Incidence of Long COVID and Impact of Medications on the Risk of Developing Long COVID in a Nationwide Cohort of IBD Patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected 633 million people and is associated with 6.5 million deaths worldwide as of November 18, 2022.¹ Coronavirus disease 2019 (COVID-19) was initially reported as presenting with acute onset of symptoms, but over time, sequelae of acute COVID-19 infection were described when symptoms such as fatigue and shortness of breath, among others, continued to persist. This was defined as ‘long COVID.’² At present, there is no consensus on the exact definition of long COVID. However, it is broadly considered to be a constellation of symptoms that occur during or after confirmed COVID-19 infection, with these symptoms persisting for more than 4 weeks.^{3 , 4}

Inflammatory bowel disease (IBD) is a chronic immune mediated disorder of the gastrointestinal system comprising ulcerative colitis (UC) and Crohn’s disease (CD) that is classically managed with immunosuppressive agents. Although various aspects of the interaction of SARS-COV-2 and IBD have been extensively evaluated, to the best of our knowledge, no multicenter study has evaluated long COVID among patients with IBD and antecedent COVID-19 infection. Our aim was to explore the incidence of long COVID among patients with IBD, identify factors that may be associated with its development, and evaluate for possible differences in risk of long COVID among different IBD medication exposures. To achieve this goal, we conducted a retrospective study in a nationwide cohort of patients with IBD followed in the Veteran Affairs Healthcare System (VAHS).

This was a retrospective cohort study using data from a well-established VAHS cohort of patients with IBD.⁵ We included patients who were diagnosed with SARS-CoV-2 via polymerase chain reaction testing between March 10, 2020, and January 24, 2021. Patients were excluded if they had less than 28 days of follow-up from the time of SARS-CoV-2 infection or died within this interval. Each chart was reviewed and patients who had confirmed IBD and were taking an IBD medication prescribed in the VA were selected. This was done to ensure that these patients were followed in the VA, and our primary aim was to evaluate the impact of medications on the risk of developing long COVID. Demographics, body mass index, and IBD medication data were obtained for each patient. IBD medication classes were categorized as 5-aminosalicylic acid, thiopurines (TP), anti-tumor necrosis factor alpha (anti-TNF), anti-TNF+TP, vedolizumab, and ustekinumab. Baseline corticosteroid usage was also captured, as well as COVID-19 vaccination and type prior to SARS-CoV-2 infection. Comorbidity data was obtained and included history of chronic obstructive pulmonary disease (COPD), congestive heart failure, and Charlson comorbidity index (CCI). All charts were then reviewed to determine recent IBD hospitalization, hospitalization for SARS-CoV-2 infection, and stability of IBD control pre- and post-infection (defined as no symptoms of bloody diarrhea, no change in medication, no new prescription of corticosteroids, or no hospitalization for IBD 3 months prior and 3 months post COVID-19 diagnosis). COVID-19 hospitalizations were reviewed for intensive care unit (ICU) requirement and need for intubation. COVID-19 treatments including remdesivir, monoclonal antibody infusions, and corticosteroids were also ascertained. The primary outcome was development of long COVID, which was defined as the presence of at least one of the following symptoms: fatigue, shortness of breath/dyspnea, joint pain, chest pain, anxiety/depression/sleep disorder, or headache that persisted for more than 4 weeks after COVID-19 infection, consistent with recent literature.^{3 , 4} Manual chart adjudication was used to confirm long COVID diagnoses in all cases. The study follow-up period ended on January 24, 2022. For statistical analysis, refer Supplementary Appendix.

A total 677 patients with SARS-CoV-2 infection were included in the cohort, of which 49 (7.3%) were diagnosed with long COVID. Only 6 patients in the cohort received COVID-19 vaccination prior to infection. The median follow-up duration was 365 days (interquartile range, 365–365 days). There were no significant differences in age, sex, race, IBD subtype, or IBD medication class between patients with and without long COVID diagnosis (each P > .05); however, hospitalization for COVID-19, ICU requirement, COPD, and higher CCI were associated with long COVID diagnosis (each P < .05) (Table 1 ). In final multivariable Cox regression analysis, COVID-19 hospitalization was associated with a 3.56-fold increased hazard of long COVID relative to patients who were not hospitalized (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.80–7.09; P < .001) (Supplementary Table 1). ICU requirement and COPD were also associated with long COVID diagnosis (HR, 2.20; 95% CI, 1.18–4.08; P = .01 and HR, 2.41; 95% CI, 1.03–5.64; P = .04, respectively). Adjusted survival curves are shown in Supplementary Figure 1. Relative to patients who were not hospitalized, patients hospitalized in the ICU had an 8.61-fold increased hazard of long COVID (HR, 8.61; 95% CI, 3.98–18.65; P < .001). There were no significant interactions between COVID-19 hospitalization and age (P = .94) or IBD medication category (P = .94).

Table 1.

Cohort Characteristics

Factor	No long COVID	Long COVID	P-value
Number of patients	626	49
Age, y	61.5 (47–72)	64 (54–72)	.40
Age category, y			.86
<40	93 (14.9)	6 (12.2)
40–65	252 (40.3)	19 (38.8)
>65	281 (44.9)	24 (49.0)
Male sex	568 (90.7)	45 (91.8)	1.00
Race			.53
White	476 (76.0)	35 (71.4)
Black	101 (16.1)	11 (22.4)
Other	49 (7.8)	3 (6.1)
BMI, kg/m2	29.7 (26.4 33.7)	31.5 (27.7–35.2)	.12
IBD subtype			.54
Ulcerative colitis	398 (63.6)	29 (59.2)
Crohn’s disease	228 (36.4)	20 (40.8)
IBD medication			.88
5-ASA	336 (53.9)	26 (53.1)
TP	43 (6.9)	4 (8.2)
Anti-TNF	140 (22.5)	13 (26.5)
Anti-TNF+TP	14 (2.2)	0 (0.0)
VDZ	57 (9.1)	5 (10.2)
Ustekinumab	33 (5.3)	1 (2.0)
Baseline corticosteroids	48 (7.7)	8 (16.3)	.053
Recent IBD hospitalization	45 (7.2)	6 (12.2)	.25
Hospitalized for COVID-19	81 (12.9)	23 (46.9)	< .001
ICU requirement	17 (2.7)	9 (18.4)	< .001
Remdesivir treatment for COVID-19	33 (5.3)	8 (16.3)	.006
Monoclonal antibody infusions for COVID-19	3 (0.5)	0 (0.0)	1.00
Corticosteroid treatment for COVID-19	84 (13.4)	13 (26.5)	.019
COVID-19 vaccination (first dose) prior to infection	6 (1.0)	0 (0.0)	1.00
COVID-19 vaccination (second dose) prior to infection	1 (0.2)	0 (0.0)	1.00
Stable IBD prior to COVID-19	582 (93.0)	45 (91.8)	.77
Stable IBD after COVID-19	557 (89.0)	40 (81.6)	.16
COPD	89 (14.2)	16 (32.7)	.002
Congestive heart failure	35 (5.6)	2 (4.1)	1.00
CCI	1 (0–2)	1 (0–3)	.02
CCI category			.04
0	309 (49.4)	17 (34.7)
1	136 (21.7)	9 (18.4)
2+	181 (28.9)	23 (46.9)

Note: Data are presented as number (%) or median (interquartile range).

5-ASA, 5-aminosalicylic acid; BMI, body mass index; CCI, Charlson comorbidity index; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; IBD, inflammatory bowel disease; ICU, intensive care unit; TNF, tumor necrosis factor alpha; TP, thiopurines; VDZ, vedolizumab.

Supplementary Figure 1.

Multivariable Cox regression: development of long COVID, stratified by SARS-CoV-2 hospitalization and ICU requirement.

Previous data addressing long COVID among patients with IBD is limited. Salvatori et al conducted a single center study of 53 patients with IBD and found that 40% of their patients developed long COVID,⁶ a much higher incidence than we observed. Among the general population, the rates of long COVID are variable depending upon the methodology.⁷ Considering 14 symptoms, Sudre et al reported that 13.3% of participants reported symptoms lasting ≥28 days.⁸

A key finding in our study was that exposure to a specific IBD medication did not impact the risk of developing long Covid. We did find a significant association between hospitalization and ICU care for COVID-19 as well as underlying COPD and the development of long COVID. These findings suggest that the likelihood of long COVID is proportional to the severity of index COVID-19 infection and the presence of COPD but is not significantly impacted by concomitant exposure to the immunosuppressive medications used in IBD management. The association with hospitalization is also consistent with multiple prior studies.^{9 , 10}

A major strength of this study is the utilization of a nationwide cohort of patients with IBD exposed to a diverse group of IBD medications in the VAHS. Each chart was individually reviewed, and all clinical documentation was evaluated to confirm the diagnosis of long COVID. However, there are important limitations. First, because this is a retrospective study, there is a possibility of misclassifying exposure and outcome data. Second, external validity may be limited, given that the VAHS cohort consists primarily of older white males.

In conclusion, we found that the rates of developing long COVID were similar among patients exposed to different IBD medications. Hospitalization and ICU care for COVID-19 and concomitant COPD were associated with an increased risk. The overall rates of long COVID, although difficult to compare with other studies due to differing methodologies and modes of ascertainment of symptoms, do not appear to be higher in the IBD population. These findings should help reassure and inform patients with IBD about the risk of long COVID.

Supplementary Appendix

Descriptive statistics were presented as medians and interquartile ranges for continuous data, and as frequencies and percentages for categorical data. Data were stratified by presence of absence of long coronavirus disease 2019 (COVID), and statistical comparisons were made using the Wilcoxon rank sum, χ², or Fisher exact test, as indicated. To identify variables associated with development of long COVID, we used a survival analysis approach and multivariable Cox regression. The index time was date of severe acute respiratory syndrome coronavirus 2 infection, and observations were right-censored at death or loss-to-follow-up. Backwards stepwise selection and a priori testing of variables plausibly associated with long COVID were used as selection approaches. In the final model, the hazard ratios and 95% confidence intervals were reported. A 5% alpha level was used as the threshold for statistical significance. We tested for a priori interactions between COVID-19 hospitalization and (1) age and (2) inflammatory bowel disease medication category. This project received Institutional Review Board approval from the Corporal Michael J. Crescenz Philadelphia Veterans Affairs Medical Center. All data management and analyses were performed using STATA 17.0/BE (College Station, TX).

Supplementary Table 1.

Multivariable Cox Regression Analysis

	Multivariable analysis
	HR (95% CI)	P-value
COVID-19 hospitalization	3.56 (1.80–7.09)	< .001
ICU requirement	2.20 (1.18–4.08)	.01
COPD	2.41 (1.03–5.64)	.04

CI, Confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; HR, hazard ratio; ICU, intensive care unit.