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Superimposed infections in inflammatory bowel diseases
Abbreviations
Crohn’s disease Clostridioides difficile infection Campylobacter jejuni infection cytomegalovirus Epstein–Barr virus hematoxylin and eosin human papillomavirus herpes simplex virus gastrointestinal inflammatory bowel disease ileocecal valve intestinal tuberculosis tuberculosis tumor necrosis factor ulcerative colitis CD
CDI
CJI
CMV
EBV
H & E
HPV
HSV
GI
IBD
ICV
ITB
TB
TNF
UC
Introduction
Crohn’s disease (CD) and ulcerative colitis (UC) are the two most common forms of immune-mediated chronic inflammatory bowel diseases (IBD). The disease course of IBD is characterized by relapsing or persistent inflammation. Disease flare-up may reflect intrinsic natural disease course or triggered by superimposed or opportunistic infections.
Gut microbiota plays an important role in the pathogenesis and disease progression of IBD mainly in the form of dysbiosis or alteration in gut commensal bacteria or fungi. On the other hand, dysbiosis may promote superimposed infections either by opportunistic or acute extrinsic pathogens. Furthermore, immunomodulator and biological therapies help to subside inflammation and attain remission in IBD. However, these therapies could impair the immune system and make IBD patients prone to superimposed infections. Patients’ general health and nutritional status, and underlying disease, along with the use of immunosuppressive medications predispose them to infections of opportunistic or extraneous pathogens. Commonly used immunosuppressive agents include corticosteroids, immunomodulators (such as purine analogs and methotrexate), anti–tumor necrosis factor (anti-TNF), antiintegrin, and antiinterleukin agents, and Janus kinase inhibitors. The severity of the complications secondary to infections in IBD patients depends upon geographic location, age, nutritional status, comorbidities, complexity of IBD, degree of immunosuppression. Overall, a multidisciplinary approach is often required to manage superimposed infections in IBD, consisting of IBD specialists, infectious disease specialists, pathologists, and colorectal surgeons. The managing clinician should remain vigilant to infectious etiology of disease flare-up. In addition to the evaluation of clinical presentation, imaging, and laboratory tests, endoscopy with the ability of aspiration of luminal contents and tissue biopsy plays a key role in the identification of pathogens and diagnosis. Some superimposed infections may present with characteristic endoscopic features. The identification of infectious causes of disease flare-up or refractoriness to conventional immunosuppressive therapy makes proper medical treatment possible, which alter the disease course, in some case, avoid unnecessary escalation of immunosuppressive therapy or surgery.
Superimposed infections in IBD harbor a wide spectrum of etiologies including bacterial, viral, fungal, or parasitic infections ( Table 23.1 ) . These infections are more likely limited to the gut but also could manifest systemic or extraintestinal complications, leading to significant morbidities .
Table 23.1
Common microbiological agents associated with superimposed infection in inflammatory bowel disease.
| Etiology | Pathogens |
|---|---|
| Bacterial |
|
| Viral |
|
| Fungal |
|
| Parasitic |
|
Bacterial infections
Infections of Clostridium (also known as Clostridioides ) difficile, Campylobacter sp. (spp.), and Mycobacterium tuberculosis are frequently encountered in IBD patients. Other agents include Campylobacter , Salmonella , Shigella , and Escherichia coli O157:H7, Yersinia , Aeromonas species, and Plesiomonas . These bacterial infections may contribute to pathogenesis or exacerbation of IBD. Endoscopic features of the bacterial infections may be different from that in IBD patients. It is critical to distinguish superimposed bacterial infections in IBDfrom flare-up of IBD. However, the distinction is sometimes difficult. Stool culture or even gene-based multipathogen panel should be obtained. In addition, flexible sigmoidoscopy or ileocolonoscopy may be performed.
Clostridioides difficile
C. difficile , a Gram-positive, anaerobic, spore-forming bacillus, is a common pathogen identified during flare-ups of CD, UC , pouchitis , or enteritis (in patients with ileostomies) ( Figs. 23.1–23.3 ) . C. difficile infection (CDI) was reported that nearly 10% of the IBD patients would develop CDI and approximately 40% of them did not have prior exposure to antibiotics . In addition, the incidence of CDI may be gradually increasing in IBD patients . Concerns exist on relapse or refractoriness of CDI after medical therapy .
C. difficile can exist in the gut as asymptomatic colonization in favorable conditions the pathogen may induce mild-to-severe diarrhea, or even toxic megacolon. Interestingly, clinical symptoms of acute IBD flare and CDI can plausibly overlap; therefore the existence of both in any severity prompts precise diagnosis and effective management to avoid the adverse outcomes . As severity of clinical presentations and laboratory tests do not necessarily correlate, endoscopic assessment of mucosal inflammation is often required. However, endoscopic features of CDI in IBD can range from completely normal mucosa to severe or fulminant colitis or enteritis. Classic pseudomembranes of CDI in non-IBD patients is often absent on ileoscopy or colonoscopy in IBD patients ( Fig. 23.1 ) . On the other hand, pseudomembrane may be present in IBD without CDI ( Fig. 23.2 ). Notably, CDI is not limited to the colon. In patients with colectomy or ileostomy, CDI can be presented as pouchitis ( Fig. 23.2 ) or enteritis ( Fig. 23.3 ) .
Campylobacter spp
Campylobacter is a nonspore forming, Gram-negative, helical-shaped bacillus. Campylobacter jejuni infection (CJI) is the most commonly found foodborne infections in the United States. Uncontrolled CJI can lead to Guillain–Barré syndrome and reactive arthritis. In addition, CJI is one of the enteropathogenic infections in UC patients, which can mimic or exacerbate UC . Patients with CJI are often present with fever and leukocytosis. The diagnosis of CJI is mainly based on stool tests. Colonoscopy findings of CJI in IBD patients appear to be nonspecific. Patients with CJI and UC may have worse clinical outcomes than UC patients without CJI. However, it is not clear whether the eradication of this superimposed infection with oral erythromycin or azithromycin can lead to improved outcomes of underlying IBD.
Mycobacterium spp
Globally, there is a great concern over morbidity and mortality from tuberculosis (TB). M. tuberculosis is considered as a pathogenic bacterium responsible for causing active TB or latent TB infection. Overlap of endoscopic, histologic, and imaging features exists between CD and intestinal tuberculosis (ITB) ( Chapter 25 ). Both granulomatous diseases have a predilection toward the involvement of the ileocecal valve (ICV) and terminal ileum . It was reported that the gut could be the sixth most common site of extrapulmonary spread in patients with latent TB . Clinically ITB could lead to stricture, fistula, intestinal perforation, abscess, and ascites .
The distinction between CD and ITB is critical, as clinical management is different. Endoscopy and histology along with microbiological workup play a key role in the distinction . Their distinguishing features are listed in Table 25-2 . CD is characterized by longitudinal ulcers along the edge of the mesentery and deformed or strictured ICV, while ITB is featured with circumferential ulcers and patent or nodular ICV .
On the other hand, CD and latent TB may coexist, suggesting that latent TB may be a part of etiopathogenesis of CD. This notion has been supported by the fact that Mycobacteria are isolated from intestinal mucosal specimens in IBD patients as well as non-IBD immunocompromised patients . A recent study from South Korea showed a higher incidence of TB in IBD patients treated with TNF inhibitors than the general population regardless of their latent TB status at baseline . Superimposed ITB infection can potentially lead to IBD flare.
Other enteric bacterial pathogens
Enteric gut flora including Enterobacteriaceae is implicated in the pathogenesis and disease flare-up of IBD. Superimposed infections by Salmonella , Enterococcus faecalis , enterovirulent E. coli , adherent invasive E. coli , Aeromonas spp. , and Clostridium perfringens may trigger disease exacerbation of IBD ( Fig. 23.4 ).
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