Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by impaired microbial killing and susceptibility to bacterial and fungal infections. Cure of the disease can be achieved by stem cell transplantation when performed early in its course, and before severe infections have developed. Invasive aspergillosis constitutes a very high risk for transplantation. We report a 4-year-old boy with X-linked CGD who underwent successful HLA-identical peripheral blood stem cell (PBSC) transplantation during invasive pulmonary aspergillosis and osteomyelitis of the left fourth rib, which was unresponsive to antifungal treatment. During the 2 months prior to the transplant he received G-CSF-mobilized granulocyte transfusions (GTX) from unrelated donors three times a week in addition to the antifungal treatment. This resulted in clinical improvement in his respiratory status. He also received GTX during the aplastic period after the conditioning regimen, until he had engrafted. Post-transplant superoxide generation test revealed that neutrophil function was within normal range. One year post transplant the CT scan showed almost complete clearance of the pulmonary infiltrates and a marked improvement in the osteomyelitic process. Based on other reports and our own experience, GTX can serve as important treatment in patients with CGD who have failed conventional anti-fungal treatment and for whom stem cell transplantation is the only chance for cure. Bone Marrow Transplantation (2000) 26, 1025–1028.
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by a defect in the generation of the oxidative burst that normally accompanies phagocytosis of microorganisims. Mutations in one of the four subunits of the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase lead to failure to generate superoxide and impaired killing of microorganisms. Increased susceptibility to bacterial and fungal (especially aspergillosis) infections characterize the course of the disease. However, there is considerable heterogeneity in the clinical course among individuals affected by CGD. The prognosis of patients with CGD has improved substantially in the last few decades due to prophylactic antibiotic therapy, prompt treatment of established infections and administration of γ-interferon.123 Bone marrow transplantation in CGD can be curative and has been successful in several cases.4567891011 However, it carries a substantial risk of morbidity and mortality due to the toxicity of the preparative regimen, especially in patients who already are debilitated as a consequence of severe and recurrent infections.
Recently, Oszhim et al10 described an 8-year-old boy with CGD who underwent a successful HLA-identical BMT during invasive multifocal aspergillosis, supported with G-CSF-mobilized granulocyte transfusions during the aplastic period.
We have used this approach as a preparation for stem cell transplantation in a 4-year-old boy with CGD and severe pulmonary aspergillosis. He received granulocyte transfusions in addition to liposomal amphotericin and 5FC in the 2 month period prior to the transplant. The combined treatment resulted in clinical improvement and allowed him to tolerate the transplant procedure better.
A 4-year-old boy with X-linked CGD (C688 → T mutation in exon VII resulting in a change from arginine to a stop codon) was referred to our department for allogeneic PBSC transplantation. The boy had had recurrent bacterial and fungal infections since the first month of his life and was diagnosed with CGD at the age of 4 months. A year and a half prior to his admission, he had bilateral pulmonary infiltrates and the diagnosis of aspergillus infection was confirmed by open lung biopsy. Despite treatment with amphotericin B, 5FC, liposomal amphotericin and itraconazole, the lung infection progressed to involve the pleura and the left fourth rib. The boy was febrile, dyspnoeic and tachypnoeic and was bedridden most of the time. CT scan of the chest demonstrated bilateral pulmonary infiltrates, pleural masses (Figure 1a, arrows) and a lytic lesion of the left fourth rib (Figure 1b, arrow).
Due to failure of the antifungal treatment and progression of the infection we decided to prepare him with granulocyte transfusions (GTX) and to proceed to PBSC transplantation after his condition stabilized. During a 2 month period he received G-CSF-mobilized, irradiated GTX from unrelated ABO-compatible donors, three times a week. Each donor was given G-CSF at 5 μg/kg s.c. the night before granulocyte collection. Leukopheresis was performed on the Cobe Spectra blood cell separator by continuous-flow centrifugation (Cobe, Lakewood, CO, USA). The final product was irradiated with 25 Gy. Informed consent for G-CSF mobilization was obtained from all donors. The donors tolerated the procedure without serious side-effects. The patient received 1 × 109/kg granulocytes at each transfusion in addition to liposomal amphotericin and 5FC. He tolerated the transfusions well except for fever and chills, which were treated with corticosteroids and acetaminophen. Although there was no change in the CT scan obtained 1 month after the initiation of the GTX, he became less tachypnoeic and dyspnoeic and there was resolution of the fever. The patient was transplanted from his HLA-identical brother. The conditioning regimen consisted of busulfan to a total dose of 16 mg/kg (days −9 to −6) with monitoring of blood levels, cyclophosphamide to a total dose of 200 mg/kg (days −5 to −2) and ATG (Fresenius, Hamburg, Germany) 10 mg/kg/day (days −5 to −2). GVHD prophylaxis included cyclosporin A and methotrexate. On day 0 he received 27 × 108/kg nucleated cells containing 17 × 106/kg CD34+ cells and 1 × 109/kg CD3+ cells. He was started on G-CSF at a dose of 10 μg/kg/day from the day of transplant until his blood counts had stabilized. Engraftment was rapid: ANC >0.5 × 109/l was on day 9 and time to platelet transfusion independence was 11 days. During the period of aplasia he continued with GTX until his blood counts recovered. Engraftment was confirmed by microsatellite studies, showing complete donor chimerism, as well as by the superoxide generation test which was performed 2 weeks after the last GTX and showed that his granulocytes were capable of generating superoxide within the normal range (Table 1).
Post-transplant complications included grade III skin GVHD on day 60, which was treated with high-dose corticosteroids, ATG, cyclosporin A and mycophenolate and gradually resolved. On day 92 he developed hemorrhagic cystitis associated with BK viruria and reactivation of CMV. All symptoms resolved within a month of treatment with fluids, ganciclovir and IVIG.
Started on day 15 post transplant, the antifungal treatment was switched to voriconazole at the dose of 50 mg twice a day, and continued for 1 year without any side-effects. CT scan obtained 4 months post transplant demonstrated marked improvement of his pulmonary disease and 8 months later there was almost complete disappearance of the lung and pleural infiltrates (Figure 1c) and healing of the osteomyelitic process in the rib with new bone formation (Figure 1d arrow).
The boy is now 16 months post transplant, with good health and performance status with no evidence of infections.
In recent years, renewed interest has arisen in granulocyte transfusions (GTX) with the increased use of G-CSF which enables the collection of large number of granulocytes. G-CSF given to normal donors increased the total number of the granulocytes substantially, provided a longer duration of coverage and was well tolerated by the donors.12 GTX can serve as a therapeutic option in cancer patients with severe neutropenia and life-threatening infections, in BMT recipients and also in patients with congenital disorders of neutrophil function like CGD. To date, several patients with CGD complicated by life-threatening bacterial or fungal infections have been reported to benefit from GTX.13141516 Until recently, stem cell transplantation was usually contraindicated in CGD patients with invasive aspergillosis. Oszhim et al10 were the first to use a combination of GTX and antifungal treatment in the context of BMT. Their patient, an 8 year-old boy with X-linked CGD and invasive aspergillosis was treated with G-CSF-mobilized granulocytes during the period of aplasia post BMT. They also showed that administration of G-CSF to the recipient prolonged the viability of the transfused granulocytes, which was confirmed in vitro by apoptosis assays and positive nitroblue tetrazolium (NBT) tests. Recently, another possible approach to reduce the toxicity of the preparative regimen was reported by Nagler et al11 using a submyeloablative conditioning regimen and donor leukocyte infusion. The patient in our case received GTX as preparation prior to PBSC transplant with clear improvement in his clinical status. The advantage of using PBSC in this case was that neutrophil engraftment was rapid and the patient needed only three more GTX before recovery of his own counts.
Repeated GTX can result in alloimmunization to HLA and neutrophil antigens which can lead to refractoriness to platelet transfusion, difficulty with engraftment and to transfusion reactions.1718 Our patient had one episode of platelet refractoriness which was treated with HLA-matched platelets from his donor and soon after his own platelets recovered. There was no delay in engraftment, a fact that can be attributed to the large dose of CD34+ cells that he had received.
In conclusion, the use of granulocyte transfusions, PBSC transplantation and G-CSF post transplant can enable cure of CGD patients previously considered an unacceptable risk for transplantation.
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Cite this article
Bielorai, B., Toren, A., Wolach, B. et al. Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation. Bone Marrow Transplant 26, 1025–1028 (2000). https://doi.org/10.1038/sj.bmt.1702651
- chronic granulomatous disease
- G-CSF-mobilized granulocyte transfusion
- peripheral blood stem cell transplantation
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