A high prevalence of Epstein-Barr virus (EBV) infection in patients with inflammatory bowel disease (IBD) has been reported in many case reports and studies; thus, the association between EBV and IBD has gained increasing attention. Patients with IBD are at an increased risk of opportunistic EBV infection owing to the common use of immunomodulators. EBV infection in IBD patients can cause various complications, including superimposed viral colitis, which is associated with chronicity, exacerbation, and poor prognosis of refractory IBD, and can induce progression to lymphoproliferative disorders, such as EBV-positive mucocutaneous ulcer (EBVMCU), lymphomatoid granulomatosis (LYG), hemophagocytic lymphohistiocytosis (HLH) and diffuse large B-cell lymphoma (DLBCL). It has been suggested to screen for EBV before initiating immunosuppressive therapy and monitor the status of EBV infection in patients with IBD, especially those who are EBV-seronegative and have a risk of primary EBV infection. Clinicians should also be careful of misdiagnosing IBD and EBV-associated lymphoproliferative diseases due to similarities in both clinical symptoms and endoscopic manifestations. Withdrawal of immunosuppressants has been shown to be an effective strategy to achieve remission of disease at the time of EBV diagnosis, but antiviral therapy remains controversial. The present review aims to describe the characteristics of the complications caused by EBV infection and generalize the recent research progress on and challenges caused by EBV infection in IBD patients. The literature for writing this review was collected from 'PubMed' research engine. The keywords 'inflammatory bowel disease and Epstein-Barr virus' or 'ulcerative colitis and Epstein-Barr virus' or 'Crohn's disease and Epstein-Barr virus' were used to collect the literature and relevant papers were collected to help writing this review.

Macrophage activation syndrome is a life-threatening syndrome of uncontrolled immune activation with variable clinical presentation making early diagnosis difficult. It is often manifested by the development of multi-organ failure due to systemic inflammatory response. Patients with ulcerative colitis (UC) on purine antimetabolites are at high risk for severe myelosuppression due to the mechanism of thiopurine toxicity which potentially contributes to the development of macrophage activation syndrome. We present a case of a 39-year-old woman with a 2-year history of UC previously treated with 6-mercaptopurine (6-MP) and recent COVID-19 infection, who was admitted to our emergency department for C. difficile infection and subsequently developed macrophage activation syndrome. This case report also raises the question of whether abrupt discontinuation of 6-MP may have contributed to the worsening of the patient's symptoms of underlying hemophagocytic lymphohistiocytosis (HLH) and her rapid deterioration. Both macrophage activation syndrome and COVID-19 infection can produce a large number of pro-inflammatory cytokines termed "cytokine storm," but a pro-inflammatory cytokine panel breakdown helps to differentiate between the two. Our case report emphasizes the importance of close monitoring of patients on purine antimetabolite therapy who present with signs and symptoms of systemic toxicity.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and often fatal disease if not diagnosed and treated promptly. HLH can be due to genetic factors or infections, malignancies and collagen-associated vascular diseases. Malignancy-associated HLH is not only more common in the setting of T/NK-cell lymphomas, but may also rarely be seen in the setting of B-cell lymphoma. Here, we describe a unique case of a patient who initially was diagnosed with HLH secondary to Epstein Barr virus (EBV) infection and subsequently developed EBV-positive diffuse large B-cell lymphoma affecting the brain. This case highlights the spectrum of findings associated with EBV infections and the challenges in diagnosing underlying diseases associated with HLH.

Epstein Barr virus (EBV) primoinfection may contribute to the development of post-mononucleosis lymphomas in EBV-seronegative adult males with inflammatory bowel disease (IBD) under thiopurine therapy, but data on children are sparse. Knowledge of the EBV status may influence the type of surveillance and therapy in a group particularly vulnerable to the occurrence of EBV primoinfection. We aimed to determine the EBV status at diagnosis, the primoinfection rate, and complications in a pediatric Portuguese population with IBD.

This was a retrospective analysis of clinical records of pediatric patients with IBD. Demographic data, EBV status, as well as clinical and therapeutic data on primoinfection were collected.

Of the 250 patients evaluated, 229 (91.6%) had documented EBV screening and 50.8% were male. Mean age ± SD was 13.0 ± 2.8 years at diagnosis and 14.7 ± 2.3 years at EBV screening. EBV IgG serology was positive in 76.0% of patients. A total of 218 patients had been on therapy with azathioprine at some point. The average length of exposure to azathioprine was 4 years, and 91 patients (39.7%) were on azathioprine at EBV assessment. EBV primoinfection was documented in 4 patients (1.6%), all females, 2 of whom were on azathioprine. Two presented clinical signs of infection and 2 were identified at diagnostic screening; the first 2 suspended azathioprine and the other 2 did not initiate it.

A significant proportion of pediatric Portuguese IBD patients are EBV-naïve. Systematic screening of EBV status enables the identification of patients at risk of primoinfection, and the occurrence of symptoms suggestive of acute EBV infection in seronegative patients should lead to rapid confirmation of the diagnosis. Timely diagnosis may allow the adjustment of therapeutic strategy sparing patients from potentially severe iatrogeny.

To report a case of a female patient with hemophagocytic lymphohistiocytosis (HLH) and to systematically review the available cases of the association between HLH and inflammatory bowel disease (IBD).

In accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, retrieval of studies was based on Medical Subject Headings and Health Sciences Descriptors, which were combined using Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE (PubMed), Biblioteca Regional de Medicina, Latin American and Caribbean Health Sciences Literature, Cochrane Library for Systematic Reviews and Opengrey.eu. Languages were restricted to English, Spanish and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually.

The search strategy retrieved 223 references. In the final analysis, 28 references were included, with the report of 35 cases. The most common clinical finding was fever, 57% of patients had a cytomegalovirus infection and 30 patients were on thiopurines previously to HLH diagnosis. Most patients were treated with steroids and antiviral therapy. All-cause mortality was 22%.

These findings suggest that there might be a connection of HLH to IBD, opportunistic viral infections and the use of thiopurines. Due to the severity of such disease, the clinical suspicion is paramount to early diagnosis and therapy.

There are now 354 inborn errors of immunity (primary immunodeficiency diseases (PIDDs)) with 344 distinct molecular etiologies reported according to the International Union of Immunological Sciences (IUIS) (Clin Gastroenterol Hepatol 11: p. 1050-63, 2013, Semin Gastrointest Dis 8: p. 22-32, 1997, J Clin Immunol 38: p. 96-128, 2018). Using the IUIS document as a reference and cross-checking PubMed ( www.ncbi.nlm.nih.pubmed.gov ), we found that approximately one third of the 354 diseases of impaired immunity have a gastrointestinal component [J Clin Immunol 38: p. 96-128, 2018]. Often, the gastrointestinal symptomatology and pathology is the heralding sign of a PIDD; therefore, it is important to recognize patterns of disease which may manifest along the gastrointestinal tract as a more global derangement of immune function. As such, holistic consideration of immunity is warranted in patients with clinically significant gastrointestinal disease. Here, we discuss the manifold presentations and GI-specific complications of PIDDs which could lead patients to seek advice from a variety of clinician specialists. Often, patients with these medical problems will engage general pediatricians, surgeons, gastroenterologists, rheumatologists, and clinical immunologists among others. Following delineation of the presenting concern, accurate and often molecular diagnosis is imperative and a multi-disciplinary approach warranted for optimal management. In this review, we will summarize the current state of understanding of PIDD gastrointestinal disease involvement. We will do so by focusing upon gastrointestinal disease categories (i.e., inflammatory, diarrhea, nodular lymphoid hyperplasia, liver/biliary tract, structural disease, and oncologic disease) with an intent to aid the healthcare provider who may encounter a patient with an as-yet undiagnosed PIDD who presents initially with a gastrointestinal symptom, sign, or problem.

With the advent of biologic therapies for the treatment of inflammatory bowel disease, the roles of thiopurines have continued to evolve. This review will focus on recent advances in pharmacology and the safety and efficacy of thiopurines as maintenance therapies for steroid-induced remissions and post-surgical maintenance of remission and as combination therapies to reduce immunogenicities of biologic agents.

Due to pharmacogenetics of thiopurine S-methyltransferase, thiopurine dosing is more effectively based on monitoring of thiopurine metabolites rather than weight-based dosing. Thiopurines continue to have a role as maintenance therapy after steroid-induced remissions and in combination with biologics to induce and maintain remission. Safety monitoring includes measurements of blood counts, liver chemistries, and dermatologic evaluations and protection from sun exposure. Thiopurines appear to be safe during pregnancies and while very uncommon, lymphomas (including hepatosplenic T cell lymphomas) remain a recognized risk, particularly in younger and older males.

Little is known about the impact of Epstein-Barr virus (EBV) infection on clinical outcomes in adults with inflammatory bowel disease (IBD).

To evaluate seroprevalence, seroconversion rate and complications associated with EBV infection in an adult IBD cohort attending a tertiary care hospital in Spain between 2006 and 2016.

EBV serological status was determined. In seronegative patients, the seroconversion rate was evaluated. The complications associated with primary and latent EBV infection are described.

One thousand four hundred and eighty-three patients over the age of 17 were included in the study (mean age at EBV serological status determination was 48.3). Overall seroprevalence of EBV was 97.4% (95% CI: 96.6%-98.2%). The seroconversion rate was 29.7% (95% CI: 16.2-45.9) after a mean of 47.5 months. There were no differences in seroconversion rates between patients 35 years or younger and patients older than 35 years. A 66-year-old man, on treatment with thiopurines, developed lymphoma and a hemophagocytic syndrome during a primary EBV infection. Overall, six patients (one with primary infection and five with prior EBV infection) developed lymphoma. In three of five patients with lymphoma and thiopurine use, EBV was associated to the development of lymphoma.

There is a small percentage of adults with IBD at risk of primary EBV infection. The risks of seroconversion and its complications remain through adulthood. Our results suggest that, when considering the use of thiopurines in IBD, the information on EBV serological status should be taken into account at any age.

Immunosuppressive therapy for inflammatory bowel disease (IBD) in pediatric patients is thought to increase the risk of malignancy and lymphoproliferative disorders, including hemophagocytic lymphohistiocytosis (HLH). We compared unadjusted incidence rates of malignancy and HLH in pediatric patients with IBD exposed to infliximab (IFX) with patients not exposed to biologics and calculated standardized incidence ratios (SIRs).

We collected and analyzed data from 5766 participants in a prospective study of long-term outcomes of pediatric patients with IBD (NCT00606346), from May 31, 2007 through June 30, 2016. Patients were 17 years old or younger and had Crohn's disease, ulcerative colitis, or IBD-unclassified with 24,543.0 patient-years of follow-up. We estimated incidence rates for malignancy and HLH as events/1000 patient-years of follow-up. We calculated age-, sex-, and race-adjusted SIRs, with 95% confidence intervals (CIs), using the Surveillance, Epidemiology, and End Results Program (SEER) database.

Thirteen of the 15 patients who developed a malignancy and all 5 of the patients who developed HLH had been exposed to thiopurines; 10 patients with malignancy had also been exposed to a biologic agent. Unadjusted incidence rates showed no increased risk of malignancy (0.46/1000 patient-years) or HLH (0.0/1000 patient-years) in patients exposed to IFX as the only biologic vs those unexposed to biologics (malignancy: 1.12/1000 patient-years; HLH: 0.56/1000 patient-years). SIRs did not demonstrate an increased risk of malignancy among patients exposed to IFX (SIR, 1.69; 95% CI, 0.46-4.32) vs patients not exposed to a biologic agent (SIR, 2.17; 95% CI, 0.59-5.56), even when patients were stratified by thiopurine exposure.

In determination of age-, sex-, and race-adjusted SIRs using data from a large clinical study and the SEER database, we found that IFX exposure did not associate with increased risk of malignancy or HLH in pediatric patients with IBD. Thiopurine exposure is an important precedent event for the development of malignancy or HLH in pediatric patients with IBD.

We report a case of Epstein-Barr virus (EBV)-driven haemophagocytic lymphohistiocytosis (HLH) in a man with Crohn's disease treated with 6-mercaptopurine and adalimumab therapy who was successfully treated with rituximab therapy alone. This is the first published case in an adult patient with EBV-driven HLH in the setting of thiopurine use and inflammatory bowel disease to be successfully treated with rituximab therapy alone. Here, we will discuss putative immunological mechanisms which may contribute to this potentially life-threatening complication.

Nearly one-quarter of patients with inflammatory bowel disease (IBD) are younger than 20 years of age at diagnosis. Furthermore, the incidence of IBD in children continues to increase. Nevertheless, variation in management exists within the care of patients with IBD with regards to disease screening and preventive care. A multidisciplinary approach that involves the general practitioner and pediatric gastroenterologist is needed to routinely monitor growth, bone health, vitamin and mineral deficiencies, vaccination status, and endoscopic surveillance. It is also important to monitor for extraintestinal manifestations of IBD that may affect the liver, joints, skin, and eyes. The purpose of this article is to provide an updated overview of comprehensive care for pediatric patients with IBD.

Children and adolescents with inflammatory bowel disease (IBD) receiving therapy with tumor necrosis factor α inhibitors (anti-TNFα) pose a unique challenge to health care providers in regard to the associated risk of infection. Published experience in adult populations with distinct autoinflammatory and autoimmune diseases treated with anti-TNFα therapies demonstrates an increased risk of serious infections with intracellular bacteria, mycobacteria, fungi, and some viruses; however, there is a paucity of robust pediatric data. With a rising incidence of pediatric IBD and increasing use of biologic therapies, heightened knowledge and awareness of infections in this population is important for primary care pediatricians, pediatric gastroenterologists, and infectious disease (ID) physicians. This clinical report is the result of a consensus review performed by pediatric ID and gastroenterology physicians detailing relevant published literature regarding infections in pediatric patients with IBD receiving anti-TNFα therapies. The objective of this document is to provide comprehensive information for prevention, surveillance, and diagnosis of infections based on current knowledge, until additional pediatric data are available to inform evidence-based recommendations.