Autologous bone marrow stem cell transplantation for the treatment of ulcerative colitis complicated with herpes zoster: a case report

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with continuous or recurrent symptoms. A 42-year-old male patient with intermittent diarrhea accompanied by bloody mucopurulent stools was admitted to our hospital. The diagnosis of UC was confirmed by a combination of laboratory examination, colonoscopy, and histological assay. The patient developed herpes zoster in the hospital, which challenged traditional treatments. Therefore, we performed an autologous bone marrow cells to modulate the immune system with his permission. Autologous bone marrow mononuclear cells were collected and injected locally into the bowel mucosa, and subsequently injected systemically through a peripheral vein. After the patient underwent auto bone marrow mononuclear cells transplantations twice, the patient’s symptoms were alleviated. Furthermore, he recovered from hematochezia, and his hypersensitive C reactive protein decreased. Colonoscopy results showed reduced lesions and decreased areas with bleeding and edema in the sigmoid colon and rectum. No recurrence occurred in the subsequent two years, but long-time monitoring is still necessary for the prophylaxis of colorectal cancer.

Keywords

autograft / bone marrow stem cells / ulcerative colitis / cell therapy

Introduction

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) characterized by chronic inflammation, relapsing diarrhea, and ulceration of the colon and rectum. The precise etiology of UC remains unclear, but several risk factors, such as infection, genetic susceptibility, and environmental and microbiological factors, have been identified [ 1]. Genetically susceptible hosts with dysfunctional T cells in the mucosa lack the ability to efficiently suppress the inflammatory response. In response to constant exposure to phlogistic luminal constituents, these patients develop an unrestrained inflammatory response, leading to chronic inflammation, tissue destruction, and fibrosis [ 2]. The inflammatory process in UC is confined to the mucosa. UC is primarily diagnosed through colonoscopy, whereas other tests, such as perinuclear anti-neutrophilic cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies, are promising but not yet recommended for routine use. The current medications used for UC, such as anti-TNF-α antibody and immunosuppressants, are not suitable for patients who have weakened immune defenses because of complications from viral infections.

Recent studies have identified bone marrow stem cell (BMSC) as a promising alternative solution for UC treatment [ 3– 5]. Hematopoietic stem cell (HSC) [ 6– 8] and mesenchymal stem cell (MSC) [ 9] are extensively applied in studies for IBD treatment. Both of these cell types originate from BMSC and exhibit strong immunomodulatory capacities to reset the immune system [ 10, 11]. These immunomodulatory capacities include defensive autoimmune activity and enhanced defense against exogenous pathogens [ 12]. In the present study, we report the effective use of auto-BMSC transplantation to treat a 42-year-old man suffering from UC and herpes zoster, and we present a literature review of this disease.

Case presentation

A 42-year-old Chinese male was admitted to The First Affiliated Hospital of the PLA General Hospital on May 21, 2013. The patient complained of intermittent diarrhea with bloody mucopurulent stools for four years, and he suffered from abdominal pain for a half year. The patient denied fever, arthralgia, or weight loss during the past years and was initially diagnosed with UC through colonoscopy examination after experiencing daily diarrhea four to five times a day. The patient was hospitalized two years after the diagnosis and was treated with enemas of metronidazole and prednisone. Oral mesalamine was also administered to maintain the remission after discharge. However, these treatments failed to control the symptoms during the previous two years. The patient had neither a systematic disease nor communicable disease. He was a heavy drinker and smoker for 16 years, but quit these habits four and six years ago, respectively. No related information was identified in his family history and experience, except for a blood transfusion during a rivet internal fixation operation 17 years ago. The results of the physical examination were negative. The laboratory examination of the peripheral blood showed that the levels of white blood cells (WBCs) and neutrophils were high, with absolute values of 26.3×10⁹/L (normal: 3.5×10⁹/L-10×10⁹/L) and 23.7×10⁹/L (normal: 1.2×10⁹/L-6.8×10⁹/L), respectively. The percentage of neutrophils increased to 90.4% (normal: 40%–75%). Feces examination showed WBCs 35–40/high power (HP) and red blood cells (RBCs) 25–30/HP . The fecal occult blood test was positive. The feces bacterial smear indicated dysbacteriosis in the intestinal tract. The serum total protein (TP), albumin, and transferrin (TRF) were all under normal levels at 58.5, 22, and 1.8 g/L, respectively. The level of high-sensitivity C-reactive protein (hs-CRP) was 4.6 mg/L, which was higher than normal (0–3 mg/L). However, the levels of immunoactive factors, such as rheumatoid factor (RF), immunoglobulins (IgA, IgM, IgG, and IgE), complement components (C3 and C4), and antistreptolysin-O (ASO), had no significant changes. Colonoscopy results revealed diffused ulcerative lesions in the sigmoid colon and rectum. The impaired mucus layers were fragile and easily bled after touching (Fig. 1). Histopathological examination results indicated the predominance of granulation tissue hyperplasia, inflammatory cell invasion, and mucus layer erosion (Fig. 2). No evidence of malignancy was obtained. Basing on these results, we confirmed a diagnosis of UC according to the diagnosis consensus of UC in Europe [ 13].

The patient developed painful papules after admission to the hospital. The papules were diagnosed as herpes zoster by a dermatologist. After treatment for one week with an anti-inflammatory (mesalamine), anti-viral (valacyclovir), and intestinal flora-modulating (Clostridium butyricum tablets) drugs, the patient was subjected to bone marrow stem cell mobilization before transplantation. After receiving ethical approval from the Institutional Ethics Committee and obtaining an informed consent from the patient, we performed the stem cell transplantation. Autologous bone marrow stem cells were prepared as previously described [ 14]. Briefly, a daily dose of 300 mg of recombinant human granulocyte colony-stimulating factor (G-CSF) (5 mg/kg) was divided into two doses, which were subcutaneously injected for 5–7 consecutive days. After these injections, a total volume of 252 ml of bone marrow was aspirated from the bilateral ilia. The bone marrow slides showed the active proliferation of granulocytes (M/E= 4.38:1) and the absence of abnormal cells (Fig. 3). First, a suspension of the entire stem cells was transplanted at several locations through submucosal injection (2–4 ml per location). A total of nearly 4.0 × 10⁸ cells (volume: 50 ml) were transplanted. Auto-BMSC transplantation was performed through colonoscopy, and a disposable injector syringe (Olympus, NM-200U-0425, Japan) was used for endoscopic injection into the intestinal submucosa. The selected stem cells were injected into the intestinal submucosa around the each ulcerative colitis lesion (two to three locations per lesion). Subsequently, the same volume of stem cell suspension was intravenously transplanted. The patient’s symptoms were remarkably alleviated after the first transplantation, which did not cause adverse reactions. The white and red blood cells in the stool decreased to 15–20/HP and 10–15/HP, respectively. The patient recovered from herpes zoster in two weeks and did not suffer other complications. The patient accepted an additional transplantation one month later. Two months after the stem cell transplantations, the colonoscopy results showed that the ulcerative lesions were nearly recovered in the sigmoid colon and rectum, and the areas of bleeding and edema were dramatically decreased (Fig. 4). The serum immunological parameters (C3, C4, IgA, IgG, IgE, and IgM) were measured by using Beckman Coulter-IMMAGE 800. The immunologic detection items were negative with normal reference values for all the parameters tested. In addition, the plasma levels of hs-CRP were reduced to normal values (from 4.6 mg/L to 1.0 mg/L) before and after treatment. In the subsequent two years, the patient had no relapse with the support of 5-aminosalicylic acid compounds. The herpes zoster infection may have been cured by valacyclovir.

Discussion

UC is an inflammatory bowel disease characterized by the diffused inflammation of the colonic mucosa. The patient in the present study was a middle-aged man with typical symptoms of bloody diarrhea, urgency, and tenesmus (straining at stool). However, this patient did not show any extraintestinal manifestation, such as arthritis, aphthous stomatitis, or uveitis. The diagnosis of UC for this patient was achieved by using a combination of patient history and physical assessments of endoscopy and histology. Similar to previous UC patients, he had a latent risk of abnormity in the intestinal bacterial flora. The reported blood transfusion might present another risk, as this procedure could potentially transfer unpredictable antigens to his body. The patient denied other risk factors, such as genetic factors and psychological disorders.

According to the severity of the disease, the patient showed a moderate to severe degree of UC with immunodeficiency [ 13], thus increasing the risk of failure to respond to treatments of corticosteroids or infliximab [ 15]. Novel biological therapies, such as anti-adhesion molecules, anti-IL-12/23, and anti-IL-6R, are still being evaluated and have no definite conclusions [ 16].

BMSC transplantation is a promising strategy for the treatment of autoimmune diseases [ 6, 17– 20]. Auto-BMSC is regarded safe because of the absence of immunological reaction and disease transmission [ 21, 22]. Recently, we have explored autologous hematopoietic stem cell transplantation in young patients with type 1 diabetes mellitus according to our guidelines on clinical trials [ 14, 23]. Several clinical studies have confirmed that BMSC transplantation could reduce autoimmune inflammation and stimulate the reparative process in the intestinal mucosa, thereby increasing the duration of remission and reducing the risk of disease recurrence and frequency of hospitalization [ 24]. The present study confirmed the immunomodulation of the BMSC, which was included in the bone marrow stem cell suspension. A summary of the results of clinical trials on BMSC transplantation for the treatment of UC is presented in Table 1.

The goals for the treatment of UC include the induction of remission, limitation of side effects, modification of the disease pattern, and prevention of complications [ 25]. Previous studies have demonstrated that, compared with normal populations, patients with persistent colitis are at high risk of developing colorectal cancer [ 26], particularly those diagnosed at an early age [ 26] or with severe inflammation [ 27]. In addition, the patient in the present study is still being monitored and currently undergoing periodic colonoscopy examination, blood routine, biochemistry parameters, and hs-CRP.

Conclusions

The preliminary results presented in this study corroborate the efficiency of the auto-transplantation of BMSC in the treatment of immunodeficient UC. This treatment alleviated the symptoms of UC and maintained remission in patients through subsequent treatment with mesalamine. Notably, long-term monitoring is necessary for the prophylaxis of colorectal cancer.

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