Intestinal amoebiasis and pediatric inflammatory bowel disease in an endemic region: Three case reports

Abstract

BACKGROUND

Differentiating superadded amoebic colitis (AC) from a disease flare in children with ulcerative colitis (UC) is challenging, particularly in endemic regions, yet remains crucial for guiding appropriate therapy and preventing adverse outcomes.

CASE SUMMARY

We report three children with UC and intestinal amoebiasis; two presenting as disease exacerbation and one with first presentation as acute severe colitis (ASC), highlighting key diagnostic and therapeutic dilemmas. Two children with UC, previously in clinical remission on maintenance therapy, presented with abdominal pain and bloody diarrhea; one had fever of short duration. A provisional diagnosis of disease flare was made in both. The third case presented for the first time as ASC, was treated outside with corticosteroids and referred due to non-response. Stool microscopy identified amoebic trophozoites with haemophagocytosis, consistent with Entamoeba histolytica in all. Initial anti-amoebic therapy with metronidazole resulted in transient clinical improvement; however, each patient subsequently required escalation of immunosuppression for symptom control. Our cases suggest the co-existence of AC over active UC at the same time.

CONCLUSION

Amoebiasis screening in endemic regions is helpful in flare of UC to avoid misdiagnosis and inappropriate escalation of immunosuppressive therapy.

Key Words: Amoebic colitis; Ulcerative colitis; Inflammatory bowel disease; Entamoeba histolytica; Amoebiasis; Immunosuppressive therapy; Case report

Core Tip: Amoebic colitis (AC) can closely mimic ulcerative colitis (UC) activity, particularly in regions where amoebiasis is endemic. Failure to recognize this infection may lead to inappropriate escalation of immunosuppressive therapy and worsening disease. Through this case series of three children with UC, presenting with concomitant AC, we highlight the diagnostic challenges and emphasize the importance of evaluation for infectious etiologies in inflammatory bowel disease flare before intensifying immunosuppressive treatment.

INTRODUCTION

Intestinal infections play an important role in inflammatory bowel disease (IBD), as they can mimic IBD at initial presentation and also precipitate disease flares, particularly in immunosuppressed patients[1]. Gastrointestinal infections are implicated in 20% of disease flares in IBD patients and amoebiasis is one of the incriminated causes[2,3]. Entamoeba histolytica (E. histolytica) is of particular importance, as amoebic colitis (AC) if unrecognized or inadequately treated, can result in severe complications[4]. Amoebiasis is a problem not only in endemic areas, like India, but also in the developed world related to increase in global travel and migration[5].

Chan et al[6] have described three possible patterns of association between amoebiasis and ulcerative colitis (UC): (1) AC mimicking UC; (2) Superimposed amoebic infection on established UC; mimicking disease flare; and (3) Asymptomatic carriage in UC patients[6]. Given the significant overlap in clinical presentation, distinguishing superadded infection from a UC flare remains challenging[7].

Differentiation of these two entities and correct diagnosis is important because misdiagnosing the episode as a disease flare and adding corticosteroid or biologics can complicate underlying intestinal amoebiasis[4,8]. While incorrectly prolonging therapy for presumed infections can delay the treatment of active UC and is again detrimental[9,10]. Furthermore, rational antibiotic usage is important in IBD as perturbation of gut microbiota, including that caused by antibiotics, may trigger an IBD flare[11].

Although amoebiasis is endemic in our region, symptomatic cases of AC either in isolation or in children with IBD are seen infrequently (unpublished data). This apparent infrequency may, in part, reflect diagnostic limitations, as stool microscopy often the most readily available test in endemic settings, has poor sensitivity and may underestimate true coexistence[12]. These uncommon, but clinically relevant cases posed important diagnostic and therapeutic challenges for us, particularly in differentiating infection-related symptoms from true disease activity and in determining the appropriate timing of escalation of immunosuppressive therapy. However, pediatric data regarding the coexistence of AC and UC remains extremely limited, with no clear guidance regarding diagnostic evaluation or timing of therapy escalation in such situations. Through this case series, we aim to highlight the diagnostic uncertainty, therapeutic sequencing challenges, and practical management considerations encountered in real-world clinical practice.

CASE PRESENTATION

Chief complaints

Case 1: Worsening gastrointestinal symptoms in follow up case of UC.

Case 2: Worsening gastrointestinal symptoms suggestive of UC flare.

Case 3: Bloody diarrhea for 3 months.

History of present illness

Case 1: A 14-year-old boy with UC presented with worsening gastrointestinal symptoms suggestive of disease flare. He had pancolitis and had remained in sustained remission for two years on azathioprine and infliximab therapy. At presentation, the pediatric UC activity index (PUCAI) score was 50.

Case 2: An 18-year-old girl, a follow up case of steroid-dependent UC, presented with worsening gastrointestinal symptoms suggestive of disease flare. At presentation, the PUCAI score was 60.

Case 3: A 12-year-old girl presented with bloody diarrhea of three months duration and was experiencing her first episode of acute severe colitis (ASC). Initial treatment with intravenous methylprednisolone at an outside facility resulted in minimal clinical improvement. On referral, the PUCAI score was 60, and corticosteroids were continued while diagnostic evaluation was completed.

History of past illness

Case 1: The child had been diagnosed with very early onset IBD (UC phenotype) at 2 years of age and was on azathioprine and infliximab maintenance therapy.

Case 2: She had been diagnosed with UC two years back and was receiving azathioprine and 5-aminosalicylate therapy. She had steroid-dependent disease.

Case 3: She had no prior gastrointestinal symptoms and was experiencing her first episode of ASC.

Personal and family history

Cases 1, 2, and 3: No significant family history was present.

Physical examination

Case 1: General physical and systemic examination findings were unremarkable.

Case 2: Clinical examination findings were unremarkable.

Case 3: Clinical examination was unremarkable except for moderate pallor.

Laboratory examinations

Case 1: Stool microscopy performed on three consecutive days fresh stool samples using concentration techniques demonstrated trophozoites of E. histolytica containing phagocytosed red blood cells. Testing for Clostridium difficile toxin and cytomegalovirus (CMV) were negative. Stool polymerase chain reaction (PCR), and antigen-based assays for E. histolytica were unavailable at our center.

Case 2: Stool microscopy demonstrated trophozoites of E. histolytica, while the remainder of the infectious work-up was negative.

Case 3: Laboratory investigations revealed elevated inflammatory markers, including C-reactive protein of 55 mg/L, hemoglobin 9.5 g/dL, erythrocyte sedimentation rate of 56 mm/hour and hypoalbuminemia (albumin 2.9 g/dL). Infectious work-up demonstrated intestinal amoebiasis with stool microscopy revealing trophozoites of E. histolytica. CMV infection was detected on rectal biopsy tissue, with CMV PCR of 21000 copies/mg tissue, while immunohistochemistry (IHC) was negative.

Imaging examinations

Case 1: Short colonoscopy findings were consistent with active UC.

Case 2: Short colonoscopy revealed active left-sided colitis with a Mayo endoscopic score of 3.

Case 3: Proctosigmoidoscopy showed continuous superficial ulcers with Mayo grade 3 disease.

FINAL DIAGNOSIS

Case 1

A diagnosis of UC flare with concomitant intestinal amoebiasis was made.

Case 2

A diagnosis of intestinal amoebiasis with concurrent UC flare was made.

Case 3

A diagnosis of ASC with concomitant intestinal amoebiasis and CMV infection was made.

TREATMENT

Case 1

The patient received anti-amoebic therapy with metronidazole followed by diloxanide furoate. Due to only transient partial improvement and subsequent worsening of symptoms, escalation of UC-directed therapy was required with a short course of systemic corticosteroids along with scheduled infliximab therapy.

Case 2

The patient received anti-amoebic therapy with subsequent microbiological clearance. However, gastrointestinal symptoms persisted despite eradication of infection, necessitating escalation of IBD therapy from azathioprine to tofacitinib.

Case 3

The parents were counselled regarding disease severity and available treatment options. They refused surgery and required some time for arranging finances for biologics. She was given metronidazole and intravenous ganciclovir, while corticosteroids were continued under close monitoring. Despite one week of steroid, she showed only mild response, with a PUCAI score of 45. Hence, induction therapy with infliximab was given (Supplementary material).

OUTCOME AND FOLLOW-UP

Case 1

Following anti-amoebic therapy, stool microscopy became negative. However, clinical improvement was only transient, with PUCAI decreasing from 50 to 40 followed by worsening to 60. After escalation of UC therapy, the patient improved and continued on azathioprine and infliximab, remaining in clinical remission for the subsequent 8 months.

Case 2

Despite successful clearance of amoebic infection, symptoms persisted due to ongoing active UC, requiring escalation to tofacitinib therapy. Child is in clinical and biochemical remission for last 4 months.

Case 3

After one week of corticosteroid therapy, the patient showed only mild response with persistent disease activity. Following induction with infliximab, she improved clinically and was discharged with a PUCAI score of 15.

DISCUSSION

Our three cases highlight the dilemma of managing children with UC and concomitant enteric infections like amoebiasis. The clinical presentation of intestinal amoebiasis is variable; from asymptomatic to colitis, particularly in immunosuppressed patients[8]. In endemic regions, coexistent E. histolytica infection can mimic or exacerbate IBD flares, posing management dilemmas[7,8]. Studies from Indian pediatric and mixed-age cohorts, report asymptomatic amoebiasis carriage rates of 3%-23%, and symptomatic infection ranging from 5%-12% in children[13] and 0.64%-11% in general population, underscoring the substantial endemic burden[14]. Even in developed world, intestinal amoebiasis has been seen in the setting of increasing global travel and migration, and in homosexual men[5]. This highlights the need of awareness of parasitic colitis among medical practitioners across the world. The British Society of Gastroenterology guidelines for adults with IBD, state that stool microscopy for E. Histolytica should be done in subjects with a “relevant travel history”[15].

Differentiating AC from a UC flare is complicated due to overlapping clinical, endoscopic and histological features[16]. Stool microscopy (three consecutive samples) for trophozoites, although widely used in endemic settings, has poor sensitivity[12]. Stool microscopy was performed on multiple stool samples using standard wet mount examination and concentration techniques for our cases.

Microscopic examination of stool may not differentiate between pathogenic (E. histolytica) and nonpathogenic entamoeba (Entamoeba dispar), except when erythrocytes are seen in the trophozoites[17]. This is a unique feature of E. histolytica[17], and was seen in all our cases. Stool PCR offers higher sensitivity and the ability to detect multiple enteric pathogens; however, its use is constrained by cost and availability particularly in resource-limited settings[18]. The stool antigen test detects specific proteins using enzyme-linked immunosorbent assay or a rapid chromatographic immunoassay for antigens released by E. histolytica specifically, rather than nonpathogenic Entamoeba dispar. Stool PCR and antigen-based assays could not be done as the tests were not available at our center during the evaluation period.

Amoebic serology does not reliably distinguish active infection from past exposure and is therefore of limited utility in endemic areas[18]. Colonoscopy in AC classically shows multiple discrete or punctate ulcers/erosions with or without exudates, with normal mucosa in-between. The most common site of involvement is caecum and ascending colon followed by rectum, in contrast to the continuous mucosal involvement starting from rectum, typically seen in UC[18,19]. Other described features such as mucosal bump sign (in about 5%) and ameboma (in < 5%) are uncommon and may not be consistently observed[18]. Importantly, these endoscopic features have limited diagnostic utility, when AC occurs over pre-existing UC. Identification of amoebic trophozoites on colonic biopsy is highly suggestive of invasive amoebiasis; however, their absence does not exclude AC[16,18,19].

A high index of suspicion is essential in endemic settings, especially when the UC patients fail to respond to standard therapy. Misdiagnosis as disease flare can lead to inappropriate prescription of steroids and biologics and worsening amoebic infection[4]. Published reports highlight that protozoal infections may sustain inflammation in UC and that empirical anti-amoebic therapy may be reasonable in selected severe cases while awaiting microbiological confirmation, provided close clinical reassessment is ensured[16]. But this cannot be recommended in all cases, as antibiotics including metronidazole have been shown to increase the risk of flare, secondary to alteration of gut microbiota[11]. Therefore, judicious and responsible use of antibiotics is recommended in this population.

Metronidazole (30-50 mg/kg/day in 3-4 divided doses for 5-10 days) is a tissue amoebicide, and is the most widely used agent for invasive amoebiasis[19,20]. However, tinidazole had greater efficacy with fewer adverse events in a Cochrane review[20]. This should be followed by a luminal agent like diloxanide furoate (20 mg/kg/day in two divided doses for 7-10 days) or paromomycin for eradication of luminal cysts and preventing relapse[18]. All three patients in our series received complete anti-amoebic therapy with documented microbiological clearance, yet exhibited only partial clinical response. This, supported the notion that the persistent symptoms following adequate anti-amebic treatment were more likely attributable to underlying UC activity rather than ongoing infection, warranting escalation of UC therapy. Two of our cases (case 2 and 3) required initiation of biologics or small molecule drug for disease control (infliximab-1, tofacitinib-1) while the third child (case 1) responded to a course of corticosteroids with continuation of infliximab. This suggests that perhaps the symptoms, were both due to underlying active UC and superadded amoebiasis, as the patients responded only after eradication of amoebiasis and escalation of immunosuppressive therapy.

This highlights the clinical challenge of distinguishing active UC from symptoms attributable to concurrent E. histolytica infection, particularly in endemic settings where diagnostic tools have inherent limitations.

This raises the clinically relevant question of the optimal interval to assess response following anti-amoebic therapy in children with underlying UC. Our patients were reassessed after completion of metronidazole therapy, and immunosuppressive escalations was undertaken after approximately five days due to persistent symptoms. This approach is consistent with available literature suggesting that symptomatic improvement in invasive amoebiasis typically occurs in 2-5 days of initiating appropriate anti-amoebic treatment[21]. Prolonged deferral of IBD-directed therapy in the absence of clinical response may result in ongoing inflammation, increased disease severity, and a higher risk of colectomy. Therefore, a balanced pragmatic approach incorporating close clinical and laboratory monitoring, rather than fixed treatment timelines, appears most appropriate (Figure 1 and Table 1).

Figure 1 Clinical timeline of three patients with ulcerative colitis showing disease course, detection of Entamoeba histolytica and cytomegalovirus (case 3), and corresponding immunosuppressive and antimicrobial treatment. ASC: Acute severe colitis; VEO: Very early onset; IBD: Inflammatory bowel disease.

Table 1 Clinical profile, therapeutic decisions and timeline of response in the three cases.

Timeline/event	Case 1	Case 2	Case 3
Age at diagnosis	2 years	16 years	12 years
Current diagnosis	Follow up case of VEOIBD (UC) with flare	Follow up case of UC (steroid dependent) with flare	ASC
Prior immunosuppression	Azathioprine and infliximab	Azathioprine and 5-aminosalicylate	Intravenous corticosteroid (methylprednisolone)
Duration of disease	12 years	2 years	3 months
Stool microscopy findings	Trophozoites of E. histolytica	Trophozoites of E. histolytica	Trophozoites of E. histolytica
CMV status	Negative	Negative	CMV PCR (colonic biopsy-21000 copies/mg of tissue IHC negative
Anti-amoebic therapy	Metronidazole followed by diloxanide furoate	Metronidazole followed by diloxanide furoate	Metronidazole followed by diloxanide furoate
PUCAI at baseline	50	60	60
Duration in days before reassessment	3	5	7
PUCAI at reassessment	Improved to 40 then worsened 60	50	45
Reason for escalation of UC therapy	Worsening PUCAI	Suboptimal response	Suboptimal response
Escalation therapy given	Steroid short course, and scheduled dose of infliximab	Tofacitinib	Infliximab, gancylovir concomitant for CMV
Clinical response (PUCAI at discharge)	Yes, PUCAI 10	Yes, PUCAI 20	Yes, PUCAI 15
Follow-up outcome	In clinical remission	In clinical remission	In clinical remission

VEOIBD: Very early onset inflammatory bowel disease; UC: Ulcerative colitis; ASC: Acute severe colitis; E. histolytica: Entamoeba histolytica; CMV: Cytomegalovirus; PCR: Polymerase chain reaction; IHC: Immunohistochemistry; PUCAI: Pediatric ulcerative colitis activity index.

A related unsolved issue is whether ongoing IBD therapy, including immunomodulators or biologics should be withheld or delayed during anti-amebic therapy in children presenting with worsening of symptoms and invasive amoebiasis. We could not find any recommendation in literature regarding this.

A population-based study from Bosnia and Herzegovina reported a higher prevalence of AC among IBD patients compared with general population (16% vs 1.7%) suggesting an increased susceptibility in this group[22]. In our series, all three children were receiving immune-suppressive therapy at presentation, including biologic (n = 1), immunomodulators (n = 2) and systemic corticosteroid (n = 1), which may have contributed to an increased risk of acquiring opportunistic infections including amoebiasis[21]. Further, genome wide association studies suggest a genetic link between IBD and E. histolytica diarrhea. Genetic variants in the cAMP responsive element modulator locus are associated with E. histolytica diarrhea and the same has been implicated as a susceptibility locus for IBD[23]. Together, these factors may partly explain the increased risk of E. histolytica infection or colonization observed in IBD patients.

Our third case highlights the diagnostic and therapeutic complexity associated with multiple concurrent enteric infections at the onset of severe UC. This girl had amoebic trophozoites in stool microscopy and high CMV-PCR (> 250 copies/mg) on colonic biopsy, with no response to corticosteroids administered outside. She had features of severe disease, including anemia (hemoglobin 9.5 g/dL) and hypoalbuminemia (albumin 2.9 g/dL) reflecting a high inflammatory burden.

It is arguable that anti-CMV therapy may not have been mandatory in the absence of cytopathic changes on biopsy with negative CMV IHC. CMV detection by PCR alone may represent viral reactivation secondary to severe mucosal inflammation, particularly in patients exposed to corticosteroids, rather than true CMV driven disease[24]. However, in the setting of a sick patient with severe colitis, prior steroid exposure with no-response and high colonic tissue CMV burden, antiviral therapy was initiated along with anti-amebic treatment after multidisciplinary discussion. This reflects the ongoing controversy regarding indications of CMV treatment in patients with UC and the need for individualized management rather than reliance on a single diagnostic modality[25]. One could argue, that we could have stopped the steroids and given only ganciclovir and metronidazole therapy. However, we decided to complete the steroid therapy while simultaneously treating the infections and observing her closely for response/worsening. In the developing world, initiating infliximab requires time, both for arranging finances and excluding tuberculosis which further delays the management with biologics.

As this child received simultaneous treatment with anti-amoebic, antiviral, corticosteroids and subsequent biologics, the relative contribution of amoebiasis towards the symptoms and anti-amoebic therapy to the clinical response cannot be ascertained. Anti-amoebic therapy in this setting can be best interpreted as a practical therapeutic decision in a patient with severe colitis and suggestive infectious findings.

This case series has certain limitations. In our patients, endoscopic evaluation was limited to proctosigmoidoscopy because of disease severity. Although full colonoscopy may aid in defining disease distribution, endoscopic appearance alone cannot reliably differentiate AC from UC, as amoebic infection- particularly in severe presentations-may show diffuse, continuous involvement including the rectosigmoid colon and closely mimic UC. Therefore, in such settings, microbiological and histopathological findings are more informative than the extent of endoscopic involvement. However, in the setting of established UC, superimposed infection often obscures these distinguishing features, limiting the incremental diagnostic value of full colonoscopy.

Prevention is better than cure and our cases highlight the utility of educating our IBD children regarding safe water practices, sanitation and hand hygiene to prevent enteric infections including amoebiasis. Preventing enteric infections, assumes even greater importance as the 2-year IBD outcome (composite of steroid-dependent IBD, colectomy, and/or IBD therapy class change/dose escalation) following flare with enteric infections was worse than flare without enteric infection, specifically Clostridium difficile infection[26]. Whether this hold true for E. histolytica also requires further investigation.

CONCLUSION

Our small case series highlights that a practical, context- specific management approach is the best for children from endemic areas presenting with disease flare or first episode of UC. Concomitant amoebiasis should be considered and administration of two step anti-amoebic therapy in those with confirmed infection along with close clinical follow-up is suggested. Persistence of symptoms despite microbiological clearance should prompt reassessment for active UC and timely escalation of disease- directed therapy.