Chronic Granulomatous Disease: Lessons from a Rare Disorder
2010; Elsevier BV; Volume: 17; Issue: 1 Linguagem: Inglês
10.1016/j.bbmt.2010.09.008
ISSN1523-6536
AutoresBrahm H. Segal, Paul Veys, Harry L. Malech, Morton J. Cowan,
Tópico(s)Bacterial biofilms and quorum sensing
ResumoChronic granulomatous disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins, which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mold-active antifungal agents and the administration of interferon-γ has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT), although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures, and use of reduced toxicity conditioning have resulted in event-free survival (EFS) of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of graft-versus-host disease (GVHD) and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID, and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs, which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells (HSCs). Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins, which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mold-active antifungal agents and the administration of interferon-γ has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT), although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures, and use of reduced toxicity conditioning have resulted in event-free survival (EFS) of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of graft-versus-host disease (GVHD) and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID, and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs, which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells (HSCs). Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal infections and excessive inflammation. CGD affects approximately 1 in 200,000 persons [1Winkelstein J.A. Marino M.C. Johnston Jr., R.B. et al.Chronic granulomatous disease: report on a national registry of 368 patients.Medicine (Baltimore). 2000; 79: 155-169Crossref PubMed Scopus (1241) Google Scholar]. CGD was first described in the 1950s as a fatal granulomatous disease of childhood. In the 1960s, classic studies linked CGD with impaired neutrophil bactericidal activity. Neutrophils from CGD patients failed to show an increase in oxygen consumption and hydrogen peroxide formation. This rapid oxygen consumption ("respiratory burst") was initially attributed to increased mitochondrial respiration, but later linked to the NADPH oxidase. CGD was subsequently identified as a disorder of NADPH oxidase activation. The phagocyte NADPH oxidase functions to rapidly generate superoxide anion by transferring electrons from NADPH to molecular oxygen (Figure 1). The cytochrome of NADPH oxidase, composed of gp91phox (phox, phagocyte oxidase) and p22phox, is embedded in membranes. Upon activation of the oxidase, the cytoplasmic subunits p47phox, p67phox, and p40phox appear to translocate en bloc to the membrane-bound cytochrome. Activation of Rac, a member of the low molecular weight GTP-binding proteins, and translocation of Rac to the membrane-bound cytochrome are also critical for NADPH oxidase activation. CGD results from disabling mutations in genes encoding phox proteins. Approximately two-thirds of CGD cases are X-linked (gp91phox-deficient), and the remainder are autosomal recessive [1Winkelstein J.A. Marino M.C. Johnston Jr., R.B. et al.Chronic granulomatous disease: report on a national registry of 368 patients.Medicine (Baltimore). 2000; 79: 155-169Crossref PubMed Scopus (1241) Google Scholar]. NADPH oxidase activation results in production of superoxide anion and downstream antimicrobial oxidant metabolites, such as hydrogen peroxide and hypohalous acid. Reeves et al. [2Reeves E.P. Lu H. Jacobs H.L. et al.Killing activity of neutrophils is mediated through activation of proteases by K+ flux.Nature. 2002; 416: 291-297Crossref PubMed Scopus (889) Google Scholar] showed that activation of the NADPH oxidase also leads to the activation of antimicrobial proteases sequestered in the primary (azurophilic) granules of neutrophils. Activation of these granular proteases likely enhances killing of pathogens within phagolysosomes. Neutrophils also release granule proteins and chromatin that comingle in the extracellular space and together form neutrophil extracellular traps (NETs). These NETs bind to and kill extracellular bacteria, degrade bacterial virulence factors [3Brinkmann V. Reichard U. Goosmann C. et al.Neutrophil extracellular traps kill bacteria.Science. 2004; 303: 1532-1535Crossref PubMed Scopus (5997) Google Scholar], and target fungi [4Bianchi M. Hakkim A. Brinkmann V. et al.Restoration of NET formation by gene therapy in CGD controls aspergillosis.Blood. 2009; 114: 2619-2622Crossref PubMed Scopus (430) Google Scholar]. Release of NETs requires death of neutrophils and breakdown of cell membranes [5Fuchs T.A. Abed U. Goosmann C. et al.Novel cell death program leads to neutrophil extracellular traps.J Cell Biol. 2007; 176: 231-241Crossref PubMed Scopus (2147) Google Scholar]. Neutrophils from CGD patients are deficient in NET formation [4Bianchi M. Hakkim A. Brinkmann V. et al.Restoration of NET formation by gene therapy in CGD controls aspergillosis.Blood. 2009; 114: 2619-2622Crossref PubMed Scopus (430) Google Scholar, 5Fuchs T.A. Abed U. Goosmann C. et al.Novel cell death program leads to neutrophil extracellular traps.J Cell Biol. 2007; 176: 231-241Crossref PubMed Scopus (2147) Google Scholar]; this deficiency was reversed in neutrophils from a CGD patient following gene therapy [4Bianchi M. Hakkim A. Brinkmann V. et al.Restoration of NET formation by gene therapy in CGD controls aspergillosis.Blood. 2009; 114: 2619-2622Crossref PubMed Scopus (430) Google Scholar], supporting the role of NADPH oxidase in NET generation. CGD patients are susceptible to a spectrum of bacterial and fungal infections. Patients with the X-linked CGD appear to be at greater risk for infection and early mortality compared to patients with autosomal recessive forms of CGD [1Winkelstein J.A. Marino M.C. Johnston Jr., R.B. et al.Chronic granulomatous disease: report on a national registry of 368 patients.Medicine (Baltimore). 2000; 79: 155-169Crossref PubMed Scopus (1241) Google Scholar]. In a U.S. registry of 368 patients with CGD, pneumonia was the most frequent type of infection, occurring in 79% of patients, with Aspergillus species being the most common cause [1Winkelstein J.A. Marino M.C. Johnston Jr., R.B. et al.Chronic granulomatous disease: report on a national registry of 368 patients.Medicine (Baltimore). 2000; 79: 155-169Crossref PubMed Scopus (1241) Google Scholar] (Table 1). Fifty-three percent of patients had suppurative adenitis, 42% had a subcutaneous abscess, and 27% had a liver abscess; Staphylococcus aureus was the most common cause of soft tissue and liver abscesses. Twenty-five percent (25%) had osteomyelitis (Serratia marcescens was the most prevalent cause), and 18% had sepsis (Salmonella species were the most prevalent cause). The most common causes of death were pneumonia and/or sepsis because of Aspergillus species (23 patients) or Burkholderia cepacia (12 patients). A European registry of 429 CGD patients showed that the most frequently cultured pathogens per episode were S. aureus (30%), Aspergillus species (26%), and Salmonella species (16%); Aspergillus species (111 cases) were the most common cause of pneumonia [6van den Berg J.M. van Koppen E. Ahlin A. et al.Chronic granulomatous disease: the European experience.PLoS ONE. 2009; 4: e5234Crossref PubMed Scopus (504) Google Scholar].Table 1Infections in CGDSiteMost Common PathogensDiagnostic MethodsLungs (pneumonia)Aspergillus species and other molds, B. cepacia, S. aureus, Nocardia speciesSputum culture (least invasive but insensitive for molds); blood culture (in cases of pneumonia and secondary bacteremia); bronchoalveolar lavage (BAL) and biopsy; percutaneous lung biopsy; and thoracoscopic or open lung biopsy. More than one pathogen can be present.Lymph nodes (suppurative adenitis)S. aureusCultureSkin (subcutaneous abscesses; infected cysts)S. aureusCultureLiver (abscesses)S. aureusCultureBone (osteomyelitis)S. marcescensCultureBlood (sepsis)Salmonella species, S. aureus, B. cepaciaCultureCGD indicatres chronic granulomatous disease. Open table in a new tab CGD indicatres chronic granulomatous disease. In addition to recurrent infections, CGD is also characterized by abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enteritis resembling Crohn's disease [7Marciano B.E. Rosenzweig S.D. Kleiner D.E. et al.Gastrointestinal involvement in chronic granulomatous disease.Pediatrics. 2004; 114: 462-468Crossref PubMed Scopus (304) Google Scholar] and genitourinary obstruction. "Mulch pneumonitis" is a recently described life-threatening hyperinflammatory response to fungal pneumonia in CGD, requiring both antifungal therapy and systemic corticosteroids [8Siddiqui S. Anderson V.L. Hilligoss D.M. et al.Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease.Clin Infect Dis. 2007; 45: 673-681Crossref PubMed Scopus (117) Google Scholar]. Mouse models of CGD support the notion that excessive inflammatory responses are not simply the result of unresolved infection, but rather reflect an important role of NADPH oxidase in regulating inflammation. For example, Morgenstern et al. [9Morgenstern D.E. Gifford M.A. Li L.L. Doerschuk C.M. Dinauer M.C. Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus.J Exp Med. 1997; 185: 207-218Crossref PubMed Scopus (300) Google Scholar] showed that intratracheal administration of heat-killed A. fumigatus hyphae elicited mild self-limited inflammation in wild-type mice, but robust and persistent inflammation in CGD mice. Romani et al. [10Romani L. Fallarino F. De Luca A. et al.Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease.Nature. 2008; 451: 211-215Crossref PubMed Scopus (449) Google Scholar] linked impaired antifungal host defense and excessive inflammation in CGD mice to defective activation of tryptophan catabolism and generation of regulatory T cell responses. Segal et al. [11Segal B.H. Han W. Bushey J.J. et al.NADPH oxidase limits innate immune responses in the lungs in mice.PLoS ONE. 2010; 5: e9631Crossref PubMed Scopus (151) Google Scholar] showed that CGD mice and peripheral blood mononuclear cells (PBMCs) from CGD patients had impaired activation of Nrf2, a redox-sensitive transcriptional factor that induces oxidant scavenging pathways and functions to limit cellular injury and inflammation. These results support a model in which NADPH oxidase can limit innate and T cell responses by modulating specific redox-sensitive pathways. The first component in care of the CGD patient is early diagnosis. CGD should be suspected in patients with recurrent or unusually severe infections, such as a liver abscess caused by Staphylococcus aureus. In addition, specific opportunistic infections should prompt an evaluation for CGD; these include invasive mold diseases (eg, aspergillosis), and infections by B. cepacia, S. marcescens, and Nocardia species in the absence of a known immunodeficiency. Inflammatory disorders such as inflammatory bowel disease at an early age and granulomatous cystitis can be manifestations of CGD. A family history of males with severe or unusual infections can be a clue to the diagnosis of X-linked CGD, whereas consanguineous parents increase the risk for autosomal recessive disorders. The diagnosis of CGD requires demonstration of defective NADPH oxidase activity in neutrophils. The most common diagnostic assays are the nitroblue tetrazolium dye reduction method (a measure of superoxide anion release) and flow cytometry evaluating dihydrorhodamine 123 (DHR) fluorescence (a measure of intracellular hydrogen peroxide). DHR fluorescence is likely to be the most sensitive method for diagnosis, particularly in cases of variant X-linked and autosomal recessive forms of CGD, where low levels of NADPH oxidase activity may lead to false-positive results with the nitroblue tetrazolium method. CGD patients should receive antibacterial and mold-active antifungal prophylaxis. Trimethoprim-sulfamethoxazole is generally the recommended agent for antibacterial prophylaxis. It is well-tolerated in CGD patients, and has activity against the majority of bacterial pathogens encountered in CGD patients: S. aureus (including the predominant community-acquired strain of methicillin-resistant S. aureus), B. cepacia, and Nocardia species. If trimethoprim-sulfamethoxazole is not feasible (eg, because of allergy), an antistaphylococcal penicillin (eg, dicloxacillin) is advised. Given the high risk of invasive fungal diseases in CGD, mold-active antifungal prophylaxis is also warranted. Itraconazole was safe and effective in patients with CGD [12Gallin J.I. Alling D.W. Malech H.L. et al.Itraconazole to prevent fungal infections in chronic granulomatous disease.N Engl J Med. 2003; 348: 2416-2422Crossref PubMed Scopus (293) Google Scholar]. Extended-spectrum azoles (voriconazole and posaconazole) are alternative agents that can be used as prophylaxis. In a randomized trial, recombinant interferon-γ significantly reduced the incidence of serious infections in patients with CGD [13The International Chronic Granulomatous Disease Cooperative Study GroupA controlled trial of interferon gamma to prevent infection in chronic granulomatous disease.N Engl J Med. 1991; 324: 509-516Crossref PubMed Scopus (692) Google Scholar]. Interferon-γ was beneficial regardless of age, the use of prophylactic antibiotics, and the type of CGD (X-linked or autosomal recessive), and was well tolerated. Although prior studies showed that interferon-γ could augment superoxide production in phagocytes from CGD patients, there were no significant changes in the measures of superoxide production by phagocytes in the randomized trial. Thus, the benefit of prophylactic recombinant intereferon-γ likely results from augmentation of oxidant-independent pathways. CGD patients may not manifest typical signs of infection. Fever and leukocytosis may be absent, and an elevated sedimentation rate may be the only abnormal laboratory test. In a review of aspergillosis in CGD patients at the National Institutes of Health (NIH), one-third of patients were asymptomatic at diagnosis, and only ∼20% were febrile [14Segal B.H. DeCarlo E.S. Kwon-Chung K.J. et al.Aspergillus nidulans infection in chronic granulomatous disease.Medicine (Baltimore). 1998; 77: 345-354Crossref PubMed Scopus (214) Google Scholar]. In many of these patients, a pulmonary infiltrate on routine screening chest X-ray or computed tomography (CT) scan was the first indication of an infection. The white blood cell count was ≤10,000/μL in 13/23 cases, and the sedimentation rate was ≤40 mm per hour in 9/20 cases. When infections are suspected, it is important to establish a culture diagnosis when feasible prior to initiating antimicrobial therapy. Chest CT scans are useful to detect early pneumonia. If noninvasive testing (eg, blood and sputum cultures) are nondiagnostic, an invasive procedure should be considered. Serum galactomannan (a diagnostic marker for invasive aspergillosis) appears to be insensitive in CGD patients; this may be related to the fact that hyphal vascular invasion, a common feature of invasive aspergillosis in neutropenic patients, is generally not observed in invasive aspergillosis in CGD. A percutaneous lung biopsy is probably the most useful approach for peripheral lung lesions. Biopsy material should be submitted for pathology as well as bacterial and fungal culture, including Nocardia. Frequent radiographic evaluation (eg, chest radiographs during routine clinic visits and CT scans in patients with fever or focal signs) is critical to making early diagnoses. Debridement or resection of infected tissue may be required. Infections that involve bone or deep soft tissue are generally most effectively treated with antibiotics and surgery. Aspergillus nidulans is associated with severe infections in CGD patients, frequently manifesting with extension to the chest wall and vertebrae, and requiring prolonged therapy in combination with debridements [14Segal B.H. DeCarlo E.S. Kwon-Chung K.J. et al.Aspergillus nidulans infection in chronic granulomatous disease.Medicine (Baltimore). 1998; 77: 345-354Crossref PubMed Scopus (214) Google Scholar]. Adjunctive granulocyte transfusions have been used for severe or refractory infections in CGD patients. Use of granulocyte transfusions in CGD is supported by the principle that a small proportion of normal phagocytes may be able to complement the oxidative defect in CGD phagocytes. Hydrogen peroxide generated by normal neutrophils can diffuse into CGD neutrophils and provide the necessary reagent to generate hypohalous acid and hydroxyl anion in vitro. Transfused granulocytes retain respiratory burst activity and appear to traffic normally based on their recovery from sites of infection. Granulocyte transfusions are generally well tolerated, but adverse effects include fevers, development of leukoagglutinins leading to rapid loss of transfused granulocytes, and rarely, pulmonary leukostasis. The likelihood of pulmonary leukostasis may be increased if amphotericin B and granulocytes are administered concomitantly; therefore, granulocyte transfusions and amphotericin B should be administered several hours apart. Granulocyte transfusions can predispose to alloimmunization, which is of concern for patients under consideration for hematopoietic cell transplantation. HCT provides curative therapy for patients with CGD, although controversy exists over the requirement for HCT in all patients, and the optimal timing for any HCT procedure. Although uncomplicated CGD is not necessarily an indication for transplantation, HCT should be considered for CGD patients whose clinical history demonstrates significant morbidity (recurrent life-threatening infections, an ongoing infection refractory to treatment, progressive granulomatous restrictive lung disease, and/or high-dose steroid-dependent or refractory severe granulomatous colitis). In patients with these morbidity indicators, nonavailability of specialist medical care or noncompliance with long-term antimicrobial prophylaxis may additionally influence the decision to transplant [15Seger R.A. Modern management of chronic granulomatous disease.Br J Haematol. 2008; 140: 255-266Crossref PubMed Scopus (198) Google Scholar]. In the largest reported series, 27 patients underwent HCT for CGD complicated as above in 14 cooperating European centers between 1985 and 2000 [16Seger R.A. Gungor T. Belohradsky B.H. et al.Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000.Blood. 2002; 100: 4344-4350Crossref PubMed Scopus (228) Google Scholar] (Table 2). Most transplants were in children (n = 25), received a myeloablative busulfan-based regimen (n = 23), and had unmodified marrow allografts (n = 23) from HLA-identical sibling donors (MSD). Twenty-three of 27 (85%) survive, with 22/23 survivors cured of CGD. Preexisting infections and chronic inflammatory lesions cleared in all engrafted survivors, even children with severe lung restriction profited, slowly normalizing decreased oxygen saturation and reversing clubbing of fingers and toes. Survival was especially good in patients without infection at the time of HCT (18/18), and one could argue that with the availability of a geno-identical donor, HCT should be performed in all patients early in life, at a time when HCT is more easily tolerated, and prior to the development of complications that cannot be predicted by laboratory parameters. With the introduction of in vivo T cell depletion using alemtuzumab excellent outcomes have also been reported using matched unrelated donors (MUD) in 9/10 CGD patients undergoing largely myeloablative HCT [17Soncini E. Slatter M.A. Jones L.B. et al.Unrelated donor and HLA-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with good long-term outcome and growth.Br J Haematol. 2009; 145: 73-83Crossref PubMed Scopus (100) Google Scholar]; as a consequence, the same arguments for performing HCT from a sibling donor could equally be applied to CGD patients with a closely matched unrelated donor.Table 2Summary of HCT Studies for CGDStudyNo.RegimenDonorOSEFSSegar et al. 16Seger R.A. Gungor T. Belohradsky B.H. et al.Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000.Blood. 2002; 100: 4344-4350Crossref PubMed Scopus (228) Google Scholar25MAMSD85%81%Güngör et al. 18Güngör T. Halter J. Klink A. et al.Successful low toxicity hematopoietic stem cell transplantation for high-risk adult chronic granulomatous disease patients.Transplantation. 2005; 79: 1596-1606Crossref PubMed Scopus (70) Google Scholar, 19Güngör T. Halter J. Stussi G. Scherer F. Schanz U. Seger R. Successful busulphan-based reduced intensity conditioning in high-risk paediatric and adult chronic granulomatous disease—The Swiss experience.Bone Marrow Transplant. 2009; 43: S75Google Scholar8RICMSD/MUD88%88%Veys (personal communication)5RICMUD/MMUD100%100%Horwitz et al. 23Horwitz M.E. Barrett A.J. Brown M.R. et al.Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft.N Engl J Med. 2001; 344: 881-888Crossref PubMed Scopus (237) Google Scholar10NMAMSD70%70%Kang (personal communicaiton)11NMAMSD/MUD91%82%MA indicates myeloablative; RIC, reduced-intensity condition; NMA, nonmyeloablative; MSD, matched sibling donor; MUD, matched unrelated donor; MMUD, antigen mismatched unrelated donor; OS, overall survival; EFS, event-free survival. Open table in a new tab MA indicates myeloablative; RIC, reduced-intensity condition; NMA, nonmyeloablative; MSD, matched sibling donor; MUD, matched unrelated donor; MMUD, antigen mismatched unrelated donor; OS, overall survival; EFS, event-free survival. In contrast to HCT in the uncomplicated child, HCT during active infection (eg, aspergillosis) or inflammation (eg, colitis) is sometimes complicated by severe inflammatory reactions at the site of infection/inflammation [16Seger R.A. Gungor T. Belohradsky B.H. et al.Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000.Blood. 2002; 100: 4344-4350Crossref PubMed Scopus (228) Google Scholar]. Ideally, infections and inflammatory lesions should be brought under control prior to HCT, but in chronically infected patients or patients with ongoing inflammation, morbidity may be reduced by employing less toxic conditioning regimens and including serotherapy with ATG or alemtuzumab. HCT using reduced-intensity conditioning (RIC) combining busulfan 8-10 mg/kg (adjusted with busulfan kinetics in pediatric patients), fludarabine 180 mg/m2, and ATG 40 mg/kg and matched donors (matched sibling donor [MSD] = 5, matched unrelated donor [MUD] = 3) was performed in 8 high-risk CGD patients. With this approach, 90% to 100% donor chimerism was achieved in all cases at a median follow-up of 26 months [18Güngör T. Halter J. Klink A. et al.Successful low toxicity hematopoietic stem cell transplantation for high-risk adult chronic granulomatous disease patients.Transplantation. 2005; 79: 1596-1606Crossref PubMed Scopus (70) Google Scholar, 19Güngör T. Halter J. Stussi G. Scherer F. Schanz U. Seger R. Successful busulphan-based reduced intensity conditioning in high-risk paediatric and adult chronic granulomatous disease—The Swiss experience.Bone Marrow Transplant. 2009; 43: S75Google Scholar]; this was despite the use of bone marrow rather than mobilized peripheral blood stem cells (PBSC) in 7/8 cases. Seven patients are alive and well and all active inflammatory and infectious foci are resolved. One adult patient who had received PBSC from a cytomegalovirus (CMV)-negative MUD died on day +150 of CMV pneumonitis. An alternative RIC regimen (4 Gy of total-body irradiation [TBI], cyclophosphamide 50 mg/kg, and fludarabine 200 mg/m2) followed by 2 mismatched unrelated cord blood units in a single adult McLeod (K0 red cell) phenotype CGD patient with invasive aspergillosis also resulted in full donor engraftment and cure [20Suzuki N. Hatakeyama N. Yamamoto M. et al.Treatment of McLeod phenotype chronic granulomatous disease with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation.Int J Hematol. 2007; 85: 70-72Crossref PubMed Scopus (23) Google Scholar]. However, all 5 CGD patients who received alemtuzumab and fludarabine in combination with melphalan 140 mg/m2 [21Rao K. Amrolia P.J. Jones A. et al.Improved survival after unrelated donor bone marrow transplant in children with primary immunodeficiency using a reduced intensity conditioning regimen.Blood. 2005; 105: 879-885Crossref PubMed Scopus (194) Google Scholar] survived, but sustained donor engraftment was achieved in only 2/5 (T. Gungor 2008, personal communication), suggesting that the risk of graft rejection may be increased in CGD patients with this protocol in comparison to other phagocytic disorders (Table 2). Busulfan may also be substituted with treosulfan [22Greystoke B. Bonanomi S. Carr T.F. et al.Treosulfan-containing regimens achieve high rates of engraftment associated with low transplant morbidity and mortality in children with non-malignant disease and significant co-morbidities.Br J Haematol. 2008; 142: 257-262Crossref PubMed Scopus (56) Google Scholar], and RIC HCT employing Alemtuzumab, treosulfan 42 g/m2 and fludarabine 150 mg/m2 resulted in full donor chimerism and cure in 5/5 CGD patients undergoing matched or mismatched (single HLA antigen) unrelated donor HCT with mobilized peripheral blood stem cells (Veys 2010, personal communication) (Table 2). One of these children undergoing mismatched unrelated donor HCT had severe CGD complications prior to HCT including lung and cerebral aspergillosis, which has resolved completely post-HCT. Horwitz and colleagues [23Horwitz M.E. Barrett A.J. Brown M.R. et al.Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft.N Engl J Med. 2001; 344: 881-888Crossref PubMed Scopus (237) Google Scholar] reported 10 patients with CGD who underwent HCT with minimal intensity conditioning comprising cyclophosphamide (120 mg/kg), fludarabine (125 mg/m2), and ATG (160 mg/kg), followed by transplant of CD34+-selected PBSCs from matched sibling donors (Table 2). Delayed donor lymphocyte infusions were given at intervals of 30 or more days to increase the level of donor chimerism. After a median follow-up of 17 months, donor myeloid chimerism in 8/10 patients ranged from 33% to 100%, a level that could be expected to provide normal host defense. In 2 patients, graft rejection occurred. Significant aGHVD developed in 3 of 4 adult patients with engraftment, 1 of whom subsequently had extensive cGVHD. Seven patients were reported to have survived from 16 to 26 months. Two patients died of transplant-related complications. In an ongoing transplant study initi
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