Pitfalls in the differential diagnosis of diarrhea after kidney transplantation: challenges in identifying Yersinia enterocolitica infection

Abstract

We present the case of a 14-year-old boy with a history of kidney transplantation due to focal segmental glomerulosclerosis who developed severe diarrhea and abdominal pain following an episode of antibody-mediated rejection. Despite stable kidney function, the patient required increased immunosuppressive therapy, raising concerns regarding possible drug-induced enteritis or infections. Initial investigations, including stool tests for common pathogens and imaging, failed to identify the causative agent. Colonoscopy revealed thickening of the terminal ileum and aphthae in the colon; however, common infections, such as cytomegalovirus and Epstein–Barr virus, were excluded. Given the persistence of symptoms and worsening ultrasound findings showing enlarged lymph nodes and mucosal thickening, Yersinia enterocolitica infection was suspected. Special stool culture media for Yersinia spp. confirmed the infection, and the patient responded well to antibiotic therapy. Our case highlights several challenges in diagnosing gastrointestinal infections in kidney transplant recipients, including the non-specific nature of symptoms and the difficulty in distinguishing between drug-induced enteritis, viral or bacterial infections, and other transplant-related complications. This underscores the importance of considering rare pathogens, such as Yersinia, in the differential diagnosis of gastrointestinal symptoms in immunocompromised transplant patients, including pediatric patients, and emphasizes the need for specialized diagnostic techniques, such as stool culture on selective media, to confirm the diagnosis.

Introduction

Kidney transplantation is the preferred treatment for children with end-stage renal disease, as it substantially improves survival and quality of life. However, post-transplant complications, such as infections and gastrointestinal symptoms, are common due to the use of immunosuppressive therapies. Gastrointestinal symptoms, including diarrhea, are reported by 29–64% of patients within the first 3 years after transplantation [1]. Infectious diarrhea is particularly concerning, as it may lead to persistent symptoms and negatively impact kidney function due to dehydration and fluctuations in immunosuppressive drug levels [2].

Infections caused by Yersinia species are rare in kidney transplant recipients, particularly in pediatric patients. Yersinia enterocolitica is primarily known to cause mild gastroenteritis, especially in infants or older adults, with most cases being self-limiting [3, 4]. However, in immunocompromised individuals, the presentation may be more severe, thus prompt diagnosis and treatment are crucial [5].

To the best of our knowledge, we report the first case of Yersinia enterocolitica infection in a pediatric kidney transplant recipient. This case underscores the importance of considering rare infections, such as Yersinia, when evaluating gastrointestinal symptoms in immunosuppressed patients following kidney transplantation.

Case report

A 14-year-old boy with kidney failure due to focal segmental glomerulosclerosis underwent a living-donor kidney transplant at the age of 12 years. Pre-transplant immunologic tests revealed a negative complement-dependent lymphocytotoxicity crossmatch and a negative flow cytometry crossmatch for a blood type-compatible transplant. The LABScreen Single Antigen test detected anti-HLA antibodies, but no donor-specific HLA antibodies (DSA). The patient received four immunosuppressive drugs for induction, namely, tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab, and was maintained on two drugs: tacrolimus and mycophenolate mofetil. The baseline creatinine level was 0.6 mg/dL.

At 1 year and 5 months post-transplant, the patient’s baseline creatinine increased to 0.9 mg/dL, and he developed active antibody-mediated rejection. Renal pathology revealed mild interstitial inflammation, tubulitis, and C4d deposits in the peritubular capillaries, which led us to suspect rejection. In response, we increased the methylprednisolone dose from 2 to 4 mg/day and the tacrolimus hydrate dose from 3 to 4 mg/day.

Two weeks later, the patient was hospitalized with fever, diarrhea, and severe lower right abdominal pain. He resided a considerable distance from our hospital. However, a cooperating hospital in his area maintained close communication with us, and we monitored his condition through consultations and intravenous infusions at that facility when necessary. Due to persistent fever and diarrhea, the patient was subsequently admitted to our hospital for further evaluation.

On admission, his temperature was 38.6 °C and pulse rate was 88 bpm. There was no history of consuming pork, undercooked meat, or well water, which are associated with the onset of Yersinia gastroenteritis. Additionally, no family members exhibited similar symptoms of gastroenteritis. There were no physical findings such as arthritis or skin lesions. Laboratory examination results revealed a hemoglobin level of 12.3 g/dL and a leukocyte count of 12,400/μL. Kidney function test results showed a serum creatinine level of 1.2 mg/dL (estimated glomerular filtration rate of 60 mL/min/1.73 m², which was consistent with his usual levels) and a blood urea nitrogen level of 15 mg/dL. His C-reactive protein level was elevated at 2.42 mg/L. Ultrasonography revealed thickening of the terminal ileal wall and enlarged lymph nodes.

The results of the rapid stool antigen tests for rotavirus, adenovirus, and norovirus were negative, although the occult blood test result was positive. Stool cultures revealed the presence of Escherichia coli, Proteus mirabilis, and Enterococcus faecalis. Several potential causes of diarrhea were considered, including drug-induced diarrhea, viral or bacterial enteritis not detected by rapid antigen tests, cytomegalovirus (CMV) enteritis, post-transplant lymphoproliferative disorder due to Epstein–Barr virus (EBV), and inflammatory bowel disease (Table 1).

Table 1.

Comparison of this case with differential diseases

		Drugs	CMV	PTLD	IBD	Y. enterocolitica enteritis	This case
		(MMF)	Enteritis
Fever			+	+	++	+	Yes
Abdominal pain		–	+	+	++	++	Yes
Bloody stool		–	+	+	++	–	Yes
Location	Terminal ileum	++	++	++	+	++	Yes
	Right-side colon	–	+	++	+	+	Yes
	Sigmoid colon	–	+	+	+	–	No
	Rectum	–	+	–	+	–	No
Colonoscopy findings		+	+	+	++	+	Yes
		+	+	+	++	+	Yes
Pathological findings		IBD like	Giant cell with nuclear inclusion body	Proliferation of polyclonal lymphocytes without atypia	·Non-caseating epithelioid cell granuloma	·Lymphocyte and lymph follicle proliferation	Collection of lymphocytes in the mucosal intrinsic layer around the erosive ulcer site
					·Mucin granuloma	·Infiltration of neutrophils and eosinophils
Specific test		Improvement by reducing medications	·Tissue CMV-immunohistochemistry	·Tissue EBV-encoded small RNA in situ hybridization		Y. enterocolitica was detected in CIN agar medium	Y. enterocolitica was detected in CIN agar medium
			·Serum CMV antibody	·Serum EBV-polymerase chain reaction

The symbols indicate frequency as follows: occasionally: –, sometimes: +, generally: ++ [1–3]

MMF: mycophenolate mofetil, CMV: cytomegalovirus, PTLD: post-transplant lymphoproliferative disorder, IBD: inflammatory bowel disease, Y. enterocolitica: Yersinia enterocolitica, EBV: Epstein–Barr virus, CIN: cefsulodin-irgasan-novobiocin

Based on this differential diagnosis, we decided to reduce the dosage of immunosuppressive drugs; however, the diarrhea persisted. Ultrasonography failed to identify a clear cause of diarrhea, prompting further investigation through colonoscopy. Colonoscopy revealed thickening of the terminal ileum and aphthae throughout the colon (Fig. 1a), as well as a map ulcer in the terminal ileum (Fig. 1b). Given the lack of improvement in enteritis after reducing the immunosuppressive drug dosage and colonoscopy findings, drug-induced diarrhea was ruled out. We administered ganciclovir as a diagnostic treatment; however, fever and diarrhea persisted. Further testing for CMV enteritis (serum CMV antigenemia and tissue CMV immunohistochemistry) and EBV enteritis (serum EBV polymerase chain reaction and tissue EBV-encoded small RNA in situ hybridization) returned negative results, leaving the cause of diarrhea undetermined.

Fig. 1.

Colonoscopy (a, b) and ultrasonography findings (c, d) of the terminal ileum. a Aphthae throughout the colon (arrow). b Map of ulcer (arrow). c Thickening of the terminal wall of the ileum (arrow) and the mucosal ulcer (arrowhead). d Lymph node enlargement (arrow)

Repeat ultrasonography showed worsening terminal ileum thickening (Fig. 1c) and considerable lymph node enlargement (Fig. 1d) compared to the previous examination. Based on these findings, we suspected Yersinia enterocolitica infection. Specialized stool culture using a medium designed for Yersinia species confirmed the diagnosis of Yersinia enterocolitica infection. By the time stool culture results were available, the patient’s diarrhea had decreased to 3–4 episodes per day, his fever had resolved, and his CRP levels were decreasing. The patient was treated with 1 g of ceftazidime hydrate (CAZ); the patient’s body weight was 35 kg, and the standard dose of ceftazidime per body weight was 85 mg/kg per day, intravenously daily for 1 week, leading to resolution of the Yersinia enterocolitica infection and prevention of recurrence. The diarrhea disappeared, CRP levels normalized, and there was no recurrence of diarrhea or fever after discontinuation of CAZ (Fig. 2).

Fig. 2.

Clinical course of the patient. TAC: tacrolimus, MMF: mycophenolate mofetil, m-PSL: methylprednisolone, CAZ: ceftazidime hydrate, CRP: C-reactive protein

Discussion

Although Yersinia enterocolitis has been reported in adult kidney transplant recipients [4, 5], to the best of our knowledge, this is the first documented case of Yersinia enterocolitis occurring after kidney transplantation in a pediatric patient. As previously noted, gastrointestinal symptoms are common following kidney transplantation [1]. In particular, infectious diarrhea carries a heightened risk of persistent symptoms and may impair kidney function due to dehydration and fluctuations in blood levels of immunosuppressive drugs, making prompt treatment essential [2]. In our patient, severe diarrhea persisted for 2 weeks despite stable kidney function, possibly due to timely intravenous fluid administration and close monitoring of immunosuppressive drug levels.

This case highlights several challenges in identifying the origin of gastroenteritis in pediatric kidney transplant recipients. First, diarrhea in this patient population can arise from a variety of causes (Table 1), including drug-induced enteritis from medications such as mammalian target of rapamycin inhibitors or mycophenolate mofetil [3], viral or bacterial enteritis, post-transplant lymphoproliferative disorder, and inflammatory bowel disease. Reports indicate that Yersinia species account for only 2–3% of diarrhea cases in kidney transplant recipients [1, 6]. In this case, the immunosuppressive drug dosage was initially reduced in response to concerns about potential drug-induced enteritis and the risk of infection due to the patient’s immunocompromised state; however, the patient’s symptoms persisted. While we attempted to rule out more common causes of post-transplant diarrhea, the diagnosis was complicated by the lack of specific characteristic findings during the initial testing.

Second, the clinical presentation in this case deviated from the typical course of Yersinia enterocolitis, an intestinal infection caused by Yersinia enterocolitica or Yersinia pseudotuberculosis [7]. Yersinia enterocolitis typically manifests as mild symptoms and often resolves spontaneously following antibiotic treatment. Severe cases are rare and generally occur in infants or older adults [8]. Our patient exhibited severe symptoms that were likely exacerbated by immunosuppressive therapy.

Third, the initial routine blood and stool tests failed to provide any positive findings indicative of Yersinia infection. The suspicion of Yersinia infection was initially low because of its infrequent association with diarrhea in kidney transplant recipients and the absence of a typical food poisoning history. Thus, routine stool culture and rapid stool antigen tests were performed. Unlike other enteritis-causing bacteria, Yersinia species require specialized isolation media, such as cefsulodin-irgasan-novobiocin agar, and thrive at lower temperatures [9]. Testing using a specialized medium is essential when Yersinia infection is suspected, and antibiotic treatment prior to pathogen identification can make diagnosis difficult.

Ultimately, we were able to make a diagnosis after repeating the diagnostic tests and considering the evolving clinical picture. Although the initial ultrasonography findings did not raise suspicion of Yersinia infection, repeat imaging showed substantial lymph node enlargement in the terminal ileum and thickening of the intestinal wall, prompting us to perform a specialized stool test, which confirmed the presence of Yersinia infection. This case underlines the need for clinicians to consider multiple potential causes of diarrhea in kidney transplant recipients, as each potential cause can present with non-specific symptoms. Imaging and pathological results can be inconclusive, necessitating further differential diagnoses. Differential diagnosis of Yersinia enterocolitica infections should be considered in cases of persistent gastrointestinal symptoms following kidney transplantation, even in pediatric patients.

Authors' contributions

Conceptualization: TO, TT, YS, and YU; Writing—original draft preparation: AH; Writing—review analysis: TO. All authors read and approved the final manuscript.

Funding

Not applicable.

Availability of data and material

Data sharing is not applicable to this article as no datasets were generated or analyzed.

Declarations

Conflict of interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This work was performed in line with the principles of the 1964 Declaration of Helsinki and its later amendments.

Consent to participate

Informed consent was obtained from the patient’s parents.

Consent for publication

The patient’s parents provided informed consent for the publication of the case report and any accompanying images.