Gastrointestinal Eosinophilic Granulomatosis with Polyangiitis following a Clostridium difficile Infection

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA), historically named Churg-Strauss syndrome, is a rare vasculitis affecting small- and medium-sized blood vessels. The disease has a predilection for numerous organs including the lungs, sinuses, kidneys, heart, nerves, and gastrointestinal tract but is prominently associated with asthma, rhinosinusitis, and eosinophilia. Gastrointestinal involvement is common; however, a gastrointestinal manifestation as the cardinal symptom following an infection is atypical. Here, we present a case of a 61-year-old male who presented with persistent diarrhea following a toxigenic Clostridium difficile infection despite multiple antibiotic courses. Repeat testing confirmed eradication of the infection, and further evaluation with colon biopsy revealed small and medium-sized vasculitis with eosinophilic infiltration and granulomas. Treatment with prednisone and cyclophosphamide resulted in rapid improvement of his diarrhea. Gastrointestinal symptoms in EGPA are associated with worse prognosis, so prompt identification and treatment of the disease is crucial. EGPA is rarely documented in histopathological samples from the gastrointestinal tract as endoscopic biopsies are typically too superficial to sample the submucosal layer containing the affected vessels. Additionally, the link between EGPA and infections as a potential trigger has not been clearly established, but gastrointestinal EGPA manifesting after a colonic infection raises concerns that this may have been a triggering event. Ultimately, further study is needed to understand, diagnose, and treat gastrointestinal and postinfection EGPA.

Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA), historically referred to as Churg-Strauss syndrome, is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis involving small and medium-sized blood vessels. The disease has a mean age of onset between 38 and 54 years and primarily manifests with asthma, peripheral blood eosinophilia, and eosinophilic infiltration of tissues. EGPA has variable presentation across affected individuals and commonly involves numerous organs including the lungs, sinuses, kidneys, heart, nerves, and gastrointestinal (GI) tract [1].

While GI involvement is common, affecting 20–50% of patients with EGPA, GI symptoms are infrequently a primary presenting symptom as patients more commonly develop asthma or chronic rhinosinusitis in the earlier phase of the disease [2–4]. Histopathologic evidence of GI tract involvement is rarely documented as most endoscopic biopsies only reveal the superficial mucosal layer which is not abundant in the small and medium-sized vessels affected by the disease [5]. Additionally, EGPA following infections is a rare entity, and infections have been speculated as a triggering agent of the disease [6, 7]. Here, we present a unique case of EGPA in a 61-year-old male that presented with a primary complaint of persistent diarrhea after failing treatment for toxigenic Clostridium difficile. Further investigation revealed histopathologic evidence of necrotizing granulomatous vasculitis in the colon. To the best of our knowledge, this is the first reported case of EGPA following a C. difficile infection. This case highlights unique aspects regarding GI manifestations and potential infectious triggers of EGPA.

Case Presentation

A 61-year-old male with a past medical history of chronic obstructive pulmonary disease (COPD) presented for an 8-week history of profuse, watery diarrhea. He reported 15–20 episodes of diarrhea daily but denied any abdominal pain, nausea, vomiting, hematochezia, melena, or jaundice. He had no fevers or weight loss. His only other symptom was a right foot drop with associated right lower extremity paresthesias that he had developed over the last few weeks. His only medications were albuterol, fluticasone, and vilanterol inhalers. He denied any supplement use. Social history was notable for smoking tobacco, but the patient had quit 2 years prior. He denied any alcohol or illicit drug use. He had no recent history of travel or adverse foods. On physical exam, he had no abdominal tenderness or distension. Rectal tone was normal without blood or stool in the rectal vault. Neurologic exam revealed weakness to dorsiflexion of the right foot.

The patient previously had an elective laparoscopic cholecystectomy at an outside hospital 8 weeks prior. His postoperative course was complicated by diarrhea secondary to toxigenic C. difficile which was diagnosed via positive immunoassay for glutamate dehydrogenase and toxin A/B. He was treated with oral vancomycin followed by fidaxomicin but continued to have persistent and worsening diarrhea. He was then readmitted to that hospital due to dehydration and was subsequently transferred to our facility for fecal microbiota transplant.

On arrival, initial laboratory workup was remarkable for white blood cell count of 20.1 k/cumm (reference range: 3.6–10.6 k/cumm), and differential notably revealed an absolute eosinophil count of 12.5 k/cumm (reference range: 0.0–0.3 k/cumm). Interestingly, repeat C. difficile testing was negative for glutamate dehydrogenase and toxins A/B suggesting eradication of toxigenic C. difficile. He then underwent extensive workup for his eosinophilia and diarrhea to evaluate for alternative causes of persistent diarrhea. Stool PCR panel, stool culture, and comprehensive stool ova and parasite analysis were all negative. Blood cultures and urinalysis were unremarkable. HIV-1 and 2 antibodies and HIV-1 p24 antigens were not detected. Strongyloides IgG antibody was negative. Fecal calprotectin was normal. He ultimately underwent colonoscopy which showed rectal erythema but a normal-appearing colon and terminal ileum. However, random colon biopsy (shown in Fig. 1) revealed necrotizing granulomatous vasculitis of the small and medium-sized arteries with dense eosinophilic infiltration and granulomas consistent with EGPA.

Fig. 1.

Colonic biopsy showing necrotizing granulomatous vasculitis with eosinophil-rich inflammatory infiltrate (hematoxylin-eosin), original magnification, ×200 (a, b), ×400 (c, d).

After diagnosis of EGPA, further inquiry revealed no history of rhinitis, sinusitis, nasal polyps, or asthma aside from COPD which had been diagnosed several years prior via pulmonary function testing. He then underwent further workup to characterize and risk-stratify the extent of his EGPA. ANCA immunofluorescence assay was less than 1:20 (reference range: <1:20). Chest X-rays were only significant for a small left pleural effusion. Echocardiogram revealed an ejection fraction of 36%, stage 2 diastolic dysfunction, and left anterior descending artery and right coronary artery wall motion abnormalities. Cardiac MRI displayed patchy epicardial and myocardial enhancement consistent with myocarditis.

Based on the severity of his disease, he was treated with prednisone and cyclophosphamide. He showed rapid improvement of his diarrhea and normalization of his peripheral eosinophil count within 72 h of treatment initiation. He was then discharged with a plan to follow up with a local rheumatologist and start maintenance therapy upon achieving disease remission.

Discussion

EGPA is a rare ANCA-associated vasculitis that involves eosinophilic granulomatous inflammation of small to medium-sized vessels. The disease was formerly referred to as Churg-Strauss after two pathologists who first published a form of vasculitis characterized by findings of asthma associated with eosinophilia and granulomatous necrotizing vasculitis [1]. The disease has since been renamed EGPA to better describe the pathologic features of the disease [1, 3].

EGPA represents the rarest of the ANCA-associated vasculitides with an estimated prevalence of 10.7–17.8 cases per million people [3]. Symptom onset typically occurs from 38 to 54 years old with a median age of presentation at 40 years old [1]. No ethnic or gender predilections have been established in relation to EGPA [8]. Given the scarcity of EGPA cases, research has been limited compared to other ANCA-associated vasculitides although some recent progress has been made [3].

The disease has extensive multisystemic involvement and classically manifests with three specific phases that are delineated based on clinical and pathologic findings. The initial phase is referred to as the prodromal phase and consists of asthma, rhinosinusitis, or nasal polyps. These symptoms can persist for several years before progressing to the eosinophilic phase. In this second phase, there are findings of peripheral blood eosinophilia and eosinophilic infiltration of multiple organs such as the lungs and GI tract. After months to years, patients then progress to the vasculitic phase in which small and medium-sized vasculitis develops with granulomatous inflammation. In this stage of the disease, numerous organs can be affected including the lungs, heart, kidneys, intestines, and peripheral nerves [1, 4, 8].

Given the variability in organs involved and that ANCA positivity is only seen in 40% of EGPA cases, the American College of Rheumatology (ACR) has developed specific criteria for diagnosis of the disease. These six criteria consist of asthma, migratory pulmonary infiltrates, paranasal sinus abnormalities, mononeuritis or polyneuritis, peripheral blood eosinophilia (greater than 10% of the total leukocyte count), and eosinophilic tissue infiltrates on biopsy [1, 3]. Patients must meet four out of six of these criteria for diagnosis, and this method of diagnosis carries 99.7% specificity and 85% sensitivity [1].

Our patient’s presentation was atypical as he did not strictly meet four of the described criteria, follow the classic triphasic pattern, or have any clear EGPA symptoms until the onset of his diarrhea. There have been multiple cases reported of EGPA with GI involvement that did not meet the necessary four ACR criteria but were diagnosed histologically [9]. This raises concern that GI involvement of EGPA may manifest atypically and requires a high degree of suspicion for appropriate and timely diagnosis. Furthermore, a GI manifestation as the first symptom of EGPA is highly uncommon as the majority of patients have some history of asthma accompanied by rhinitis as their initial symptoms [2–4]. Notably, this patient did carry a longstanding diagnosis of COPD in the setting of smoking; however, it stands to reason that his COPD may have been a misdiagnosis of adult-onset asthma or that treatment of COPD confounded the presentation of asthma.

While GI manifestations may not typically be an initial complaint, they are frequent with 20–50% of patients having GI involvement [2]. The most commonly affected site is the small bowel followed by the stomach and colon. Symptoms are typically nonspecific including diarrhea, vomiting, and abdominal pain [5]. However, more severe manifestations of GI disease can be seen including small bowel obstruction, ileus, ulcerations, and perforations [2, 5]. Cases of acalculous cholecystitis, pancreatitis, and appendicitis have also been reported [9].

GI manifestations of EGPA are thought to be due to either eosinophilic infiltration or ischemia secondary to vasculitic changes [1, 2]. These vasculitic changes in the GI tract are rarely documented because endoscopic biopsies typically sample the superficial mucosal layer, but the small and medium-sized vessels that are affected by the disease are more prominent in the deeper submucosal layer. Despite the rarity of such biopsy findings, our patient uniquely had histopathologic evidence of vasculitic changes on colon biopsy [2, 5].

Given that our patient had an atypical presentation of EGPA, other differentials for eosinophilia and granulomas on colon biopsy were considered. For example, Crohn’s disease and tuberculosis are more commonly associated with granuloma formation; allergic colitis, helminth infection, and hypereosinophilic syndrome are more commonly associated with eosinophilic infiltration. However, none of these diseases would present with necrotizing vasculitis within the submucosa [5, 10]. The pathological triad of necrotizing vasculitis, granulomas, and eosinophilic infiltration was highly consistent with GI EGPA [5, 8]. Although he did not meet the clinical criteria outlined by the ACR, our patient was able to achieve a definitive diagnosis through his biopsy findings.

Once the diagnosis is made, severity and prognosis of the disease can be determined. Poor prognosis has been associated with GI involvement based on the revised Five-Factor Score. This scoring system represents a tool that has been developed to identify patients in need of more aggressive treatment. It consists of five points given for GI involvement, cardiac insufficiency, renal insufficiency, absence of otolaryngological manifestations, and age greater than 65. Presence of any of these criteria is associated with worse prognosis and overall mortality, and any score greater than or equal to two was associated with a 40% 5-year mortality [11]. Our patient had GI and cardiac disease without otolaryngological findings which gave him a Five-Factor Score of three indicating a poor prognosis.

Following the determination of the severity of active EGPA, a treatment plan can be tailored. Initial treatment typically involves corticosteroids with or without the addition of a cytotoxic medication such as cyclophosphamide. Patients with a better prognosis can be treated with steroids alone, whereas patients with poorer prognosis often require combination therapy. Remission can then be maintained with cytotoxic agents such as azathioprine, methotrexate, or cyclosporine [1]. Concern with corticosteroid use has been noted due to reports of intestinal ulceration and perforation that can occur following the initiation of steroids. This is thought to be due to suppression of fibroblast proliferation, collagen synthesis, and glycosaminoglycan synthesis which can induce peptic ulcers and GI hemorrhage. Given this concern, it may be prudent to screen patients for evidence of intestinal erosion or ulceration before initiation of steroid treatment to reduce risk of complications [2]. As mentioned previously, our patient had three poor prognostic factors for EGPA based on the Five-Factor Score which included GI manifestations, cardiac insufficiency, and lack of otolaryngological findings. Considering the poor prognosis, morbidity from his diarrhea, and grossly normal colonoscopy findings, he was initiated on multimodal therapy with prednisone and cyclophosphamide to rapidly induce remission and reduce symptomatic burden. Cyclophosphamide was added to the treatment plan to reduce our patient’s risk of relapse because patients with poor prognostic factors have a higher likelihood of relapse in general and when tapering steroids [1].

Lastly, one aspect of this presentation worth noting is that this patient’s EGPA surfaced following a C. difficile infection. This raises suspicion that his infection was a triggering event for an EGPA flare. Involvement of environmental triggers in EGPA remains unclear, and various proposed triggers have included medications, cocaine, allergies, animal exposures, vaccines, and infections [7]. There have been a number of cases suggesting that influenza and SARS-CoV-2 have triggered ANCA-associated vasculitides in predisposed individuals [6, 12, 13]. However, despite many observations to suggest that infection can contribute to induction and reactivation of many vasculitides, confirmatory evidence does not exist. There have been two theorized mechanisms as to how infectious agents may trigger the disease [14]. The first and direct mechanism involves a microbe or infectious toxin that damages the vascular wall leading to an inflammatory response. The second and indirect mechanism involves the microbe stimulating an immune response against blood vessels due to cross-reactivity between vascular and microbial antigens [15]. Previously, pulmonary infections such as influenza or SARS-CoV-2 have manifested with pulmonary involvement of ANCA-associated vasculitides [6, 12, 13]. Similarly, it stands to reason that a GI infection such as C. difficile would manifest with colonic involvement of EGPA as a local inflammatory or immune response may be activated before disseminated EGPA. While it is tempting to speculate that a C. difficile infection contributed to the initial flare of this patient’s EGPA, data are insufficient to draw a reliable conclusion as cases of infection followed by EGPA diagnosis are rare. Furthermore, to the best of our knowledge, no other cases of C. difficile-associated EGPA have been reported. Ultimately, further study is needed to understand how infections, specifically of the GI tract, may be involved with EGPA and its GI manifestations.

In summary, EGPA with diarrhea as the cardinal symptom and histopathologic evidence of vasculitic disease in the colon is a rare occurrence. Additionally, EGPA following infections, in this case a C. difficile infection, is not well understood but possibly represents a triggering agent for the disease. EGPA presenting in this manner can constitute a diagnostic challenge as GI manifestations are often nonspecific, infection can obscure the disease, and GI tract biopsies are not reliable in revealing vasculitis. Thus, diagnosing EGPA in patients presenting with GI symptoms or following an infection requires a high degree of clinical suspicion. Early diagnosis and intervention remain crucial as GI involvement is well established as an indicator of poor prognosis. Ultimately, further study is necessary to understand diagnosis, management, outcomes, and complications of postinfection and GI EGPA. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000530373).

Statement of Ethics

This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of their medical case and accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors have no funding sources or sponsors to declare.

Author Contributions

Haseeb Mohideen, MD, is the primary author and contributor of the manuscript and was responsible in all steps of manuscript preparation including data collection, writing, editing, and review of the manuscript. Wegahta Weldemichael, MD, was responsible for assembling images, figures, and figure descriptions for the manuscript. Dushyant Singh Dahiya, MD, and Hafsa Hussain assisted in writing and editing the manuscript. Andrea Shin, MS, MD, was assisted in reviewing and editing the manuscript.

Funding Statement

The authors have no funding sources or sponsors to declare.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.