Date Published: May 8, 2018
Publisher: BioMed Central
Author(s): Kara Robertson, Stephen Couban, Desmond Leddin, Imran Ahmad, Lori Connors.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by recurrent life-threatening bacterial and fungal infections, granuloma formation and intestinal disease. This disease is caused by defects in NADPH oxidase, which result in the inability of phagocytes (neutrophils, monocytes and macrophages) to destroy certain microbes. The only established curative therapy for CGD is hematopoietic stem cell transplantation.
A 23-year-old Caucasian male with X-linked chronic granulomatous disease underwent a reduced-intensity conditioning, matched unrelated donor peripheral blood stem cell transplant, after which he was started on tacrolimus and mycophenolate for graft-versus-host disease prophylaxis. Seven months later, he was admitted to hospital for nutritional support secondary to odynophagia and anorexia. Upper endoscopy revealed ulcers in his esophagus, and he was initially treated with acyclovir due to the risk of CMV infection until biopsies came back negative for viral colitis. Following a sigmoidoscopy that showed nonspecific colitis, he was started on mesalamine. Although pathology showed a pattern of widespread inflammatory changes initially suggestive of CGD colitis, a peripheral blood chimerism study showed 100% donor alleles suggesting CGD remission. Since this patient’s colitis was refractory to other immunomodulators, and due to its severity, the patient underwent a partial colectomy 1 year after his HSCT and will likely require the removal of the remaining large bowel.
This case demonstrates a unique presentation of colitis in a post-transplant CGD patient. Since CGD colitis could be excluded due to the patient’s recent successful hematopoietic stem cell transplantation, a broad differential diagnosis is required for determining the etiology of this new-onset colitis in this patient with pre-existing chronic granulomatous disease. This case delineates the need for interdisciplinary care and describes a severe case of colitis after hematopoietic stem cell transplantation.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by recurrent life-threatening bacterial and fungal infections, granuloma formation and intestinal disease . CGD is a recessive genetic disorder caused by a defect in one of five genetic loci coding for NADPH oxidase, a critical enzyme required in the phagocytosis pathway.
A 23-year-old Caucasian male with X-linked CGD (gp91phox mutation) underwent a reduced-intensity conditioning , matched unrelated donor peripheral blood stem cell transplant as curative therapy for his CGD. He was then started on tacrolimus and mycophenolate for GvHD prophylaxis post-HSCT. The transplant was well tolerated, with no documented evidence of acute GvHD, but 7 months later, he was admitted to hospital for nutritional support secondary to odynophagia and anorexia. Upper endoscopy revealed ulcers in his esophagus. He was initially empirically treated with IV acyclovir and biopsies were performed while the patient was on prophylactic doses of immunosuppressive therapy. However, these biopsies came back negative for HSV/CMV and IV acyclovir was discontinued. The pathology report showed a non-specific pattern of widespread inflammatory changes. There was no personal for family history of IBD or GI disease in either the donor or recipient prior to HSCT. Following a sigmoidoscopy showing nonspecific colitis, he was started on mesalamine. To rule out HSCT failure and recurrence of CGD, we performed NBT testing and peripheral blood chimerism studies. NBT testing demonstrated proper neutrophil functioning, and peripheral blood chimerism studies (VNTR) showed 100% donor alleles, showing no evidence of CGD or HSCT failure. It was then thought he might have chronic GvHD, and he was treated with IV steroids. Unfortunately, the patient was refractory to this treatment and subsequently had several episodes of lower GI bleeding.
This patient with chronic granulomatous disease initially presented to us with a new-onset gastrointestinal inflammation and ulceration following HSCT. This was initially suggestive of a diagnosis of CGD colitis, a common gastrointestinal manifestation of X-linked CGD. However, CGD colitis is pathologically distinct from an inflammatory bowel disease colitis due to the presence of hyperpigmented macrophages, a predominantly eosinophilic inflammatory infiltrate, and a scarcity of neutrophils and within the colonic wall . We were therefore able to exclude CGD colitis and HSCT failure with confidence in our patient. After allelic testing, GvHD was then suspected due to the widespread inflammation, and plethora of phagocytes and lymphocytes within the gastrointestinal lining. Although GvHD can manifest with nonspecific symptoms suggestive of upper and lower gastrointestinal tract involvement , GvHD serologically presents with marked proliferation of CD4+ and CD8+ T cells, and very few CD56+ NK cells , which was not seen on flow cytometry. We were therefore also able to exclude a typical presentation of GvHD from our differential, as the characteristic typical GvHD cutaneous and hepatic reactions were not seen in conjunction with this patient’s gastrointestinal symptoms. However, there were three principle findings that prevent us from ruling out atypical GvHD in our patient. These include presence of apoptotic bodies, mucosal necrosis, ulceration, submucosal fibrosis, and crypt and gland destruction on pathology, as well as detection of alloreactive donor-derived cells against the patient’s gut mucosa, and lastly, our observation of lymphocytic infiltration of the gut mucosa as important yet atypical elements seen in GvHD. As a result, we are not able to rule out an atypical presentation of GvHD for the etiology of this colitis.
A broad differential diagnosis is required for colitis presenting after HSCT in a patient with pre-existing CGD. We have been able to rule out common etiologies such as recurrent CGD, typical GvHD, and viral colitis, but we have yet to exclude another Crohn’s-like colitis, an atypical presentation of GvHD or other unknown viral etiology from our differential diagnosis, however the current plan for this patient’s colitis involves future elective total colectomy for disease control, with observation for disease recurrence. This case serves to delineate the importance for multidisciplinary care and describes a severe case of colitis after HSCT.