A 14-year-old girl with NBS presented with a typical phenotype and genotype (homozygotic NBN gene mutation 657del5) has suffered since early childhood from acute and chronic infections of the respiratory tract, paranasal sinuses, cryptococcal meningoencephalitis, chronic bronchitis, chronic pneumonia, symptomatic Epstein-Barr virus (EBV) reactivation, hepatitis of unknown etiology with cholestasis, and skin infections including disseminated actinomycosis and non-tuberculosis granulomas. She has also been diagnosed and treated for secondary hemophagocytic lymphohistiocytosis (HLH), complicated with facial vasculitis, hypertension and cardiomyopathy. Additionally, she had a tri-lineage hematological insufficiency and hypogammaglobulinemia (IgA < 10 mg/dl, IgG 85 mg/dl). Absolute numbers of lymphocytes showed combined B- and T-cell immunodeficiency: 0.266 G/l for CD3; 0.084 G/l for CD4; 0.140 G/l for CD8 and 0.077 G/l for CD19.
Due to an increasing number of life-threatening infectious complications, confirmed progressing immunodeficiency and marrow hypocellularity, she was referred for HSCT from a matched unrelated donor. On admission, she was in overall poor clinical condition, with Lansky performance score of 80, infection of the skin, symptoms of chronic pulmonary disease with various pulmonary rhonchi, oxygen saturation of 94%, and abnormal liver function tests.
The preparative RIC regimen included fludarabine (30 mg/m2/day; days from -9 to -5), cyclophosphamide (5 mg/kg bw/day; days from -5 to -2) and antithymocyte globulin (total 8 mg/kg bw divided between three consecutive days from -3 to -1). Due to previous infections, she was on continuous therapy with antibiotics. Other anti-infective prophylaxis included posaconazole and acyclovir. She received also prophylaxis against veno-occlusive disease with defibrotide. The graft included peripheral blood stem cells from HLA-matched, AB0/Rh-matched woman (11.6 x 108 NMC/kg bw; 7.8 x 106 CD34+ cells/kg bw). Prophylaxis against graft-versus-host disease (GVHD) included cyclosporine A and mycophenolate mofetil, however due to deterioration of parameters of the renal function, cyclosporine was converted to sirolimus, which in turn was converted to methylprednisolone, due to facial vasculitis (Fig. 1). Additionally, at day +5 rituximab was administered prophylactically against EBV reactivation and development of post-transplant lymphoproliferative disorder (EBV-PTLD).
During an early post-transplant period she was in otherwise good condition, however she suffered from severe mucositis, fever episodes, and necessity of total parenteral nutrition (TPN). Hematological and platelet recovery occurred at days +12 and +25, respectively. She was discharged from the transplant ward at day +28 with 49% donor chimerism, normal hematopoiesis in bone marrow, and no CMV or EBV viremia.
At day +35 she complained of acute abdominal pain accompanied by significant elevation of gamma glutamyl transpeptidase (3673 U/l), alkaline phosphatase activity (643 U/l) and a total and conjugated bilirubin level (5.17 mg/dl and 4.15 mg/dl, respectively). On magnetic resonance (MRI) cholangiopancreatography, the common bile duct (CBD) was widened with a diameter of 6 mm and in the distal part of CBD there were bile deposits of 5 x 3 mm size. She was qualified to urgent endoscopic retrograde cholangiopancreatography (ERCP). After sphincterotomy, removal of bile deposits was carried on with endoscopic basket. Additionally a 5 cm 7F prosthesis was inserted into the distal CBD (Fig. 2).
She was initially planned for early (within 7 days) CBD prosthesis removal, however this approach was postponed because of post-ERCP pancreatitis development with elevation of serum and urine amylase activity (2701 U/l and 3803 U/l, respectively). In the subsequent MRI examination, signs of pancreatic edema and irregularity of pancreatic borders were noted. Despite the presence of peripancreatic fluid collections, stranding fat densities and temporary signs of paralytic ileus she was successfully treated with TPN, fluid resuscitation and broad-spectrum antibiotics. She was qualified to elective laparoscopic cholecystectomy, which was performed 6 weeks after ERCP. On laparoscopy a thickened, callous wall of the gall bladder was revealed. Liver surface appeared to be nodular with increased consistency. Due to the problems with clear delineation of gall bladder bed, the lack of possibility of proper identification of hepatic hilum structures and bleeding, the procedure was converted to the open cholecystectomy. After gallbladder and biliary stent removal, a careful hemostasis of gallbladder fossa was performed using argon beam coagulation and 4DryField starch powder. In the early postoperative course an increased amount of drained fluid was observed but drainage was removed on the third postoperative day and spontaneous biliary flow without any complications was obtained. Due to subsequent transient elevation of serum amylase and poor wound healing she was successfully managed conservatively with vancomycin and ceftriaxone. Further postoperative course was uneventful.
Two weeks later she was admitted to hospital with mild acute lower gastrointestinal bleeding. Stool samples were tested negative for rotavirus, adenovirus and norovirus, but positive for Campylobacter jejuni and Clostridium difficile. Blood CMV and EBV reactivation were also ruled out. The ileocolonoscopy revealed a 3-4 cm crater-like ulcer located 2-3 cm from the anal margin, which was covered by yellowish slough surrounded by reactive mucosa. Another ulcer was found at the recto-sigmoid junction (Fig. 3). Microscopically, lymphocytic and neutrophilic mucosa infiltrate that focally infiltrated crypt epithelium with mild crypt distortion and signs of regeneration were present in the entire colon. Based on histopathology, CMV infection and GVHD in the colon were excluded. The girl was treated with intravenous azithromycin and orally budesonide and mesalamine. A clinical and endoscopic improvement was noted at the second endoscopy performed four weeks later.
Three month later no complaints were reported (Table 1). There were symptoms of immunological recovery, and the girl presented an increasing donor chimerism (63%).