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Original Article Incidence and treatment-based risk stratification of opportunistic infections in patients with inflammatory bowel disease: an ambispective cohort study in Brazil
José Eugenio Rios Ricci Jr1orcid, Tarsila Campanha da Rocha Ribeiro1orcid, Fernando Antonio Basile Colugnati2orcid, Lívia de Almeida Costa1orcid, Pedro de Morais1orcid, Jordana AS Lopes1orcid, Hugo B Araújo1orcid, Matheus A Pacheco1orcid, Mariana V de S Paulo1orcid, João Baptista de Paula Fraga3orcid, Lucélia Paula Cabral Schmidt1orcid, Thais de Andrade Almeida1orcid, Roberta Oliveira Raimundo Borsato1orcid, Liliana Andrade Chebli1orcid, Júlio Maria Fonseca Chebli1orcid

DOI: https://doi.org/10.5217/ir.2025.00208
Published online: May 21, 2026

1Division of Gastroenterology, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, Juiz de Fora, Brazil

2Department of Medicine, Federal University of Juiz de Fora, Juiz de Fora, Brazil

3Division of Colorectal Surgery, Hospital Therezinha de Jesus, Juiz de Fora, Brazil

Correspondence to Júlio Maria Fonseca Chebli, Inflammatory Bowel Disease Center, University Hospital of the Federal University of Juiz de Fora, Maria José Leal street, 296 Juiz de Fora, Minas Gerais 36038-330, Brazil. E-mail: julio.chebli@ufjf.br
• Received: September 4, 2025   • Revised: January 31, 2026   • Accepted: February 11, 2026

© 2026 Korean Association for the Study of Intestinal Diseases.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Background/Aims
    The risk of opportunistic infections (OIs) in inflammatory bowel disease (IBD) patients in Latin America is poorly known. We assessed the incidence and stratified the risk of OIs in IBD patients on immunosuppressive therapies.
  • Methods
    In this ambispective cohort study, we retrospectively analyzed the medical charts of IBD patients between March 2014 and March 2021 and prospectively analyzed those from April 2021 to April 2024. The incidence rate of OIs was expressed as the number per 1,000 patient-years (PY) and calculated for each treatment category. The risks of OIs associated with immunosuppressants were compared with exposure to aminosalicylates or no treatment using the Cox proportional hazards model.
  • Results
    In a total of 3,279.6 PY of follow-up, OIs occurred in 60 of 498 patients (12.0%) with an incidence rate of 18.3 per 1,000 PY. The most common OIs were herpes zoster (HZ; n=28, 5.6%) and tuberculosis (n=17, 3.4%). The incidence rates of HZ and tuberculosis were 8.5 and 5.18 per 1,000 PY, respectively. Compared with patients on aminosalicylates or no treatment, the risk of OIs was higher in those on combination therapies with anti-tumor necrosis factor (TNF) and thiopurines (hazard ratio [HR], 7.67; 95% confidence interval [CI], 2.26–26.06), followed by thiopurine monotherapy (HR, 5.35; 95% CI, 1.56–18.3), and anti-TNF monotherapy (HR, 5.04; 95% CI, 1.50–16.97).
  • Conclusions
    IBD patients on long-term anti-TNF and/or thiopurine therapy had a higher risk of OIs, especially HZ and tuberculosis, compared with non-immunosuppressed patients. In the choice of therapies for IBD, the balance of individual drug effectiveness and safety is crucial.
  • Keywords: Inflammatory bowel diseases; Immunosuppression therapy; Opportunistic infections; Tuberculosis; Tumor necrosis factor inhibitors
Inflammatory bowel disease (IBD), mainly comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, progressive, and currently incurable disorder that leads to substantial impairment of the patient’s quality of life, in addition to having the potential to cause progressive intestinal damage, loss of function, disability, and increased rates of hospitalization and intestinal surgery [1].
In moderate to severe IBD at high risk of progression, therapeutic strategies based on the use of immunosuppressants, including the various classes of biologics, have revolutionized the treatment of these disorders in recent decades [2]. However, many of these therapeutic agents have the potential to predispose patients to the occurrence of opportunistic infections (OIs). Indeed, the risk of OIs associated with immunosuppressive therapies for IBD is one of the main concerns of both patients and advanced practice clinicians in IBD care [3]. Remarkably, OIs are often difficult to recognize, are associated with appreciable morbidity or mortality, are commonly complex to treat effectively [4], and not infrequently require interruption to IBD-directed therapy, with all the inherent risks involved with this approach. However, when clinically indicated, the potential benefits of biologics and other immunosuppressants usually outweigh the risks [5].
Some studies have found that the long-term use of thiopurines increased the risk of viral infections, while anti-tumor necrosis factor (anti-TNF) agents increased the risk of several OIs, particularly when used in combination therapy with thiopurines [5,6]. Moreover, herpes zoster (HZ) infections are more frequent in IBD patients, and these patients are more likely to have complications of HZ compared with the general population [7]. Additionally, several immunosuppressive therapies amplify the risk of HZ reactivation, making this one of the most common OIs in IBD patients [8]. Conversely, biologics with a mechanism of action distinct from TNF blockade do not appear to significantly increase the risk of OIs, at least in European or North American studies[9-12]. However, data on the incidence and risk of OIs during the use of advanced therapies targeting IBD in Latin America are very scarce [13,14]. Unlike what is found in European or North American populations, in Latin America, including Brazil, there is a high burden of tuberculosis (TB) and other opportunistic pathogens [15]. Consequently, exploring data from Latin American countries regarding the incidence and risk of OIs in IBD patients using various immunosuppressive therapies is of critical importance for both a better global understanding of the epidemiology of these OIs in this scenario and improving the management of these individuals. Here, we assessed the incidence and stratified risk of OIs in IBD patients treated with immunosuppressive therapies (i.e., biologics and/or thiopurines) compared with non-immunosuppressed IBD patients using aminosalicylates. In addition, we aimed to determine the incidence and risk of TB and HZ attributed to various IBD-targeted therapies in a large cohort of IBD patients.
1. Study Design and Population
We performed an ambispective cohort observational study of patients with a diagnosis of IBD in the University Hospital of the Federal University of Juiz de Fora, a tertiary IBD center located in Brazil. We retrospectively analyzed the electronic records of IBD patients in a cohort between March 2014 and March 2021 and prospectively analyzed those who were followed up in a cohort from April 2021 to April 2024. The study population included adult patients aged 18 years or older diagnosed with CD or UC by well-established criteria (clinical, laboratory, endoscopic, imaging, and/or histopathological) and who were followed up at the IBD center for at least 3 months prior to the initial date of inclusion and/or who consented to participate in the prospective phase. Patients who had HIV infection or congenital immunodeficiency, organ transplant recipients, those undergoing cancer treatment (except those with non-melanoma skin cancer), patients who were pregnant or lactating, and those whose crucial registration data were incomplete were excluded from the study.
2. Ethical Issues
The study was approved by the ethics committee of the University Hospital of the Federal University of Juiz de Fora (Ethics Committee Number: 3.043.615/2018). All procedures were conducted in accordance with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. In the retrospective data extraction phase, the requirement for written informed consent was waived by an institutional review board. In the prospective phase of the study, all patients signed the informed consent form before inclusion in the study
3. Data Collection
For the retrospective cohort, data extraction regarding demographics, relevant medical history including comorbidities, and IBD history were captured using a standardized electronic case report form between April 2024 and May 2024, while for the prospective cohort, the patients’ data and outcomes were entered during consecutive outpatient visits. This included data regarding age, sex, race/ethnicity, body mass index, Charlson Comorbidity Index (CCI), type of IBD, age at IBD diagnosis, disease duration, disease location and phenotype using the Montreal classification, history of previous intestinal resection, IBD therapies and duration of use, follow-up time,occurrence and causative pathogen of OI, as well as the affected organs and system and the outcome of the infection (recovery or death). To evaluate the possible impact of combination therapy of systemic corticosteroids with biologics or thiopurines on the emergence of OIs, we evaluated concomitant steroid use (yes or no, and doses) in all patients who developed an OI in the corresponding period up to 3 months before its occurrence, since in this time interval there could be a residual immunosuppressive effect resulting from the use of steroids [4,6]. All participant investigators attended 2 study-specific training sessions to ensure that consistent definitions of all variables and outcomes were applied and inserted into the case report form during clinical visits for the prospective cohort and at the time of data extraction for the retrospective cohort.
4. Follow-up
In both the retrospective and prospective cohorts, all patients evaluated were followed up according to routine practice in our IBD center, typically with outpatient appointments scheduled at intervals of 1 to 3 months according to the patient’s clinical condition. In the retrospective cohort, patients had their clinical data electronically captured and subsequently analyzed until one of the following events occurred: definitive treatment discontinuation, last known follow-up, first OI, death, or March 30, 2021. In the prospective cohort, we monitored all individuals from 30 days after the initiation of the primary treatment until the occurrence of any of the following: last known follow-up, occurrence of first OI, death, or April 30, 2024, whichever occurred first.
5. Outcome Measures
The primary outcome was the occurrence of OIs, as well as the IBD therapy in use at the time of its occurrence. OIs were defined as illness caused by a microorganism that does not usually cause disease in immunocompetent individuals but is pathogenic in those with compromised immune systems [4,16]. Patients who developed an OI during the period from the first administered dose of biologic up to 3 months after its last dose or after 1 month of initiation of thiopurines up to 3 months after its last dose were considered to have an infection associated with the use of these agents. Secondary outcomes included the system/organ affected by the OI, including pulmonary, gastrointestinal, cutaneous, urinary tract, musculoskeletal, otorhinolaryngological, or of undetermined focus; and the infectious agent causing the OI, including viruses, bacteria, mycobacteria, fungi, and parasites. The main opportunistic infectious agents that were evaluated included cytomegalovirus, recurrent herpes simplex, HZ, Mycobacterium tuberculosis, Candida albicans, Histoplasma capsulatum, Aspergillus, Cryptococcus neoformans, and Cryptosporidium. Other secondary outcomes included the outcome of the infection (recovery or death) and the risk factors associated with the occurrence of OIs.
It is important to point out that in our center, latent tuberculosis infection (LTBI) screening was routinely performed using the interferon gamma release assay (IGRA) and/or Mantoux tuberculin skin test (TST), in addition to a chest radiograph before initiating advanced IBD-directed therapy. Patients who tested positive by IGRA or TST (TST >5 mm) or who had a chest radiograph finding suggestive of LTBI had the initiation of biologic therapy delayed for at least 1 month after the start of LTBI treatment.
6. Statistical Analysis
Baseline sociodemographic and IBD-related characteristics were summarized as means±standard deviations for continuous variables and as frequencies and percentages for categorical variables. The prevalence of OIs was reported as absolute numbers with corresponding percentages. Incidence rates of OIs were expressed as the number of events per 1,000 patient-years (PY) of follow-up and were calculated separately for each treatment group. Potential risk factors associated with the occurrence of OIs, including demographic characteristics, IBD-specific clinical variables, age at diagnosis, disease duration, CCI, and IBD therapies, were analyzed using Student t-test or the Mann-Whitney U test for continuous variables, depending on data distribution, and the chi-square test or Fisher’s exact test for categorical variables, as appropriate. A two-tailed P-value < 0.05 was considered statistically significant. The risk of developing OIs was further assessed using the Cox proportional hazards model, with results expressed as hazard ratio (HR) and 95% confidence interval (CI). Multivariable models were subsequently adjusted for age and sex. Kaplan-Meier survival analyses were performed to estimate the cumulative incidence of OIs, and comparisons between treatment groups were conducted using the log-rank test. IBD therapies were categorized as follows: combination therapy (i.e., anti-TNF and thiopurines), anti-TNF monotherapy (i.e., adalimumab, infliximab, or certolizumab pegol), thiopurine monotherapy (i.e., azathioprine or 6-mercaptopurine), and non-anti-TNF biologics (i.e., vedolizumab or ustekinumab), and compared with exposure to non-immunosuppressive treatment, namely, only aminosalicylates or no treatment. During follow-up, patients exposed to more than 1 advanced therapy had their therapy exposure data captured and analyzed at different time periods for each of the therapies, and could contribute to more than 1 treatment group. Thus, the risk of OI among patients who received more than 1 advanced therapy was analyzed separately for each therapy throughout the entire period of its use since the biologics were used sequentially at different times and not concomitantly. In this context, in the event of an OI during the follow-up, the OI was attributed to the first biologic if it occurred during the period from the first administrated dose of biologic up to 3 months after its last dose; conversely, if the OI occurred 1 month or more after initiation of the subsequent advanced therapy, it was attributed to this latter therapy. We also compared the risk of OIs associated with non-anti-TNF biologics with those associated with the use of thiopurines and/or anti-TNF agents. All statistical analyses were performed using SPSS software, version 22.0 (SPSS Inc., Chicago, IL, USA).
1. Population and Patient Characteristics
Between April 2014 and April 2024, in the joint population of the retrospective and prospective cohorts, 510 individuals were screened for the study, of which 12 were excluded, resulting in a final sample of 498 patients. The reasons for exclusion were follow-up of less than 3 months (n=4), incomplete clinical data (n=5), malignancy (n=2), and inconclusive IBD diagnosis (n=1). Of the total sample, 483 patients were included in the retrospective cohort and 424 were included in the prospective cohort. Of the latter, 300 belonged to the retrospective cohort and continued prospective follow-up, and 124 were patients included exclusively in the prospective cohort. The mean follow-up time was 89.02±35.30 months, totaling 3,279.6 PY of follow-up using immunosuppressive therapy and 3,017.3 PY of follow-up on aminosalicylates. In total, 339 patients (68.1%) had CD and 159 patients (31.9%) had UC. The majority were female (n=304, 61%) and white (334, 67.3%). The mean age of the patients was 46.17±15.52 years, while the time since IBD diagnosis was 10.30±8.03 years. Smokers accounted for 6.6% of individuals, and the CCI was 0.89±1.27 (Table 1). Of the 339 CD patients, there was a predominance of age at diagnosis between 17 and 40 years (A2) (n=198, 58.4%), ileocolonic involvement (L3) (n=158, 46.4%), and non-stenosing non-penetrating behavior (B1) (n=143, 38.9%). Sixty-eight patients (20.1%) had perianal disease. Of the patients with UC, there was a predominance of extensive colitis (74/159, 46.5%). Ninety-six individuals (19.3%) had a history of previous bowel resection (Table 1).
Of the total of 498 patients included, 85 (17%) individuals were consecutively exposed to different advanced therapy sequences and contributed to more than 1 treatment subgroup. The most used IBD therapies in both cohorts including the time periods in which it occurred switching biologics within the same class or outside the class of the previous biologic were anti-TNF monotherapy (n=168), aminosalicylates (n=109), thiopurine monotherapy (n=105), combination therapy (n=95), and non-anti-TNF biologics (n=59)
2. Opportunistic Infections
OIs occurred in 60 out of 498 patients (12%), with a pooled incidence rate of 18.3 per 1,000 PY. The incidence rates according to the therapy in use at the time of diagnosis of the OIs were 6.09, 5.48, 4.87, 0.91, and 0.91 per 1,000 PY for combination therapy, thiopurine monotherapy, anti-TNF monotherapy, non-anti-TNF biologics, and aminosalicylates, respectively. Compared with non-immunosuppressed patients using aminosalicylates, the risk of OIs was higher in patients on combination therapy (adjusted HR [aHR], 6.86; 95% CI, 1.97–23.92; P=0.002), followed by thiopurine monotherapy (aHR, 5.02; 95% CI, 1.45–17.33; P=0.011) and anti-TNF monotherapy (aHR, 4.70; 95% CI, 1.39–15.96; P=0.013). Conversely, non-anti-TNF biologics did not have an increased risk of OIs (Fig. 1). In turn, non-anti-TNF biologics as the primary treatment were associated with lower risks of OIs when compared with combination therapy (aHR, 0.05; 95% CI, 0.01–0.11; P<0.001), thiopurine monotherapy (aHR, 0.09; 95% CI, 0.03–0.20; P<0.001), and anti-TNF monotherapy (aHR, 0.14; 95% CI, 0.09–0.35; P=0.002) after adjusting for age and sex.
There was no association between demographic and IBD-related characteristics with the occurrence of OIs. In contrast, in univariate analysis, combination therapy, anti-TNF monotherapy, and thiopurine monotherapy significantly increased the risk of OIs compared with aminosalicylates (P=0.038), as shown in Table 1
Fig. 2 depicts the OI-free survival during follow-up between patients with IBD under treatment with biologics and/or thiopurines. Kaplan-Meier analysis showed that compared with patients using aminosalicylates or no treatment, those on combination therapy had lower OI-free survival, while those using non-anti-TNF biologics had the highest OI-free survival (P=0.001).
In OIs, the most commonly affected system/organ was the skin (n=28, 46.7%), followed by disseminated OIs (n=12, 20%), followed by the gastrointestinal (n=9, 15%) (Table 2). Only 4 of 60 (6.7%) patients (2 using thiopurines and 2 on infliximab) with OIs had recent corticosteroid exposure (e.g., within the last 3 months) in a dosage between 5.0 and 7.5 mg/day of prednisone before the development of OIs. None of the patients who developed OIs had a fatal outcome.
3. Risk of HZ and TB
The most common types of OI were HZ (n=28, 5.6%) and TB (n=17, 3.4%). It should be noted that 4 (6.7%) of the individuals with OIs had invasive fungal infections, including pulmonary aspergillosis, and disseminated cryptococcosis and histoplasmosis (Table 3). The incidence rates of HZ and TB were 8.5 per 1,000 PY and 5.18 per 1,000 PY, respectively. Of the 17 TB cases, 8 patients (47.1%) were using anti-TNF monotherapy, 7 (41.2%) were using combination therapy, 1 (5.9%) was using ustekinumab, 1 (5.9%) was using aminosalicylates, and no patients were using thiopurine monotherapy at the time of TB diagnosis. The incidence rates of TB in patients using combination therapy, anti-TNF monotherapy, non-anti-TNF biologics, and aminosalicylates were 2.4, 1.8, 0.3, and 0.3 per 1,000 PY, respectively. Compared with patients using aminosalicylates or no treatment, the risk of TB was higher in patients on combination therapy (aHR, 4.37; 95% CI, 1.19–16.07, P=0.027), followed by anti-TNF monotherapy (aHR, 4.21; 95% CI, 1.23–14.45; P=0.022). Conversely, both thiopurine monotherapy and non-anti-TNF biologics did not have an increased risk of TB (Fig. 3). Compared with anti-TNF monotherapy and combination therapy, non-anti-TNF biologics were associated with lower risks of TB (aHR, 0.07; 95% CI, 0.05–0.41; P=0.002 and aHR, 0.09; 95% CI, 0.02–0.52; P=0.003, respectively) after adjusting for age and sex. The median time between the initiation of anti-TNF monotherapy and TB diagnosis was 15 months (range, 1–96 months), while for those using combination therapy, the median time was 7 months (range, 3–55 months). Of note, of the total of 17 cases of TB disease, there was a predom inance of miliary TB (n=10; 58.8%), followed by extrapulmonary (n=4; 23.5%), and pulmonary (n=3; 17.7%) locations (Table 3)
LTBI screening was positive in 33 (11.6%) patients out of 284 who received biologics. LTBI treatment regimens included 9 months of isoniazid monotherapy (n=10), 4 months of daily rifampin (n=7) or 3 months of once-weekly isoniazid plus rifapentine (n=16). Only 1 of LTBI-positive individuals who received chemoprophylaxis showed progression to active TB disease
Of the 28 patients who had HZ, 9 (32.1%) were using thiopurine monotherapy, 9 (32.1%) were using anti-TNF monotherapy, 8 (28.6%) were using combination therapy, and 2 (7.2%) were using aminosalicylates at the time of HZ diagnosis. No cases of HZ occurred in individuals using non-anti-TNF biologics. The incidence rates of HZ in patients using thiopurine monotherapy, anti-TNF monotherapy, and combination therapy were 3.0, 2.7, and 2.1 per 1,000 PY, respectively. Compared with aminosalicylates use, there was a trend toward a higher risk of HZ during therapy with thiopurines (aHR, 4.57; 95% CI, 0.97–21.46; P=0.054), anti-TNF (aHR, 3.91; 95% CI, 0.84–18.15; P=0.081), and combination therapy (aHR, 4.24; 95% CI, 0.81–22.07; P=0.086) (Fig. 4). In contrast, non-anti-TNF biologics did not increase the risk of HZ infection compared to the use of aminosalicylates (P=0.997). The median time between the initiation of thiopurine monotherapy, anti-TNF monotherapy, and combination therapy and the HZ diagnosis was 36 months (range, 5–108 months), 44 months (range, 4–132 months), and 40 months (range, 3–66 months), respectively. Only 2 (7.1%) of the 28 patients had HZ affecting more than 1 dermatome.
Using a long-term ambispective cohort study of patients with IBD exposed to several immunosuppressive therapies, we found a high risk of OIs in decreasing order with combination therapy, thiopurine monotherapy, and anti-TNF monotherapy, compared with patients using aminosalicylates. In addition, we observed a high burden of HZ and TB, with a clear trend toward a higher risk of HZ in thiopurine users, while combination therapy and anti-TNF monotherapy increased the risk of TB by just over 4-fold. TB mainly occurred within the first year after the initiation of combination therapy or anti-TNF monotherapy, while HZ occurred later, from the third year of immunosuppressive therapy. To our knowledge, this is the first study to evaluate the risk of OIs and their specific agents in IBD patients using various immunosuppressive agents in a region of a Latin American country where there is a high burden of TB and other OIs.
We found high incidence rates of OIs in this IBD population, with levels of 6.09, 5.48, and 4.87 per 1,000 PY for combination therapy, thiopurine monotherapy, and anti-TNF monotherapy, respectively. In contrast, in a large French cohort of IBD patients, Kirchgesner et al. [6] reported much lower incidence rates of OIs—namely, 1.7, 2.1, and 4.1 per 1,000 PY exposed to these same therapies. We hypothesize that the high incidence of OIs associated with IBD-targeted therapies in the present study is due to the high TB burden in Brazil, as well as the lack of immunization against HZ in this cohort. In line with other studies, we observed the highest risk of OIs with combination therapy [6,17], while non-anti-TNF biologics did not increase the risk of OIs. In fact, analysis of safety data from pivotal trials and real-world evidence has demonstrated that anti-integrin agents, such as vedolizumab, and interleukin-12/23 inhibitors, including ustekinumab, present favorable safety profiles with minimal OI risks, probably due to both the more selective mechanisms of action of these therapies and the lower degree of systemic immunosuppression induced by them [11,18,19].
In contrast to the findings of other studies [6,17], except for the type of therapy in use, we did not find any other risk factors for OIs, including age and comorbidities. We speculate that this finding may be explained by the fact that our cohort involved younger patients (mean age, 47 years) and, consequently, patients with fewer underlying comorbidities. Furthermore, we did not find any fatal outcomes from OIs during a decade-long follow-up period. It is possible that due to the high TB burden in the country, clinicians are more attentive to the nuances of the clinical manifestations of TB, so that diagnosis is typically made earlier and specific treatment is promptly initiated.
In the present study, the incidence rate of TB (5.18 per 1,000 PY or 518 per 100,000 PY) was 13 times higher than that reported in the general Brazilian population in 2023, which was 39.8 cases per 100,000 PY [20,21], indicating the substantial amplification of TB risk attributed to the use of anti-TNF agents or combination therapy in a high TB-burden country. Comparatively, in a Korean cohort, a country that also has a high burden of TB, the incidence rate in IBD patients using anti-TNF therapy was 366.73 per 100,000 PY [22]. On the other hand, a much lower incidence of TB was seen from European or North American databases in patients with IBD and rheumatologic diseases who received anti-TNF therapy, where the reported incidence rate of TB cases per 100,000 PA was 144 in the United States [23], 130 in the UK [24], 117 in France [25], and 230 in Spain [26].
We observed a higher risk of TB with combination therapy (aHR, 4.37; 95% CI, 1.19–16.07) followed by anti-TNF monotherapy (aHR, 4.21; 95% CI, 1.23–14.45), in line with a large French cohort that also revealed a higher risk of TB in IBD patients during exposure to combination therapy (HR, 4.3; 95% CI, 2.1–8.8) and anti-TNF monotherapy (HR, 2.17; 95% CI, 1.08–4.36) [6]. It is well recognized that anti-TNF agents predispose patients to active TB due to the destabilization of granulomas and interference with T lymphocyte proliferation and macrophage activation, both essential in the immune response against M. tuberculosis [27]. In contrast, the incidence rate of TB associated with non-anti-TNF biologics was 6-fold and 8-fold lower compared to that associated with combination therapy and anti-TNF monotherapy, respectively, confirming the safety profile of these agents even in a region with a high TB burden. In fact, recent multicenter real-world studies conducted in IBD populations in Brazil confirm the low risk of OIs, including TB, in patients treated with vedolizumab or ustekinumab [28,29].
It is important to highlight that in accordance with recent recommendations, rigorous pre-biological screening is always performed in our IBD center before commencing with any immunobiological agent [4,30], and all LTBI-positive patients are treated before starting biologics. Despite this approach, active TB was diagnosed in several patients, most often within the first year after initiation of combination therapy or anti-TNF monotherapy, although some cases occurred as late as 8 years after therapy, likely resulting from reinfection in a country with a high local TB burden. This finding suggests that in Brazil, during immunosuppressive therapy based on the use of anti-TNF agents, the most common mechanism of active TB is the reactivation of a latent infection, which supports the known limitations of current screening modalities. Indeed, a meta-analysis demonstrated that more than 70% of TB cases develop in patients negative for latent TB status at baseline, independent of local TB burden [31]. It is well known that both the TST and IGRA can result in false negatives either due to the inflammatory activity of IBD or due to the use of immunosuppressants prior to screening [32]. Furthermore, even when latent TB is diagnosed and treated before the initiation of anti-TNF therapy, there is still a risk of developing active TB due to inadequate adherence to treatment, drug resistance, or reinfection in areas of high endemicity [22,33]. Thus, regardless of the implementation of routine screening for latent TB before starting biologic therapy, especially anti-TNF agents, followed by prompt treatment when indicated, the patient’s ongoing monitoring throughout immunosuppressive therapy is pivotal for the detection and prompt treatment of TB reactivation/reinfection [4,15].
HZ was the most common OI in our cohort, with an incidence of 8.5 per 1,000 PY, in line with the findings of a meta-analysis including 216,552 IBD patients, where the incidence rate of HZ was found to be 10.41 per 1,000 PY [34]. Indeed, HZ infections are more frequent in IBD patients compared with the general population [7]. Conversely, a Spanish multicenter study including 6,914 patients showed a lower incidence of HZ of 3.9 per 1,000 PY [35]. In Brazil, the HZ vaccine is not available in the public health system for IBD patients using immunosuppressants, which may justify the high incidence of this infection observed in the current study together with the frequent use of thiopurines in patients followed in this cohort. There was a clear trend toward a higher risk of HZ during thiopurine therapy (aHR, 4.57; 95% CI, 0.97–21.46; P=0.054), probably due to the drug’s action in inhibiting the proliferation of T and B lymphocytes, impairing the control of latent viral infections such as the varicella-zoster virus [36,37]. Interestingly, HZ occurred in most patients from the third year of use of thiopurines and/or anti-TNF biologics, suggesting that HZ reactivation in IBD patients often requires more prolonged immunosuppression.
Of note, in the present cohort we did not find any cases of pneumonia caused by Pneumocystis jirovecii. It is standard practice at our IBD center to initiate prophylaxis with trimethoprim/sulfamethoxazole for patients with IBD on triple immunosuppressive therapy or for those on double immunosuppressive therapy that include combination of high-dose corticosteroids and a low lymphocyte count, in accordance with European Crohn’s and Colitis Organisation guidelines.4 This routine prophylactic strategy probably explains the absence of OI occurrence due to P. jirovecii.
Our investigation has some constraints, which may limit the generalizability of our findings. First, given the retrospective nature of part of the collected data, there is a risk of recall bias and missing data inherent in retrospective studies. In particular, data regarding steroid use throughout the study were not available, which could have some influence on the results. However, we evaluated concomitant exposure of corticosteroids with thiopurines or biologics in the last 3 months before the occurrence of an OI. Indeed, only 6.7% patients with OIs had exposure to low-dose steroids (e.g., 5.0 to 7.5 mg/day of prednisone) within the last 3 months before the development of an OI. This finding strongly suggests that steroid use did not play a relevant role in the occurrence of OIs in our cohort. Second, this research was conducted at a tertiary single center for IBD in Brazil, a developing country with lower socioeconomic levels compared with North American or European nations where the incidence and prevalence of some OIs, particularly TB, is significantly lower. Third, the burden of OIs found in our study may not completely reflect the true prevalence of these infections in the IBD patients predominantly managed in community IBD clinics. In the present study, the patients with IBD were in an IBD referral center that tends to make them more likely to have more severe IBD requiring more advanced therapies than those seen in a primary care medical setting. This might bias the results toward a higher prevalence of OIs than those in the overall community of IBD patients. Lastly, due to the timeline of obtaining the data, our investigation lacked sufficient patients treated with selective IL-23 inhibitors and targeted synthetic small molecules, including Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. Thus, our findings should be interpreted within a suitable context, considering the factors discussed above.
Despite the above-mentioned limitations, our study has several strengths. First, it highlights the long-term risk of OIs in a cohort of IBD patients treated with various immunosuppressive therapies with follow-up for a decade in a region located in the largest country in Latin America. Moreover, the present study provides real-world evidence, particularly of the risk of long-term development of active TB and HZ among IBD patients exposed to immunosuppressive agents in a high TB-burden country compared with those not immunosuppressed, providing important concepts for applicability in clinical practice. Additionally, in this study, patient data extraction/insertion was obtained through a standardized electronic case report form, and all researchers received prior training on the study variables and outcomes to allow for proper completion of case report forms.
Future long-term, preferably prospective, multicenter studies involving broader IBD populations from Latin America, aiming to explore more deeply the risk of various OIs and their relationship with the wide range of advanced targeted therapies for IBD will be welcomed and may contribute to expanding knowledge on this important issue for clinicians caring for IBD patients.
In conclusion, in this long-term real-life cohort, we found that patients using thiopurine monotherapy, anti-TNF monotherapy, and especially combination therapy had a higher risk of OIs compared to aminosalicylate users, while those on non-anti-TNF biologics did not. We found a significant burden of HZ and TB related to immunosuppressive therapy, and these were the most common OIs. There was a clear trend toward a higher risk of HZ in thiopurine users and, to a lesser extent, in those on anti-TNF therapy, while TB was associated almost exclusively with anti-TNF agents or combination therapy within the first year of starting therapy. We also found a very low risk of OIs during non-anti-TNF therapy, even in a region with a high TB burden. These findings emphasize the importance of balancing the therapeutic benefits of thiopurine- and/or anti-TNF-based treatment regimens with potential risks, highlighting the need to undertake a patient-centered risk management strategy and watchful monitoring to optimize outcomes.

Funding Source

This study was supported in part by a clinical research fund from the National Council for Scientific and Technological Development (CNPq), Brazil.

Conflict of Interest

Chebli JMF has received fees for serving as a speaker and/or an advisory board member for Abbvie, Abbott, Janssen, Pfizer and Takeda; the other authors declare that they have no conf lict of interest.

Data Availability Statement

Data analyzed in this study are available from the corresponding author upon reasonable request.

Author Contributions

Conceptualization: Rios Ricci JE, da Rocha Ribeiro TC, Araújo HB, Pacheco MA, de Paula Fraga JB, Schmidt LPC, Chebli LA, Almeida TA, Borsato ROR, Chebli JMF. Data curation: da Rocha Ribeiro TC, Colugnati FAB, de Almeida Costa L, Lopes JAS, Pacheco MA, Paula MV, de Paula Fraga JB, Schmidt LPC, Chebli LA, Almeida TA, Borsato ROR, Chebli JMF. Formal analysis: Rios Ricci JE, da Rocha Ribeiro TC, Colugnati FAB, de Almeida Costa L, Paula MV, de Paula Fraga JB, Schmidt LPC, Chebli LA, Almeida TA, Borsato ROR, Chebli JMF. Funding acquisition: Chebli JMF. Investigation: Rios Ricci JE, da Rocha Ribeiro TC, de Almeida Costa L, de Morais P, Lopes JAS, Araújo HB, Pacheco MA, Paula MV, Schmidt LPC, Chebli LA, Almeida TA, Borsato ROR, Chebli JMF. Methodology: Rios Ricci JE, Colugnati FAB, de Almeida Costa L, de Morais P, Lopes JAS, Araújo HB, de Paula Fraga JB, Schmidt LPC, Chebli LA, Borsato ROR, Chebli JMF. Supervision: Chebli JMF. Writing–original draft: Rios Ricci JE, da Rocha Ribeiro TC, de Almeida Costa L, de Morais P, Lopes JAS, Araújo HB, Pacheco MA, Paula MV, de Paula Fraga JB, Schmidt LPC, Chebli LA, Almeida TA, Borsato ROR, Chebli JMF. Writing–review & editing: Rios Ricci JE, da Rocha Ribeiro TC, Colugnati FAB, de Almeida Costa L, Araújo HB, Pacheco MA, Paula MV, de Paula Fraga JB, Schmidt LPC, Chebli LA, Almeida TA, Borsato ROR, Chebli JMF. Approval of f inal manuscript: all authors.

Fig. 1.
HRs for opportunistic infections associated with biologic therapies and/or thiopurines compared with the use of aminosalicylates or no treatment in inflammatory bowel disease patients, adjusted for age and sex. HR, hazard ratio; CI, confidence interval; TNF, tumor necrosis factor.
ir-2025-00208f1.jpg
Fig. 2.
Kaplan-Meier plot depicting opportunistic infection-free survival during long-term follow-up of 498 patients with inflammatory bowel disease (IBD) under treatment with IBD-targeted therapies. Compared with aminosalicylates or no treatment, the opportunistic infection-free survival was higher, in decreasing order, with non-anti-tumor necrosis factor (TNF) biologics, anti-TNF monotherapy, thiopurine monotherapy, and combination therapy.
ir-2025-00208f2.jpg
Fig. 3.
HRs for tuberculosis disease associated with biologic therapies and/or thiopurines compared with the use of aminosalicylates or no treatment in inflammatory bowel disease patients, adjusted for age and sex. HR, hazard ratio; CI, confidence interval; TNF, tumor necrosis factor.
ir-2025-00208f3.jpg
Fig. 4.
HRs for herpes zoster associated with biologic therapies and/or thiopurines compared with the use of aminosalicylates or no treatment in inflammatory bowel disease patients, adjusted for age and sex. HR, hazard ratio; CI, confidence interval; TNF, tumor necrosis factor.
ir-2025-00208f4.jpg
ir-2025-00208f5.jpg
Table 1.
Demographic, Clinical and Treatment-Related Characteristics of IBD Patients with and without Opportunistic Infection
Variable With opportunistic infection, No. (%) Without opportunistic infection, No. (%) P-value
Race 0.824
 White 41 (12.3) 293 (87.7)
 Non-white 19 (11.6) 145 (88.4)
Mean age (yr) 46.91 46.59 0.103
Mean BMI (kg/m2) 25.49 26.34 0.233
Type of IBD 0.351
 CD 44 (73.3) 295 (67.4)
 UC 16 (26.7) 143 (32.6)
CD phenotype
 Age of diagnosis 0.182
  A1 6 (13.7) 21 (7.1)
  A2 21 (47.7) 177 (60)
  A3 17 (38.6) 97 (32.9)
 Location at inclusion 0.638
  L1 15 (34.1) 101 (34.2)
  L2 8 (18.2) 51 (17.3)
  L3 19 (43.2) 139 (47.1)
  L4 2 (4.5) 4 (1.4)
 Behavior at inclusion 0.764
  B1 15 (34.1) 128 (43.4)
  B2 21 (47.7) 111 (37.6)
  B3 8 (18.2) 56 (19)
 Perianal disease 10 (22.7) 58 (19.7) 0.836
UC extent at inclusion 0.137
 Ulcerative proctitis 4 (25) 55 (38.5)
 Left-sided UC 1 (6.2) 25 (17.5)
 Extensive UC 11 (68.8) 63 (44)
Mean IBD duration (yr) 10.66 10.25 0.709
Mean CCI score 0.54 0.94 0.440
Intestinal resection 13 (21.7) 83 (18.9) 0.935
IBD treatment 0.038
 Aminosalicylates 3 (5) 83 (24.2)
 No treatment 0 23 (5.25)
 Thiopurines 16 (26.7) 89 (20.3)
 Anti-TNF 20 (33.3) 110 (25.1)
  Adalimumab 3 32
  Infliximab 15 75
  Certolizumab pegol 2 3
 Combination therapy 18 (30) 77 (17.5)
 Non-anti-TNF biologic agents 3 (5) 56 (12.8)
  Ustekinumab 2 31
  Vedolizumab 1 25

IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; A, age; L, location; B, behavior; CCI, Charlson Comorbidity Index; TNF, tumor necrosis factor.

Table 2.
Affected Organs and Systems and Their Frequency in Opportunistic Infections
Organs and systems No. (%)
Skin 28 (46.7)
Pulmonary 5 (8.3)
Gastrointestinal 9 (15.0)
Genital tract 2 (3.3)
Othersa 4 (6.7)
Disseminated 12 (20.0)
Opportunistic infection (total) 60 (100)

a Include lymph nodes (n=2), bone (n=1), and peritoneum (n=1).

Table 3.
Types of Opportunistic Infections and Their Individualized Frequency
Types of infection No. (%)
Herpes zoster 28 (5.6)
Tuberculosis 17 (3.4)
 Pulmonary 3
 Miliary 10
 Extrapulmonary 4
  Lymph node 2
  Bone 1
  Peritoneal 1
Cytomegalovirus colitis 5 (1.0)
Recurrent herpes simplex 2 (0.4)
Esophageal moniliasis 2 (0.4)
Pulmonary aspergillosis 2 (0.4)
Cryptosporidiosis 2 (0.4)
Disseminated histoplasmosis 1 (0.2)
Disseminated cryptococcosis 1 (0.2)
Opportunistic infection (total) 60 (12.0)
No opportunistic infection 438 (87.9)
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      Incidence and treatment-based risk stratification of opportunistic infections in patients with inflammatory bowel disease: an ambispective cohort study in Brazil
      Image Image Image Image Image
      Fig. 1. HRs for opportunistic infections associated with biologic therapies and/or thiopurines compared with the use of aminosalicylates or no treatment in inflammatory bowel disease patients, adjusted for age and sex. HR, hazard ratio; CI, confidence interval; TNF, tumor necrosis factor.
      Fig. 2. Kaplan-Meier plot depicting opportunistic infection-free survival during long-term follow-up of 498 patients with inflammatory bowel disease (IBD) under treatment with IBD-targeted therapies. Compared with aminosalicylates or no treatment, the opportunistic infection-free survival was higher, in decreasing order, with non-anti-tumor necrosis factor (TNF) biologics, anti-TNF monotherapy, thiopurine monotherapy, and combination therapy.
      Fig. 3. HRs for tuberculosis disease associated with biologic therapies and/or thiopurines compared with the use of aminosalicylates or no treatment in inflammatory bowel disease patients, adjusted for age and sex. HR, hazard ratio; CI, confidence interval; TNF, tumor necrosis factor.
      Fig. 4. HRs for herpes zoster associated with biologic therapies and/or thiopurines compared with the use of aminosalicylates or no treatment in inflammatory bowel disease patients, adjusted for age and sex. HR, hazard ratio; CI, confidence interval; TNF, tumor necrosis factor.
      Graphical abstract

      Fig. 1.

      Fig. 2.

      Fig. 3.

      Fig. 4.

      Graphical abstract

      Incidence and treatment-based risk stratification of opportunistic infections in patients with inflammatory bowel disease: an ambispective cohort study in Brazil
      Variable With opportunistic infection, No. (%) Without opportunistic infection, No. (%) P-value
      Race 0.824
       White 41 (12.3) 293 (87.7)
       Non-white 19 (11.6) 145 (88.4)
      Mean age (yr) 46.91 46.59 0.103
      Mean BMI (kg/m2) 25.49 26.34 0.233
      Type of IBD 0.351
       CD 44 (73.3) 295 (67.4)
       UC 16 (26.7) 143 (32.6)
      CD phenotype
       Age of diagnosis 0.182
        A1 6 (13.7) 21 (7.1)
        A2 21 (47.7) 177 (60)
        A3 17 (38.6) 97 (32.9)
       Location at inclusion 0.638
        L1 15 (34.1) 101 (34.2)
        L2 8 (18.2) 51 (17.3)
        L3 19 (43.2) 139 (47.1)
        L4 2 (4.5) 4 (1.4)
       Behavior at inclusion 0.764
        B1 15 (34.1) 128 (43.4)
        B2 21 (47.7) 111 (37.6)
        B3 8 (18.2) 56 (19)
       Perianal disease 10 (22.7) 58 (19.7) 0.836
      UC extent at inclusion 0.137
       Ulcerative proctitis 4 (25) 55 (38.5)
       Left-sided UC 1 (6.2) 25 (17.5)
       Extensive UC 11 (68.8) 63 (44)
      Mean IBD duration (yr) 10.66 10.25 0.709
      Mean CCI score 0.54 0.94 0.440
      Intestinal resection 13 (21.7) 83 (18.9) 0.935
      IBD treatment 0.038
       Aminosalicylates 3 (5) 83 (24.2)
       No treatment 0 23 (5.25)
       Thiopurines 16 (26.7) 89 (20.3)
       Anti-TNF 20 (33.3) 110 (25.1)
        Adalimumab 3 32
        Infliximab 15 75
        Certolizumab pegol 2 3
       Combination therapy 18 (30) 77 (17.5)
       Non-anti-TNF biologic agents 3 (5) 56 (12.8)
        Ustekinumab 2 31
        Vedolizumab 1 25
      Organs and systems No. (%)
      Skin 28 (46.7)
      Pulmonary 5 (8.3)
      Gastrointestinal 9 (15.0)
      Genital tract 2 (3.3)
      Othersa 4 (6.7)
      Disseminated 12 (20.0)
      Opportunistic infection (total) 60 (100)
      Types of infection No. (%)
      Herpes zoster 28 (5.6)
      Tuberculosis 17 (3.4)
       Pulmonary 3
       Miliary 10
       Extrapulmonary 4
        Lymph node 2
        Bone 1
        Peritoneal 1
      Cytomegalovirus colitis 5 (1.0)
      Recurrent herpes simplex 2 (0.4)
      Esophageal moniliasis 2 (0.4)
      Pulmonary aspergillosis 2 (0.4)
      Cryptosporidiosis 2 (0.4)
      Disseminated histoplasmosis 1 (0.2)
      Disseminated cryptococcosis 1 (0.2)
      Opportunistic infection (total) 60 (12.0)
      No opportunistic infection 438 (87.9)
      Table 1. Demographic, Clinical and Treatment-Related Characteristics of IBD Patients with and without Opportunistic Infection

      IBD, inflammatory bowel disease; BMI, body mass index; CD, Crohn’s disease; UC, ulcerative colitis; A, age; L, location; B, behavior; CCI, Charlson Comorbidity Index; TNF, tumor necrosis factor.

      Table 2. Affected Organs and Systems and Their Frequency in Opportunistic Infections

      Include lymph nodes (n=2), bone (n=1), and peritoneum (n=1).

      Table 3. Types of Opportunistic Infections and Their Individualized Frequency

      Table 1.

      Table 2.

      Table 3.

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