Severe Enteritis after Cyclophosphamide Administration in a Patient with Microscopic Polyangiitis: A Case Report and Literature Review

Abstract

Severe enteritis is a rare side effect of cyclophosphamide (CPA) therapy, and only two cases have been reported to date. We herein report a 60-year-old man who developed severe enteritis after intravenous CPA administration for microscopic polyangiitis. He was successfully treated by discontinuation of CPA administration and long-term intensive supportive care. A diagnosis of CPA-associated enteritis was made based on the clinical course and imaging and pathological findings. This review of three cases of CPA-related enteritis, including our case, suggests that prompt CPA discontinuation and intensive systemic management are necessary when patients have gastrointestinal symptoms after CPA administration.

Introduction

Cyclophosphamide (CPA) is an alkylating agent with cytotoxic and immunosuppressive properties. It is frequently used to treat various inflammatory and malignant conditions, either as a sole agent or in combination with chemotherapeutic drugs or glucocorticoids. Toxicities associated with cyclophosphamide are well described. Significant adverse effects include dose-related leukopenia, hemorrhagic cystitis, infertility, carcinogenesis, and interstitial pneumonia (1,2). However, CPA-associated severe enteritis is extremely rare, with only two reported cases in the literature (3,4).

We herein report a 60-year-old man with microscopic polyangiitis (MPA) who presented with severe enteritis after CPA administration. The patient was successfully treated via the discontinuation of CPA and receipt of intensive supportive therapy.

Case Report

A 60-year-old man was admitted to a local hospital with respiratory distress and severe pleural effusion on computed tomography (CT). His medical history was unremarkable, and he had a 40-year history of smoking 20 cigarettes a day (since 20 years old). Based on an elevated serum myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) titer (94.7 EU; normal value: 0-3.5), interstitial pneumonia, and acute renal failure accompanied by proteinuria and hematuria, the patient was diagnosed with rapidly progressive glomerulonephritis due to MPA. He was treated with intravenous glucocorticoid pulse therapy and hemodialysis in the intensive-care unit. After steroid treatment, his respiratory condition improved, and his interstitial pneumonia was alleviated.

Intravenous CPA (500 mg) was administered as an additional treatment for MPA; however, the day after CPA administration, the patient presented with abdominal pain and hematochezia. Initially, ischemic enteritis was suspected, and supportive care was provided. However, no improvement was observed, and the patient was transferred to our department for further treatment.

On admission, his weight, height, and body mass index were 72.6 kg, 164 cm, and 26.9 kg/m², respectively. A physical examination revealed a flat, soft abdomen with slight hyperintestinal peristalsis. Laboratory examination data are presented in Table 1. A complete blood count showed mild anemia, a high MPO-ANCA titer (82 U/mL), and an elevated C-reactive protein (CRP) level (0.75 mg/dL). A urinalysis revealed proteinuria (3+), occult urine blood (2+), and red and white blood cells in the urinary sediment. Chest CT showed slight interstitial pneumonia at the bottom of the lung fields, and contrast-enhanced abdominal CT showed extensive wall thickening in the small and large intestines (Fig. 1A, B). After hospitalization, colonoscopy was performed, which showed severe mucosal edema from the ileum to the rectum with redness and erosion (Fig. 1C, D).

Table 1.

Laboratory Findings on Admission of a Patient with CPA-Associated Enteritis.

Peripheral blood					Serological tests
Red blood cells		3.37×106	/μL (3.86-4.92)		C-reactive protein		0.75	mg/dL (<0.30)
Hemoglobin		10.7	g/dL (11.6-14.8)		Ferritin		608	ng/mL (50-200)
Hematocrit		32	% (35.1-44.4)		IgG		652	mg/dL (870-1,700)
Platelet		21.6×104	/μL (15.8-34.8)		IgA		89	mg/dL (93-393)
White blood cells		5.0×103	/μL (3.3-8.6)		IgM		19	mg/dL (33-183)
Neutrophil		83	% (44-74)		C3		81	mg/dL (73-138)
Eosinophil		0	% (0-6)		C4		29	mg/dL (11-31)
Monocyte		8	% (1-14)		ANA		<1:80	(<1:80)
Lymphocyte		9	% (20-50)		Anti-ds-DNA Abs		2.9	U/mL (<9.9)
Basophil		0	% (0-1)		Anti-Sm Abs		0.6	U/mL (<6.9)
Blood chemistry					Anti-U1RNP Abs		1.1	U/mL (<4.9)
Total protein		3.7	g/dL (6.6-8.1)		Anti-SSA Abs		<0.5	U/mL (<6.9)
Total bilirubin		0.4	mg/dL (0.4-1.5)		Anti-SSB Abs		<0.5	U/mL (<6.9)
Albumin		1.6	g/dL (4.1-5.1)		MPO-ANCA		82	EU (0-3.5)
Aspartate aminotransferase		44	IU/L (13-30)		PR3-ANCA		<0.5	EU (0-2)
Alanine aminotransferase		55	IU/L (10-42)		Anti-cardiolipin Abs		3	U/mL (0-9.9)
Lactate dehydrogenase		176	IU/L (124-222)		Lupus anticoagulant		1.12	(<1.3)
γ-glutamyl transpeptidase		221	IU/L (13-64)		Anti-GBM Abs		1.7	U/mL (0-7.0)
Alkaline phosphatase		472	IU/L (106-322)		Urinalysis
Creatine kinase		7	U/L (59-248)		pH		5.5
Blood urea nitrogen		42	mg/dL (8-20)		Specific gravity		1.029
Creatinine		5.63	mg/dL (0.65-1.07)		Protein		(2+) 0.53	g/g・Cre
Sodium		132	mEq/L (138-145)		Occult blood		(3+)
Potassium		5.8	mEq/L (3.6-4.8)		Bacteria		(−)
Chlorine		102	mEq/L (101-108)		Red blood cells		50-99	/HPF
Calcium		7.0	mg/dL (8.8-10.1)		White blood cells		>100	/HPF
Glucose		204	mg/dL (73-109)		Hyaline casts		20-29	/WF
Hemoglobin A1c		5.5	% (4.9-6.0)		Granule casts		50-99	/WF
Coagulation tests					Deaf casts		30-49	/WF
PT		113.7	% (70-130)		Fat casts		1-4	/WF
APTT		28.8	s (26.9-38.1)
D-dimer		4.7	μg/mL (0-1.0)
Fibrinogen		199	mg/dL (200-400)

CPA: cyclophosphamide, PT: prothrombin time, APTT: activated partial thromboplastin time, Ig: immunoglobulin, C3: complement 3, C4: complement 4, ANA: antinuclear antibodies, Abs: antibodies, anti-ds-DNA: anti-double stranded-DNA, anti-Sm: anti-smith, anti-RNP: anti-ribonucleoprotein, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibodies, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibodies, anti-GBM: anti-glomerular basement membrane, Cre: creatine, HPF: high-power field, WF: whole field

Figure 1.

Clinical images on admission of a 60-year-old man with cyclophosphamide-associated severe enteritis. A and B: Computed tomography of the abdomen shows diffuse wall thickening from the jejunum to colon. C and D: Colonoscopy findings show severe mucosal edema from the ileum to the rectum, with redness and erosion. Panels C and D present endoscopic images of the transverse and descending colon, respectively.

A pathological examination revealed no atypia in the epithelium, and the stroma was slightly granulation tissue-like; this indicated nonspecific inflammatory findings without findings suggestive of vasculitis. Although an immunohistochemical analysis showed slightly positive nuclear staining for cytomegalovirus (CMV) in the stroma, hematoxylin and eosin staining of the biopsy specimen did not reveal inclusion bodies suggestive of CMV enteritis.

After admission, the patient was again started on steroid pulse therapy with plasma exchange to reinforce the treatment for MPA, as enteritis caused by vasculitis could not be completely ruled out. In addition, he received intravenous broad-spectrum antibiotics and ganciclovir. Anuria due to severe intravascular dehydration was observed; thus, hemodialysis was continued. The clinical course of the patient after admission is shown in Fig. 2. After treatment, while the serum MPO-ANCA and CMV antigenemia levels decreased, the gastrointestinal symptoms did not ameliorate. Steroid treatment was gradually tapered, and supportive care, such as central venous nutrition and intravenous albumin administration, was continued.

Figure 2.

Clinical course after admission of a 60-year-old man with cyclophosphamide-associated severe enteritis. After admission, steroid pulse and plasma exchange therapies were administered. The patient showed persistent soluble diarrhea with hematochezia, which gradually ameliorated. mPSL: methylprednisolone, PSL: prednisolone, MEPM: meropenem, CMV: cytomegalovirus, Cre: creatinine, Alb: albumin

Abdominal CT performed three months after admission showed a slight decrease in intestinal wall thickening, and colonoscopy revealed reduced edema of the intestinal mucosa; however, erosion and erythema of the mucosa persisted. Diarrhea with hematochezia gradually ameliorated at approximately 100 days after admission, and the gastrointestinal symptoms completely disappeared by day 140. The number of CMV antigen-positive cells rose again slightly during the course of the disease, and short-term oral administration of valganciclovir confirmed the negative result. Abdominal CT performed five months after admission revealed a further decrease in intestinal wall thickening, and colonoscopy after the improvement of enteritis showed increased normal mucosal inclusions and regenerative epithelialization (Fig. 3). The patient was transferred to a local hospital for rehabilitation.

Figure 3.

Abdominal computed tomography (CT) and colonoscopy findings of a 60-year-old man with cyclophosphamide-associated severe enteritis. Abdominal CT shows edematous changes in the small intestine and colon, which reduced over time. Colonoscopy revealed erosion of the mucosa and decreased vascular permeability, which gradually resolved. Colonoscopy images of the transverse colon after the improvement of enteritis show increased normal mucosa and regenerative epithelialization.

Discussion

We reported a case of severe enteritis after CPA administration for MPA. CPA is metabolized in the liver to its active form, which is covalently bound to the nucleus and exhibits antiproliferative effects by inhibiting deoxyribonucleic acid replication (1). These actions can result in side effects, such as myelosuppression, hemorrhagic cystitis, susceptibility to infection, and infertility (1). However, severe enteritis caused by CPA is extremely rare, with only two reported cases to date (3,4).

The first case, reported by Yang et al. (3), involved a patient with MPA who presented with nausea and watery diarrhea two weeks after CPA administration. Abdominal CT revealed diffuse wall thickening in the small and large intestines, colonoscopy revealed denuded and erythematous mucosa throughout the terminal ileum and colon, and histopathology showed full-thickness mucosal ulceration and inflammation. CPA-associated enteritis was diagnosed because other pathological conditions causing intestinal lesions - such as infection, malignancy, and vasculitis - could be clinically and pathologically excluded, and both endoscopic and pathological findings were similar to those in previous cases of CPA-associated hemorrhagic colitis. The patient eventually died from acute respiratory distress syndrome (ARDS) (5).

Sato et al. reported the second case of CPA-associated severe enteritis in a patient with granulomatosis polyangiitis (GPA). They noted radiological and endoscopic findings similar to those observed in the previous case, including massive bowel wall thickening on abdominal CT and generalized edema on colonoscopy (4). The patient presented with prolonged water-soluble diarrhea despite systemic management, including cessation of CPA and plasma exchange therapy, and her symptoms eventually ameliorated four months after their onset.

Regarding the intestinal vascular lesions in the present case, the MPA itself was not considered highly active at the time of admission, as the serum ANCA titer decreased, and interstitial pneumonia was alleviated. Furthermore, a lower endoscopic biopsy showed no vasculitis, and the patient's symptoms persisted despite steroid pulse therapy and plasma exchange. Therefore, while vasculitis cannot be completely ruled out as the cause of gastrointestinal symptoms, it was considered to be negative as the primary cause. Next, we examined the involvement of infection or malignancy among the gastrointestinal symptoms. Culture tests of samples taken from various sites were negative, and there was no improvement in the gastrointestinal symptoms with the administration of broad-spectrum antibiotics. Furthermore, a histopathological examination of the gastrointestinal mucosa revealed no findings suggestive of malignancy. Accordingly, we concluded that bacterial enteritis or malignancy were unlikely to be involved in the long-lasting gastrointestinal symptoms. However, in the present case, high serum CMV antigen titers were detected on admission. Thus, the possibility of CMV infection being involved with the gastrointestinal symptoms in this case cannot be ruled out.

However, an intestinal biopsy showed no obvious inclusion bodies suggestive of CMV enteritis, and an immunohistochemical examination revealed few CMV-positive cells in the intestinal stroma. Colonoscopy also did not reveal typical findings of CMV enteritis, such as well-defined ulcers, infiltrative ulcerative changes, or pseudomembrane formation (6). Furthermore, the gastrointestinal symptoms did not resolve despite a significant decrease in the serum CMV antigen titer after treatment with ganciclovir was observed. Therefore, we considered CMV enteritis not to be the primary cause of gastrointestinal symptoms. Conversely, we observed that our patient developed significant gastrointestinal symptoms immediately after CPA administration, and CT and colonoscopy findings were similar to those observed for the previous two cases of CPA-associated severe enteritis (3,4). Furthermore, the clinical course was similar to that of the previous two patients (3,4), including prolonged gastrointestinal symptoms despite discontinuation of CPA administration, and intensive supportive care. Considering these findings and the absence of findings suggesting other diseases, such as bacterial infection or malignancy, we considered CPA-associated enteritis to be the main cause of gastrointestinal symptoms in this case.

For a better understanding of the clinical characteristics of CPA-associated enteritis, we summarized the previous two cases, along with the present case, in Table 2. Two of the three patients were men who were over 60 years old. All patients presented with gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, after CPA administration. Two patients, including our patient, had MPA, whereas one had GPA. All three patients were treated by CPA discontinuation and intensive supportive care. In the present case and the case reported by Sato et al. (4), the gastrointestinal symptoms persisted for more than three months despite treatment but were eventually alleviated (4). Thus, prolonged symptoms, even after drug discontinuation, may be one of the clinical features of CPA-associated enteritis. In the case reported by Yang et al., the symptoms did not abate for more than four weeks after initiating intensive care. The patient eventually died from ARDS, and a postmortem examination was performed. Factors contributing to a poor prognosis in cases treated with CPA remain unclear. However, in the case of Yang et al., CPA was not discontinued immediately after the onset of gastrointestinal symptoms; instead, it was continued at a reduced dose, with the highest total amount being 2.1 g. Therefore, the total quantity of CPA may affect the duration of CPA-associated enteritis, and the drug should be promptly withdrawn if CPA-related enteritis is suspected.

Table 2.

Summary of Reported Cases of CPA-associated Enteritis.

No.	Reference	Age/ sex	Background autoimmune disease	Symptoms	Affected organ	Colonoscopy findings	CT findings	Pathological findings	Treatments	Total dose of CPA	Outcomes of enteritis
1	(3)	60/M	MPA	Nausea Vomiting Diarrhea	Small intestine Colon	Denuded and erythematous mucosa	Diffuse mural thickening	Full-thickness mucosal ulceration and inflammation throughout the terminal ileum and colon	CPA was continued for 1 month with dose reduction to 50 mg/day and subsequent discontinuation	2,100 mg	Symptoms did not improve for more than 4 weeks; patient eventually died from ARDS.
2	(4)	61/F	GPA	Nausea Vomiting Diarrhea	Stomach Duodenum Small intestine Colon	Generalized edema from the transverse colon to the rectum	Massive wall thickening with prominent contrast enhancement in the mucosa	Mild inflammatory cellular infiltration, some granulation tissues, and ulcers	Discontinuation of CPA Intensive supportive care	1,000 mg	Symptoms did not improve for more than 4 months but eventually improved.
3	Our case	60/M	MPA	Nausea Vomiting Diarrhea	Small intestine Colon	Severe edema of the mucosa from the ileum to the rectum with redness and erosion	Extensive wall thickening in the small intestine and colon	Interstitium showing slightly granulation tissue-like nonspecific inflammation	Discontinuation of CPA Intensive supportive care	500 mg	Symptoms did not improve for more than 4 months but eventually improved.

M: male, F: female, CT: computed tomography, CPA: cyclophosphamide, MPA: microscopic polyangiitis, GPA: granulomatosis with polyangiitis, ARDS: acute respiratory distress syndrome

The mechanism underlying CPA enteritis is not clearly understood; however, CPA can impair the growth of tumor cells through its genotoxic and cytotoxic properties. CPA toxicity also acts indiscriminately on tumor cells and fast-dividing healthy cells, such as intestinal stem cells (7,8). Thus, CPA may induce the development of mucositis by increasing intestinal permeability and damaging the normal intestinal epithelium (9). In general, chemotherapy-related diarrhea often results from gastrointestinal mucositis. The latter has a complex pathophysiology involving changes in the gut microbiome, and rapid changes in the microbiome can lead to excessive generation of reactive oxygen species in the epithelium and upregulation of inflammatory cytokines (10,11). Viaud et al. reported that, in a mouse model, CPA induced the translocation of particular species of Gram-positive bacteria to secondary lymphoid organs by altering the microflora composition in the small intestine (12). Thus, in addition to increased intestinal permeability, CPA-induced abnormalities in the intestinal microbiota may be a factor involved in the development of CPA-associated enteritis.

The present case demonstrated the appearance of gastrointestinal symptoms relatively early after CPA administration, compared with the two previous reports. Previous reports have indicated that CPA is more likely to cause side effects in patients with renal impairment (13,14), and the patient in this study had severe renal dysfunction at the time of CPA administration. Conversely, no information on the renal function was available in the report by Yang et al. (3), while Sato et al. (4) reported very mild renal dysfunction. Therefore, the degree of renal dysfunction at the time of CPA administration may play a role in the timing of the onset of CPA-associated enterocolitis. In addition, the CMV antigen-positive cell count in this case was high on admission; thus, we cannot rule out the possibility that CMV infection may have contributed to the earlier onset of gastrointestinal symptoms in this case than in previous reports.

In conclusion, we presented the third case of CPA-associated severe enteritis reported thus far. The patient was successfully treated with supportive care and CPA discontinuation. CPA-associated enteritis is rare but can be fatal; thus, prompt discontinuation of CPA and intensive systemic management are necessary when patients present with gastrointestinal symptoms after CPA administration. It is also necessary to accumulate more cases to determine the risk factors and development mechanisms for CPA-associated enteritis.

The authors state that they have no Conflict of Interest (COI).