Case Study: Disease Flare and Fever in Conjunction With Ulcerative Colitis

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This month: A noteworthy case study

Why has this 51-year-old man with ulcerative colitis patient developed fever, tenesmus, and pain in his lower left abdomen, in addition to bowel symptoms? That's the question facing clinicians when the man is admitted to hospital, as Xin Liu, MD, and colleagues at Second Affiliated Hospital of Xi'an Jiaotong University in People's Republic of China, reported in the Journal of Inflammation Research.

The patient told clinicians that for the previous 2 months, he had had bloody diarrhea, and the medical team subsequently learned that 4 years previously, the man had a milder bout of the same symptoms, although without any fever. At that time, he had presented to another hospital and been diagnosed with "colitis" and prescribed mesalazine. Despite that physician's recommendations, the patients had decided not to take any treatment and had not returned for follow-up.

Liu and colleagues ordered blood tests, which showed that the patient's C reactive protein (CRP) level was elevated at 35.8 mg/L, and his hemoglobin was decreased at 125 g/L. He underwent colonoscopy, which revealed extensive colitis, along with a wide mucosal defect, and clinicians noted spontaneous bleeding in the sigmoid colon.

They performed a chest CT scan, but the findings were unremarkable. Serology results were positive for cytomegalovirus (CMV) inclusion bodies. He received treatment with intravenous ganciclovir and methylprednisolone, with no improvement in symptoms, and was therefore transitioned to infliximab (Remicade).

After four sessions of infliximab treatment, the patient's stool returned to normal, his levels of CRP and hemoglobin improved, and a repeat colonoscopy showed that the lesions had also responded to treatment. However, he remained febrile, with a temperature of about 38°C (about 100.4°F); he had no other respiratory symptoms.

Clinicians revisited the chest CT and observed a mass shadow on the right lower lobe of the patient's lung. A sputum culture was positive for Acinetobacter baumannii, and antibiotics were administered in accordance with the drug sensitivity findings. The fever resolved, but the lung mass remained unchanged.

The team diagnosed the patient with ulcerative colitis (UC), and investigated the lung mass. "Puncture and biopsy of the lung mass guided by B-ultrasound revealed granulomatous inflammation and necrosis, with multiple variable-sized encapsulated yeast cells present in hematoxylin and eosin staining, hexamine silver staining, and periodic acid-Schiff staining," Liu and co-authors reported.

They diagnosed the patient with Cryptococcus neoformans pneumonia, and started him on antifungal treatment with voriconazole (0.2g oral bid), and switched from infliximab to vedolizumab (Entyvio) to treat the UC.

The bloody diarrhea resolved, and the erythrocyte sedimentation rate and CRP both returned to normal. After three infusions of vedolizumab, a follow-up colonoscopy revealed "a slight pseudomembranous colitis in rectum sigmoid colon," the case authors said. A stool sample test was positive for Clostridium difficile, and the patient was treated with oral vancomycin for 14 days.

After 3 months of voriconazole, clinicians noted that the lung lesions had been mostly absorbed. "At present, the patient continues to take voriconazole orally and receive vedolizumab treatment according to the course of treatment," the team stated, adding that the patient had no cough or sputum, his temperature returned to normal, and the bloody stool and diarrhea remained resolved.

Discussion

"This is the first reported instance of an ulcerative colitis patient who develops a Cryptococcus neoformans infection after infliximab treatment," Liu and co-authors wrote. They noted that the yeast Cryptococcus neoformans is ubiquitous in nature and in animals, and is particularly common in the intestines of pigeons. These yeasts are infectious regardless of a host's immunocompetence, although the risk of infection is greatest in the setting of impaired T lymphocyte function.

The case authors speculated that the addition of infliximab therapy may have increased the degree of immunosuppression to the level required to enable cryptococcal dissemination. Cryptococcus neoformans generally invades the central nervous system and respiratory system.

Because clinical and imaging manifestations of Cryptococcus neoformans pneumonia lack specificity, the disease may be misdiagnosed and treatment delayed. As a result, the infection may worsen.

Primary treatment options are antifungal medications, including fluconazole, amphotericin, and voriconazole, and fortunately the prognosis is good for most patients, Liu and colleagues said.

They noted that patients with inflammatory bowel disease (IBD) are at high risk of opportunistic infections, and that this patient had acute severe UC but had no history of contact with pigeons.

That his fever persisted after the UC responded to treatment with infliximab led the team to investigate further, and thus make the rare diagnosis of Cryptococcus neoformans pneumonia. Of the few such cases of Cryptococcus neoformans infection after infliximab treatment, most occurred in patients with rheumatoid arthritis. The authors said there have been only five cases reported in IBD, and all occurred in patients with Crohn's disease, making this the first case to be reported in a person with UC.

The team's literature search identified five male Crohn's disease patients receiving infliximab who developed lung infections due to Cryptococcus neoformans. "In the course of the disease, the patients had a variety of opportunistic infections, including viruses (CMV), fungi (Cryptococcus neoformans), and bacteria (Clostridium difficile)," Liu and co-authors wrote. The duration of infliximab use ranged from 8 months to 3 years, and the patients had had concomitant treatment with various medications, including prednisone, budesonide, azathioprine, prednisolone, and methotrexate.

This case highlights the importance of ongoing vigilance to identify the clinical risk of opportunistic infections associated with immunosuppressive treatment of IBD, Liu and co-authors emphasized.

Treatment with tumor necrosis factor antagonists increases vulnerability to all types of serious and opportunistic infections, whereas vedolizumab is associated with an increased risk of intestinal infections. "Opportunistic infections should be detected during immunosuppressive therapy, including bacterial, viral, fungal and other opportunistic infections," the case authors concluded.

Read previous installments in this series:

Part 1: UC: Understanding the Epidemiology and Pathophysiology

Part 2: UC: Symptoms, Exams, Diagnosis

Part 3: UC: How and Why Does It Arise?