-infected household members, IBD patients with SARS-CoV-2 were more frequently female (58.3% vs. 42.6%, p = 0.005) and had a lower BMI (25.5 vs. 26.2 kg/m², p = 0.003). Age, smoking status, type of SARS-CoV-2 testing, and vaccination status against SARS-CoV-2 and influenza did not show significant differences in the overall cohort and after pairwise matching of the IBD-COVID and the CONT-COVID cohorts (all p > 0.05). (Table 2).

Acute COVID-19 symptoms in IBD patients have been extensively studied [16]. This report focuses on post-COVID symptoms. Nevertheless, we asked all patients for acute IBD symptoms and show these results in the online supplementary Figure 1 (for all online suppl. material, see https://doi.org/10.1159/000541602).

The central question of our study focuses on the severity and frequency of post-COVID in patients with IBD. Increased fatigue was the symptom with the highest rate of persistence after the quarantine. It showed a significant difference between IBD patients (55.2%) and their household members (39.8%) (p < 0.01) and the frequency of IBD patients without SARS infection was in between (33.3%; p < 0.001 vs. IBD with SARS). Associations pointing in the same direction were found in persisting sleeping disorders (see Table 3 for percentages and p values). In contrast, reduced cognitive performance was more commonly reported by IBD-COVID than by CONT-COVID (p < 0.05) than by IBD-no-COVID patients (p < 0.001). In addition, as anticipated, abdominal symptoms such as abdominal pain (16.6% vs. 4.6%, p < 0.005), diarrhea (22.6% vs. 5.6%, p < 0.0001), and blood in stool (12.2% vs. 0%, p < 0.001) occurred more often in IBD-COVID than the CONT-COVID patients but was not significantly different from IBD patients without having COVID (Table 3).

The time course of persistent symptoms after the end of quarantine is shown in Figure 2. The occurrence of fatigue in IBD-COVID patients correlated with outpatient consultations (Spearman’s Rho 0.136, p = 0.005). Furthermore, we observed a strong correlation between fatigue and all IBD-related symptoms, e.g., blood in stool (Spearman’s Rho 0.159, p = 0.005), abdominal pain (Spearman’s Rho 0.391, p < 0.001), diarrhea (Spearman’s Rho 0.346, p < 0.001), nausea (Spearman’s Rho 0.333, p < 0.001), vomiting (Spearman’s Rho 0.134, p = 0.017), and anal problems (Spearman’s Rho 0.234, p < 0.001). Subsequently, the occurrence and duration of fatigue in IBD patients with SARS-CoV-2 infection correlated with the activity of their IBD (Spearman’s Rho 0.403, p < 0.001). The correlation between fatigue in IBD activity could also be observed in patients without SARS-CoV-2 (Spearman’s Rho 0.757, p < 0.001). The number of vaccinations was correlated with a lower risk for post-COVID smell and taste disorder (Spearman’s Rho 0.242, p < 0.001) but was not associated with the occurrence and duration of fatigue after SARS-CoV-2 infection (Spearman’s Rho 0.058, p = 0.301) or muscle/joint pain (Spearman’s Rho 0.066, p = 0.239). Additionally, the time since vaccination did not correlate with post-COVID symptoms (all p > 0.05).

As reported above, increased fatigue was the most frequent symptom in IBD patients with and without a SARS-CoV-2 infection. We therefore correlated intergroup differences and abdominal symptoms with the FAS.

Respective answer options were “never,” “sometimes” (monthly or less), “regularly” (a few times a month), “often” (weekly), and “always” (daily). Results are depicted in Figure 3.

The total FAS score correlated with gastrointestinal symptoms as well in both groups of IBD patients with or without previous SARS-CoV-2 infection. In the CONT-COVID group, the total FAS score correlated with abdominal pain, diarrhea, nausea, and fatigue only (Table 4).

Among the patients with IBD, 141 (44.2%) reported illness days due to the acute SARS-CoV-2 infection, ranging from 1 to 90 days. Following the SARS-CoV-2 infection, 38 (11.2%) of the IBD patients reported missed days of work due to IBD, compared to 26 (8.6%) patients in the period before the infection (p = 0.134). However, the number of outpatient consultations increased after the SARS-CoV-2 infection (7.8% vs. 10.9%, p = 0.008). The need for inhospital stay was comparable in patients with IBD before and after the SARS-CoV-2 infection (4.1% vs. 6.5%, p = 0.058), and only a minority of patients received rehabilitation care (3 IBD patients before the SARS-CoV-2 infection and 6 patients after the infection) or needed surgery (each 7 patients before and after the infection).

In our retrospective cohort study of 319 SARS-CoV-2-infected IBD patients and two control cohorts consisting of 108 household members with SARS-CoV-2 infection and 221 IBD patients without previous SARS-CoV-2 infection, we were able to show that (I) fatigue-dominated post-COVID syndrome was more frequent in IBD patients compared to non-IBD household members with SARS-CoV-2 infection, (II) fatigue was more common in IBD patients with SARS-CoV-2 infection than in the controls, (III) occurrence and duration of fatigue in IBD correlated with IBD activity irrespective of previous SARS-CoV-2 infection, (IV) fatigue in IBD patients after a SARS-CoV-2 infection correlated with several gastrointestinal symptoms and a higher number of outpatient consultations, and (V) anti-SARS-vaccinations were only correlated with a lower risk for post-COVID smell and taste disorders, but not with all other investigated post-COVID symptoms.

Interestingly, almost three quarters of our SARS-CoV-2-infected patients reported increased fatigue as the most reported symptom during COVID-19 disease, regardless of whether IBD was present or not. This symptom was reported by only one-third of IBD patients without COVID. However, in the postinfection period when post-COVID syndrome manifests itself, persisting fatigue was the non-abdominal symptom with the most statistically significant difference between IBD patients than their household members. This finding confirms a recently published study, which identified preexisting autoimmune disease as the larger risk of post-acute sequelae of COVID-19 than preexisting depression, anxiety, and pulmonary disease [17].

Fatigue was even the most prevalent symptom in IBD patients without previous SARS-CoV-2 infection in our study. According to a recent systematic review, the prevalence of fatigue can reach 86% in active IBD, persisting in 50% of patients with mild to inactive disease [10]. Fatigue is the most common reason for work absence in IBD, and patients often report fatigue burden to be greater than that of primary disease symptoms. The occurrence and duration of fatigue in IBD patients with SARS-CoV-2 infection correlated with IBD activity in our study. These results indicate that strict inflammation control might be a possible tool to reduce post-COVID symptoms including fatigue in patients without perceptible IBD activity.

An uncontrolled study of 21 IBD patients with long COVID symptoms showed that asthenia was the more frequent symptom as it occurred in nearly two-thirds of patients [18]. As shown in Figure 2, asthenia or more precisely, reduced physical performance was the most prevalent symptom of our 319 IBD+COVID patients in all three periods examined. Remarkably, reduced physical performance was the most prevalent symptom even in the non-IBD controls. Therefore, reduced physical performance seems to be a non-IBD specific post-COVID phenomenon and highlights the need for appropriate control groups [9, 11].

More uninfected than infected IBD patients switched or reduced their IBD medication in the respective study periods – as reported in the supplementary materials. The higher rate of “watch and wait” in SARS-CoV-2-infected patients may be explained by the rapidly developing evidence, which supports maintaining IBD patients on medications, that optimally treat their IBD during the COVID-19 pandemic [16].

IBD specialists could have been advised SARS-CoV-2-affected IBD patients maintaining IBD therapy to see which abdominal symptoms are either IBD- or COVID-19-related in short follow-up before changing IBD therapy. It is even well known that COVID-19 often provokes abdominal symptoms in patients with and without IBD [19, 20]. In agreement with previous studies, we found that the rates of developing long COVID/post-COVID symptoms were similar among patients exposed to different IBD medications [11].

Nonetheless, there are also limitations in asking about long COVID without continuously knowing the SARS-CoV-2 status of all study participants (such as multiple SARS-CoV-2 infection, bacterial and viral coinfections, but even postvaccination symptoms). This increases the risk of underreporting: people with mild long COVID symptoms or people who did not have a positive SARS-CoV-2 test might not identify their health complaints as being related to long COVID. However, the CCI was low in almost all patients. This could be a useful and valuable quality of our cohort to study IBD and (post-) COVID symptoms alone.

An observational study of approximately 214,000 individuals with confirmed COVID-19 recently reported that pre-pandemic health care utilization related to psychological, respiratory, and general/unspecified health problems were the strongest predictors for having a doctor-diagnosed post-COVID condition between 90 and 180 days after the initial infection [21]. In our study, however, we only asked for COPD and dementia as they are part of the CCI and found no association to post-COVID health problems due to low occurrence of these concomitant diseases. Low CCI could be an indication for an over-average number of patients with mild COVID-19 symptoms has been taking part in our study, while patients after severe SARS-CoV-2 infections may underrepresented. Therefore, HCRU issues may be better answered in population-based cohort studies which found, i.e., higher hospitalization rates than in our cohort [22]. An important health care aspect, however, is our finding that the number of outpatient consultations increased after SARS-CoV-2 infection, whereas other health care resources were not used more frequently. This finding could imply the need for increased staffing and funding for IBD and post-COVID outpatient clinics after future COVID outbreaks, as the majority post-COVID patients in Germany had negative experiences with ambulatory post-COVID care so far [23].

We have chosen SARS-CoV-2-infected household members as one control group of our SARS-CoV-2-infected IBD cohort. By choosing direct flat mates of the infected IBD patients, we wanted to find a control group that was as close as possible to our IBD group in terms of their socioeconomic status, education and everyday habits. We assume that this group is better suited than a population-based control group to study post-COVID symptoms because there are multifactorial causes for developing post-COVID symptoms. However, it should be kept in mind that COVID-19 can trigger symptoms of irritable bowel syndrome or even IBD even in people without previous intestinal illnesses. Early symptoms of irritable bowel syndrome or IBD could be difficult to distinguish from the abdominal post-COVID symptoms we asked about and therefore offer the possibility of bias [24, 25]. The pre-study definition of the period of interest to us in the second control group, IBD patients without history of SARS infection, is also in question of bias. For example, oligo- or asymptomatic SARS-CoV-2 infections might be overlooked in this group (selection bias). Furthermore, we asked to report symptoms that occurred during the last 3 months and compare them to the previous 3 months. This period is longer than in the SARS-CoV-2-infected IBD patients and their household members and is therefore prone to recall bias. Third, a SARS-CoV-2-independent pandemic fatigue – defined as a gradually emerging subjective state of weariness and exhaustion from, and a general demotivation toward, following recommended health-protective behaviors, including keeping oneself informed during the pandemic – has been reported in two repeated cross-sectional surveys, one panel survey, and a preregistered online experiment and may interfere with the IBD specific fatigue and cognitive impairment data in our study [26].

In conclusion, we were able to show that typical post-COVID symptoms such as fatigue, cognitive impairment, and sleep disturbances occur more frequently in IBD patients after COVID-19 than in SARS-CoV-2-infected controls without IBD, and typical IBD-associated symptoms persist for a longer period after infection. IBD medications had no impact for the occurrence of post-COVID symptoms, whereas vaccinations against SARS-CoV-2 only had a marginal effect. The main limitations of our study were the retrospective design and its limited generalizability. Most importantly, reliance on self-reported data may introduce recall bias and our specific population from eight referral centers in Germany may affect the generalizability of the findings. Ideally, should have included house hold controls also for the IBD-non-COVID patients as a third control group, but this was not part of our considerations before starting the study. Few evidence-based treatment options actually exist for IBD patients with chronic fatigue and cover (I) the resolution and of reversible factors like anemia and micronutrient deficiencies, (II) reducing fatigue perception, and (III) exercise training interventions, which are not different from treatment plans for fatigue from post-acute sequelae of COVID-19 [10, 27]. Further studies should focus on individualized treatment options of post-COVID fatigue with high evidence levels.

We thank all patients and their housemates to participate in this study.

This study was reviewed and approved by the Ethics Committee of Jena University Hospital, Jena, Germany, on 09-02-2022; approval no. 2022-2551-Bef in accordance with the Declaration of Helsinki. Written informed consent was not required as approved by the Ethics Committee of Jena University Hospital, Jena, Germany.

The authors have no conflicts of interest to declare.

2,000 Euros were covered by Niels Teich.

Benedikt Bierbaum, Andreas Stallmach, Philipp Reuken, and Niels Teich contributed to the conception or design of the work, the acquisition, analysis, and interpretation of data for the work, drafted the work for important intellectual content, and finally approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ulrike von Arnim, Renate Schmelz, Rosa Rosania, Jens Walldorf, Michael Bierbaum, Sven Geißler, and Markus Hänßchen contributed to the acquisition, analysis, and interpretation of data for the work, drafted the work for important intellectual content, and finally approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Philipp Reuken and Niels Teich contributed equally to this work.

The data that support the findings of this study are openly available in figshare: 10.6084/m9.figshare.25292791.