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Unrelated donor and hla-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with good long-term outcome and growthUnrelated donor and HLA-identical sibling haematopoieticstem cell transplantation cure chronic granulomatous diseasewith good long-term outcome and growth Laura B. K. R. Jones,1 Stephen Hughes,1Stephen Hodges,2 Terence J. Flood,1 Chronic granulomatous disease (CGD) causes recurrent infection and experience frequent hospitalisations and 50% mortality by 30 years.
Haematopoietic stem cell transplantation (HSCT) can cure CGD with resolution of infection and colitis. This study reports the survival and long- term outcome in 20 conditioned patients treated between 1998 and 2007, 2Paediatric Gastroenterology, Newcastle upon using 10 matched sibling (MSD) and 10 unrelated donors (URD). Age at Tyne Hospitals Foundation Trust, 3Regional HSCT, graft-versus-host disease (GvHD), growth, and outcome were Immunology laboratory, Newcastle upon Tyne analysed. Fourteen had ‡1 invasive infection, 10 had colitis and seven had Hospitals Foundation Trust, 4Department of growth failure before HSCT. Median age at transplantation was 75 months Haematology, Newcastle upon Tyne Hospitals (range 15 months–21 years). Eighteen (90%) were alive 4–117 months Foundation Trust, and 5Institute of Cellular (median 61) after HSCT with normal neutrophil function. Two died from Medicine, Child Health, University of Newcastle disseminated fungal infection. Two experienced significant chronic GvHD, with continuing sequelae in 1. Colitis resolved within 8 weeks of HSCT.
Mean weight and height for age Z scores on recovery from HSCT rosesignificantly (P < 0Æ001). HSCT with MSD or URD gave excellent engraftment and survival, remission of colitis and catch-up growth, with low incidence of significant GvHD. Transplant-associated complications were restricted to those with pre-existing infection or inflammation, supporting Newcastle General Hospital, Westgate Road, the argument for early HSCT for more CGD patients with a well matched *E. Soncini and M.A. Slatter contributed equally Keywords: chronic granulomatous disease, graft-versus-host disease, hae- matopoietic stem cell transplantation.
Chronic granulomatous disease (CGD) is an X-linked or to colitis with subsequent growth failure (Scha¨ppi et al, 2001; autosomal recessive primary immunodeficiency in which Jones et al, 2008; Martire et al, 2008), gastric outlet obstruc- mutations in genes encoding for nicotinamide adenine dinu- tion (Dickerman et al, 1986), inflammatory lung disease, or cleotide phosphate lead to failure of microcidal oxygen granulomata formation causing genitourinary stricture (Wal- metabolite generation in phagocytes (Roos et al, 2007). This causes impaired microbial killing, susceptibility to bacterial Lifelong antibacterial and antifungal prophylaxis with and fungal infections, granulomata formation leading to cotrimoxazole (Margolis et al, 1990) and itraconazole (Mouy inflammatory disease and premature mortality (Mouy et al, et al, 1994) has improved short and medium term survival 1989; Finn et al, 1990; Liese et al, 2000). Most patients present (Cale et al, 2000). Supportive treatment with gamma inter- with suppurative lymphadenitis, liver abscesses, or recurrent feron (IFNc) may reduce the incidence of opportunistic respiratory infection, mainly caused by catalase-positive infection (The International Chronic Granulomatous Disease micro-organisms, such as Aspergillus species, Staphylococcus Cooperative Study Group, 1991). Steroids and aminosalicy- aureus or Burkholderia cepacia (Jones et al, 2008; Martire et al, lates ameliorate colitis and other inflammatory complications, 2008). Persistent inflammatory reaction to infection may lead but these treatments do not cure the underlying genetic defect.
ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 Patients’ life quality is burdened by frequent hospitalisations, dihydrorhodamine (DHR) fluorescence (Mauch et al, 2007), recurrent diarrhoea, inflammatory lung damage, and poor and confirmed by mutation analysis. Nineteen patients had growth (Liese et al, 2000; Jones et al, 2008). Furthermore, X-linked, one autosomal recessive disease (Patient 19). All established fungal infection is difficult to eradicate, and received prophylactic cotrimoxazole and itraconazole, 10 remains a significant cause of infectious mortality (Martire received intermittent courses of IFNc, discontinued at least et al, 2008). The Kaplan–Meier survival curves remain 3 weeks prior to transplantation. Fourteen had ‡1 invasive unchanged, although the age at which decline begins has been infection before HSCT affecting liver, lung, bone, brain, spleen, postponed (Mouy et al, 1989; Jones et al, 2008; Martire et al, kidney or blood requiring antibiotic and, in some, antifungal 2008). Surprisingly, the outcome for patients with autosomal treatment and surgery. Three patients received granulocyte recessive disease is similar to that of patients with X-linked- infusions. Seven patients had previous severe lung infections, CGD (Jones et al, 2008). Annual mortality remains 2–4%; causing restrictive lung defects in five (Table I) and bronchi- invasive aspergillosis accounts for more than 30% of deaths.
ectasis in two. Ten patients had colitis, three gastric outlet (Winkelstein et al, 2000; Jones et al, 2008; Martire et al, 2008).
obstruction; two had CGD-associated urinary urgency. Colitis Even with the best prophylactic treatment, only 50% of was treated with prednisolone or aminosalicylate derivates.
patients are alive at 30 years (Jones et al, 2008; Martire et al, Before HSCT, seven patients, five with colitis, had growth 2008), so alternative curative treatments are needed.
failure, with weight and height <2 Z scores (Patients 10, 14, 15, Haematopoietic stem cell transplantation (HSCT) can cure 17–20). In a further six patients at least one growth parameter CGD with resolution of infection and colitis. Use of T conditioning regimens led to frequent graft failure and graft- versus-host disease (GVHD) (Horwitz et al, 2001). The Euro-pean multi-centre experience of T lymphocyte-replete marrow Patients were treated according to European Group for Blood transplantation using mainly human leucocyte antigen (HLA)- and Marrow Transplantation/European Society for Immuno- matched sibling donors (MSD) after myeloablative condition- deficiencies Inborn Errors Working Party guidelines (Seger ing gave better results; 23/27 patients survived, 22 were cured et al, 2000). The local ethics committee stated that ethical (81%), with deaths confined to high risk patients with active approval was not required. Patients, or parents where appro- fungal infection (Seger et al, 2000). However, the risks and priate, gave written informed consent before undergoing benefits of using URD, optimal timing of HSCT and longer treatment. Patients received cytoreductive chemotherapy in term outcome after HSCT remained unclear. This is the largest accordance with the European Group for Blood and Marrow single centre report of survival and long-term outcome after Transplantation/European Society for Immunodeficiencies HSCT for CGD: for the first time a cohort where 50% of Inborn Errors Working Party guidelines current at time of patients received unrelated donor (URD) grafts is described.
transplantation. No patients received radiotherapy. Sixteenreceived myeloablative conditioning (busulphan 16 mg/kg,cyclophosphamide 200 mg/kg) with alemtuzumab (1 mg/kg) if a non-sibling donor was used. Two patients, with activefungal infection and restrictive pulmonary disease, respec- tively, received fludarabine 150 mg/m2, melphalan 140 mg/m2, Between 1998 and 2007, 20 patients underwent HSCT for CGD and alemtuzumab 1 mg/kg. One adult patient received at the UK Northern Supra Regional HSCT Unit for Primary alemtuzumab 2 mg/kg, fludarabine 150 mg/m2 and busulphan Immunodeficiency, Newcastle upon Tyne. A retrospective data 8 mg/kg, the other CAMPATH 1-G (100 mg total dose), analysis was performed to December 2007. Age at HSCT, busulphan 16 mg/kg and melphalan 140 mg/m2. Ten patients donor type, HLA matching, conditioning, immune-reconsti- had active inflammatory disease and two had active fungal tution, significant post-HSCT complications including GvHD, growth, lung function and outcome were abstracted from Donor and recipient HLA matching was determined by medical records. Two further patients with CGD were assessed.
serology for the earlier five patients and low resolution class I During this time, one adult with end stage respiratory and liver with high resolution class II molecular DNA typing in the disease was not offered transplantation, and the family of one child with CGD who had a matched unrelated donor declined Ten patients received MSD HSC (1 umbilical cord blood stem cells, UCBSC (Bhattacharya et al, 2003)). Eight patientsreceived 10/10 HLA-identical URD HSC – 2 peripheral bloodstem cells (PBSC), six bone marrow. One patient received 9/10 HLA-matched (1 Antigen C mismatch) URD PBSC, one 9/10 Patient characteristics are shown in Tables I and II. Diagnosis HLA-matched (1 Antigen A mismatch) URD UCBSC.
was made by neutrophil oxidative burst (NOB) measured by All patients received cyclosporine as GvHD prophylaxis.
the nitroblue tetrazolium (NBT) assay; more recently by Twelve received at least two doses of methotrexate 10mg/m2; ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 URD or MSD HSCT Cures CGD with Catchup Growth ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 URD or MSD HSCT Cures CGD with Catchup Growth ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 URD or MSD HSCT Cures CGD with Catchup Growth four received prednisolone. All were isolated in laminar airflowfacilities, and received anti-fungal and anti-viral prophylaxis.
Immunoglobulin prophylaxis was continued following HSCT,until IgM production was observed. It was then discontinued,and after a 3-month washout period, vaccination wascommenced.
Neutrophil oxidative burst and chimerism measurement The NBT and DHR assays were used to measure NOB, aspreviously described (Mauch et al, 2007). Donor chimerismwas measured by labelling blood with anti-CD3, -CD19 or -CD15 micro beads and cell lines were separated using anautoMACSÒ automated bench-top magnetic cell sorter (Milt-enyi Biotec Ltd, Surrey, UK). Chimerism was determined aspreviously described (Routledge et al, 2007).
A Cox Proportional Hazards Survival Regression Analysis wasused to evaluate the impact of independent predictors(GvHD ‡ grade 2, pre-existing colitis, pre-existing inflamma-tory lung disease, pre-existing fungal infection, myelo-ablative Fig 1. Kaplan–Meier survival estimates.
or reduced intensity cytoreductive chemotherapy condition-ing, matched sibling or unrelated donor stem cell source) on Patient 20 died 1 d prior to transplantation from multiorgan patient survival. Hazard ratios (RR) were provided with their failure secondary to disseminated Aspergillus nidulans infec- 95% confidence interval (gb-stat PPCworks 6.5.4; Dynamic tion, resistant to itraconazole. Necroscopy revealed fungal Microsystems Inc, Silver Spring, MD, USA) – a value of pericarditis, a perinephric aspergilloma, pulmonary oedema P £ 0Æ05 was considered to be significant.
and congestion. Patient 10, with previous disseminatedScediosporum apiopsermum infection, died after discharge fromhospital, from catastrophic haemorrhage secondary to arterial erosion by a tracheostomy tube, placed to manage post- Median age at transplantation was 75 months (range resolved (Gompels et al, 2002). Full donor engraftment froma matched sibling had been achieved; there was no activefungal infection documented at necroscopy. There was no difference in mortality between patients receiving HLA- There was one episode of serious conditioning-related toxicity, matched sibling or unrelated donor HSC.
hepatic sinusoidal obstruction syndrome, which resolvedfollowing treatment with defibrotide. Eighteen of 20 (90%) patients were alive 4–117 months (median 61) after HSCT(Fig 1). The median length of stay on the HSCT unit was 52 d Nine patients experienced no GvHD. Seven had acute grades (range 37–248). Engraftment with functioning neutrophils was I – II skin GvHD, which resolved quickly with topical and/or observed in all 19 transplanted patients. The NOB remained systemic steroids and/or topical tacrolimus. Two patients had normal or ‡70% of neutrophils in 15 patients. In two, after significant GvHD. Patient 4 had previous hepato-biliary initial engraftment, chimerism, as assessed by percentage of surgery, and developed progressive hyperbilirubinaemia and neutrophils with positive NOB, fell to 10% and 14% (Patients transaminitis from day +8. He became icteric with a confluent 1, 2). Both received unconditioned boost marrow infusions rash, which was confirmed histologically as GvHD. Histolog- from the original donor, 7 and 9 months after the first HSCT ical assessment of hepatic biopsy showed mild early chronic respectively; subsequently the NOB was 50% and 28% liver GvHD. Despite immunosuppression, hepatic dysfunction respectively. One patient had a stable NOB of 45%; all continued. Hepatic function normalized after a bile collection, evaluable patients have normal lymphocyte counts and anti- related to a pre-existing bile duct stricture, was surgically body responses to vaccine antigens and remain infection-free regardless of NOB levels. Immune reconstitution kinetics were Patient 9, who had pre-existing colitis, developed prolonged grade II gut and liver GvHD, requiring protracted therapy with ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 prednisolone, mycophenolate mofetil, tacrolimus and inflix- restrictive defect, showed a slight improvement in lung imab, which finally resolved 6 years after HSCT. He developed function. After HSCT he had recurrent upper respiratory tract hand tremor, mild renal dysfunction, hypertension and infections (URTI), computerised tomography showed bron- osteoporosis with avascular necrosis of the right hip-joint for chiectasis; no investigation was performed before HSCT.
which he required orthopaedic intervention. He remains on Patient 5, with pre-existing chronic lung disease, and antihypertensive and antidepressant treatment, but is other- bronchiectasis, continued to have URTI following HSCT, wise well. There was no relationship between GvHD and despite antibiotic prophylaxis. Bronchiectasis progressed, with deteriorating lung function leading to poor exercise tolerance(FEV1 63% of predicted value).
Ten patients were affected by colitis pre HSCT; all had complete resolution of symptoms within 8 weeks of HSCT.
Fourteen patients had no significant infectious problems. Two Multivariate analysis did not show a significant association patients died from complications relating to disseminated of GvHD ‡grade 2, pre-existing colitis, pre-existing inflam- fungal infection. Patient 9 developed grade III haemorrhagic matory lung disease, pre-existing fungal infection, myelo- cystitis from day )4, related to polyomavirus, requiring ablative or reduced intensity cytoreductive chemotherapy bladder irrigation and diathermy. Patient 14 failed to engraft conditioning, with either donor type or with outcome.
due to incomplete myeloablation, developed Candida albicanspneumonia, which was confirmed by culture of bronchoalve- olar lavage fluid, and which completely resolved on treatmentwith liposomal amphotericin, voriconazole and IFNc. He was Growth was evaluated in 11 patients followed >2 years for re-transplanted successfully and uneventfully following fully whom there was adequate post-transplant data. The mean myeloablative chemotherapy. Patient 15 developed haemolytic weight for age Z score in the year preceding HSCT was )1Æ7 anaemia, thrombocytopenia and neutropenia 51 d post-HSCT, [standard deviation, (SD) 1Æ1]. Four patients were underweight associated with adenoviral detection in stool and blood by prior to HSCT (weight for age Z score < 2Æ0); one was severely polymerase chain reaction (PCR) and cytomegalovirus (CMV) underweight (weight for age Z score )3Æ8). All patients in blood by PCR. He responded to rituximab, immunoglob- demonstrated weight gain by the latest review. Mean weight for ulin, prednisolone, cyclosporine, cidofovir, valgancyclovir age Z score at review ()0Æ16, SD 1Æ0) was significantly greater and foscarnet. Twenty months post-HSCT he was well than before HSCT (P < 0Æ001, paired t test) (Fig 2A).
The mean height for age Z score in the year preceding HSCT No patients developed major infections beyond 3 months was )1Æ7 (SD 0Æ9). At time of HSCT, patients 17 and 18, both aged 15Æ6 years, had experienced premature growth arrest withsevere growth retardation (height for age Z score < 3Æ0). Nineothers (age range 2–17 years) had height for age Z score scores between )0Æ75 and )1Æ75. All patients at time of latest review Fifteen patients were alive and well more than 12 months post- demonstrated height gain and improvement in height for age Z HSCT (three were <1 year from HSCT), had discontinued score. The mean height for age Z score on recovery from HSCT immunoglobulin replacement and had normal lymphocyte ()0Æ39, SD 0Æ9) had risen significantly (P < 0Æ001) (Fig 2B).
numbers and immunoglobulin levels. Eleven patients have Most rapid height gain was seen in adolescents who discontinued all medication, four continue with antibiotic experienced linear growth arrest (Patients 17, 18). Less rapid prophylaxis for polysaccharide antibody deficiency or bron- growth, but better final height was seen in two further adolescents (Patients 8, 9). Excluding the dramatic catch upgrowth of patients with earlier growth arrest, the youngerpatients (aged 2–7 years) also demonstrated significant catch up linear growth from a mean height for age Z score of )1Æ1 Spirometry was performed routinely in patients >8 years of (pre-HSCT) to a mean height for age Z score of 0Æ0 at the most age, and in younger patients with respiratory symptoms who were compliant with instructions. A restrictive lung defect wasdiagnosed in four patients prior to HSCT, one of whom had bronchiectasis. In two (Patients 7, 18), lung function remainedstable after HSCT. Respiratory function dramatically improved Sixteen patients have normal thyroid function, two with a after HSCT in Patient 17, from 58Æ6% to 95Æ4% forced slightly raised anti-thyroid antibody and thyroid-stimulating expiratory volume in one second (FEV1). In Patient 8, hormone level. Two developed biochemical and clinical following HSCT, lung function improved from FEV1 63% to features of thyroid dysfunction, one requiring carbimazole 79% of predicted, despite development of mild bronchiectasis for thyrotoxicosis and one receiving thyroxine replacement for not previously documented. Patient 9, with a previous ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 URD or MSD HSCT Cures CGD with Catchup Growth sequelae. There were no differences in the complications or outcomes for recipients of matched sibling or unrelated Fungal infection remains the most serious concern following transplantation, implicated in the two deaths in this series, arguing for early transplantation prior to infection. In all survivors, CGD has been cured, with sustained NOB levels eight Z score
above that required for normal host defence, and complete lack of infection beyond the transplant period. It is of particular note that no patient has experienced fungal infection post-transplantation, despite antifungal prophylaxis being discontinued. Furthermore, whilst there was an episode of serious infection (pneumonia, suppurative adenitis, liver orlung abscess, septicaemia or osteomyelitis) every 3Æ9 patient follow up years in the recently published UK and Ireland registry series (Jones et al, 2008), there were no such infections in 80Æ5 patient follow up years in this post-transplant series.
Chimerism and NOB continue to be monitored, but previous experience of successful HSCT for neutrophil disorders showed that chimerism did not change after 1-year post- HSCT, suggesting that long-term neutrophil function will be Height Z score –3
good (Ferry et al, 2005). This is in contra-distinction to gene therapy for CGD, where gene silencing has occurred, with loss of already low levels of neutrophil function (Ryser et al, 2007; European Society of Gene Therapy (ESGT), 2006). Lymphoid reconstitution was also good, but two patients have minor humoral problems with failure to mount an antibody response Fig 2. (A) Z scores for weight pre- and post- haematopoeitic stem cell to Pneumococcus. These features together with thyroid dys- transplantation in 11 patients followed for more than 2 years post- function are occasionally observed after HSCT. Thyroid transplantation for chronic granulomatous disease. (B) Z scores for dysfunction, usually autoimmune thyroiditis, is the most height pre- and post- haematopoeitic stem cell transplantation in 11 common long-term endocrine complication after HSCT patients followed for more than 2 years post-transplantation for (Slatter et al, 2004); in this series the incidence was 2/18 chronic granulomatous disease. Patient numbers identify with those inTables I and II.
(11%). There is a risk that conditioning chemotherapy willcause infertility, although long-term data are sparse, and thereare reports of successful conception in adults who previouslyreceived myelo-ablative chemotherapy as children when undergoing HSCT for primary immunodeficiency. Of 15 The long-term survival of patients with CGD remains poor, patients followed for more than 12 months post-transplanta- despite prophylactic treatment having improved outcome tion, 9 (60%) are on no medication at all with a completely during childhood. This study analysed the outcome of 20 patients with CGD who underwent HSCT from matched Growth failure and delay in puberty is a common feature of sibling or unrelated donors following myelo-ablative or CGD patients for reasons that are not fully understood. An reduced-intensity conditioning, and showed 100% engraft- important observation of this study was the remission of ment in those transplanted and 90% survival. Both deaths inflammatory colitis and subsequent catch-up growth, a occurred in patients who had pre-existing invasive fungal feature rarely, if ever, seen in patients treated conservatively.
infection. Transplant-associated complications were restricted The positive benefits, normal growth and improvement in to those with pre-existing infection or inflammation, as has quality of life with no need for medication and only annual previously been shown in patients transplanted for primary visits to hospital for follow up are clear. This is in contrast to immunodeficiency (Antoine et al, 2003; Gennery et al, 2004).
non-transplanted patients who remain on lifelong antimicro- There was only one episode of significant conditioning bial prophylaxis, with a continued risk of infection from toxicity despite the use of mainly myeloablative regimens.
organisms resistant to the prophylactic agents, and who often There was a low incidence of significant GvHD, restricted to have frequent hospitalization with infection, inflammatory those with pre-existing inflammation or previous surgery, an complications and surgery (Jones et al, 2008; Martire et al, encouraging result considering that 47% received URD HSC.
2008). A more detailed quality of life assessment between these In all but one case, GvHD resolved with no long-term two patient groups is planned. The information from this ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 study, combined with the good outcome with low risk of Ferry, C., Ouache´e, M., Leblanc, T., Michel, G., Notz-Carre´re, A., sequelae obtained in those patients transplanted whilst young, Tabrizi, R., Flood, T., Lutz, P., Fischer, A., Gluckman, E. & Dona- with no pre-existing inflammation or fungal infection would dieu, J. (2005) Hematopoietic stem cell transplantation in severe support the argument for considering early HSCT for young congenital neutropenia: experience of the French SCN register. BoneMarrow Transplantation, 35, 45–50.
CGD patients with a well-matched donor. Additionally, the Finn, A., Hadzic´, N., Morgan, G., Strobel, S. & Levinsky, R.J. (1990) development of low toxicity conditioning regimens offers the Prognosis of chronic granulomatous disease. Archives of Disease in opportunity of HSCT for older, high-risk patients (Gu¨ngo¨r et al, 2005). It is our practice to offer HSCT early for paediatric Gennery, A.R., Khawaja, K., Veys, P., Bredius, R.G., Notarangelo, L.D., patients for whom there is a well-matched donor. The risk of Mazzolari, E., Fischer, A., Landais, P., Cavazzana-Calvo, M., Fried- complications following HSCT is generally greater in adults, rich, W., Fasth, A., Wulffraat, N.M., Matthes-Martin, S., Bensous- and therefore needs careful consideration, but the good san, D., Bordigoni, P., Lange, A., Pagliuca, A., Andolina, M., Cant, outcome using low toxicity regimens means that this option A.J. & Davies, E.G. (2004) Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the Europeanexperience, 1993–2002. Blood, 103, 1152–1157.
Gompels, M.M., Bethune, C.A., Jackson, G. & Spickett, G.P. (2002) Scedosporium apiospermum in chronic granulomatous diseasetreated with an HLA matched bone marrow transplant. Journal of E. Soncini collected, analysed and interpreted data; M.A.
Slattter, A.R. Gennery designed research, performed research, Gu¨ngo¨r, T., Halter, J., Klink, A., Junge, S., Stumpe, K.D., Seger, R. & collected, analysed and interpreted data, and drafted the Schanz, U. (2005) Successful low toxicity hematopoietic stem cell manuscript; L.B.K.R. Jones, T.J. Flood and M. Abinun helped transplantation for high-risk adult chronic granulomatous disease draft the manuscript; S. Hughes collected, analysed and patients. Transplantation, 79, 1596–1606.
interpreted data and performed statistical analysis; S. Hodges, Horwitz, M.E., Barrett, A.J., Brown, M.R., Carter, C.S., Childs, R., G.P. Spickett, D. Barge, G.H. Jackson, and M.P. Collin Gallin, J.I., Holland, S.M., Linton, G.F., Miller, J.A., Leitman, S.F., collected data, and helped draft the manuscript; A.J.C. helped Read, E.J. & Malech, H.L. (2001) Treatment of chronic granulom- design the research, interpreted data, and helped draft the atous disease with nonmyeloablative conditioning and a T-cell- depleted hematopoietic allograft. New England Journal of Medicine,344, 881–888.
Jones, L., McGrogan, P., Flood, T.J., Gennery, A.R., Morton, L., Thrasher, A., Goldblatt, D., Parker, L. & Cant, A.J. (2008) ChronicGranulomatous Disease in the UK and Ireland – A comprehensive The authors declare no competing financial interests.
national patient based registry. Clinical and Experimental Immu-nology, 152, 211–218.
Liese, J., Kloos, S., Jendrossek, V., Petropoulou, T., Wintergerst, U., Notheis, G., Gahr, M. & Belohradsky, B.H. (2000) Long-term fol- Antoine, C., Mu¨ller, S., Cant, A., Cavazzana-Calvo, M., Veys, P., low-up and outcome of 39 patients with chronic granulomatous Vossen, J., Fasth, A., Heilmann, C., Wulffraat, N., Seger, R., Blanche, disease. Journal of Pediatrics, 137, 687–693.
S., Friedrich, W., Abinun, M., Davies, G., Bredius, R., Schulz, A., Margolis, D.M., Melnick, D.A., Alling, D.W. & Gallin, J.I. (1990) Landais, P., Fischer, A. & European Group for Blood and Marrow Trimethoprim-sulfamethoxazole prophylaxis in the management of Transplantation; European Society for Immunodeficiency (2003) chronic granulomatous disease. Journal of Infectious Diseases, 162, Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99.
Martire, B., Rondelli, R., Soresina, A., Pignata, C., Broccoletti, T., Finocchi, A., Rossi, P., Gattorno, M., Rabusin, M., Azzari, C., Bhattacharya, A., Slatter, M., Curtis, A., Chapman, C.E., Barge, D., Dellepiane, R.M., Pietrogrande, M.C., Trizzino, A., Di Bartolomeo, Jackson, A., Flood, T.J., Abinun, M., Cant, A.J. & Gennery, A.R.
P., Martino, S., Carpino, L., Cossu, F., Locatelli, F., Maccario, R., (2003) Successful umbilical cord blood stem cell transplantation for Pierani, P., Putti, M.C., Stabile, A., Notarangelo, L.D., Ugazio, A.G., chronic granulomatous disease. Bone Marrow Transplantation, 31, Plebani, A., De Mattia, D. & IPINET (Italian Network for Primary Immunodeficiencies) (2008) Clinical features, long-term follow-up Cale, C.M., Jones, A.M. & Goldblatt, D. (2000) Follow up of patients and outcome of a large cohort of patients with Chronic Granu- with chronic granulomatous disease diagnosed since 1990. Clinical lomatous Disease: An Italian multicenter study. Clinical Immunol- and Experimental Immunology, 120, 351–355.
Dickerman, J.D., Colletti, R.B. & Tampa, J.P. (1986) Gastric outlet Mauch, L., Lun, A., O’Gorman, M.R., Harris, J.S., Schulze, I., obstruction in chronic granulomatous disease of childhood. Amer- Zychlinsky, A., Fuchs, T., Oelschla¨gel, U., Brenner, S., Kutter, D., ican Journal of Diseases of Children, 140, 567–570.
Ro¨sen-Wolff, A. & Roesle, J. (2007) Chronic granulomatous dis- European Society of Gene Therapy (ESGT) (2006) One of three suc- ease (CGD) and complete myeloperoxidase deficiency both yield cessfully treated CGD patients in a Swiss-German gene therapy trial strongly reduced dihydrorhodamine 123 test signals but can be died due to his underlying disease: a position statement from the easily discerned in routine testing for CGD. Clinical Chemistry, 53, European Society of Gene Therapy (ESGT). The Journal of Gene ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 145, 73–83 URD or MSD HSCT Cures CGD with Catchup Growth Mouy, R., Fischer, A., Vilmer, E., Seger, R. & Griscelli, C. (1989) Passwell, J.H., Porta, F., Slavin, S., Wulffraat, N., Zintl, F., Nagler, A., Incidence, severity, and prevention of infections in chronic granu- Cant, A. & Fischer, A. (2000) Treatment of chronic granulomatous lomatous disease. Journal of Pediatrics, 114, 555–560.
disease with myeloablative conditioning and an unmodified hemo- Mouy, R., Veber, F., Blanche, S., Donadieu, J., Brauner, R., Levron, poietic allograft: a survey of the European experience, 1985–2000.
J.C., Griscelli, C. & Fischer, A. (1994) Long-term itraconazole pro- phylaxis against Aspergillus infections in thirty-two patients with Slatter, M.A., Gennery, A.R., Cheetham, T.D., Bhattacharya, A., chronic granulomatous disease. Journal of Pediatrics, 125, 998–1003.
Crooks, B.N., Flood, T.J., Cant, A.J. & Abinun, M. (2004) Roos, D., Kuijpers, T.W. & Curnette, J.T. (2007) Chronic Granulom- Hypothyroidism post bone marrow transplantation for primary atous Disease. In: Primary Immunodeficiency Diseases; A molecular immunodeficiency syndromes without the use of total body and genetic approach 2nd, edn (ed. by H.D. Ochs, C.I.E. Smith & irradiation in conditioning. Bone Marrow Transplantation, 33, 949– J.M. Puck), pp. 525–549. Oxford University Press, Oxford.
Routledge, D., Jackson, A., Bourn, D., Bown, N., Cole, M., Slatter, The International Chronic Granulomatous Disease Cooperative Study M.A., Gennery, A.R. & Curtis, A. (2007) Quantitative assessment of Group (1991) A controlled trial of interferon gamma to prevent mixed chimaerism in allogeneic stem cell transplant patients: a infection in chronic granulomatous disease. The New England comparison of molecular genetic and cytogenetic approaches.
Journal of Medicine, 324, 509–516.
Journal of Pediatric Hematology/Oncology, 29, 428–431.
Walther, M.M., Malech, H., Berman, A., Choyke, P., Venzon, D.J., Ryser, M.F., Roesler, J., Gentsch, M. & Brenner, S. (2007) Gene therapy Linehan, W.M. & Gallin, J.I. (1992) The urological manifestations for chronic granulomatous disease. Expert Opinion on Biological of chronic granulomatous disease. Journal of Urology, 147, 1314– Scha¨ppi, M.G., Smith, V.V., Goldblatt, D., Lindley, K.J. & Milla, P.J.
Winkelstein, J.A., Marino, M.C., Johnston, Jr, R.B., Boyle, J., Curnutte, (2001) Colitis in chronic granulomatous disease. Archives of Disease J., Gallin, J.I., Malech, H.L., Holland, S.M., Ochs, H., Quie, P., Buckley, R.H., Foster, C.B., Chanock, S.J. & Dickler, H. (2000) Seger, R.A., Gungor, T., Belohradsky, B.H., Blanche, S., Bordigoni, P., Chronic granulomatous disease. Report on a national registry of 368 Di Bartolomeo, P., Flood, T., Landais, P., Mu¨ller, S., Ozsahin, H., patients. Medicine (Baltimore), 79, 155–169.
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Original Article Efficacy of Combination Therapy with Methotrexate and Misoprostol in Termination of Pregnancy in the First Trimester Abstract Background: Induced abortion is the medical or surgical ter- mination of pregnancy before fetal viability. It has maternal or fetal indications. The aim of the present study was to evaluate the efficacy of the combination of methotr