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Chronic granulomatous disease: Overview and hematopoietic stem cell transplantation

2011; Elsevier BV; Volume: 127; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2011.03.028

1097-6825

Elizabeth M. Kang, Betty Marciano, Suk See De Ravin, Kol A. Zarember, Steven M. Holland, Harry L. Malech,

Blood disorders and treatments

Chronic granulomatous disease (CGD) still causes significant morbidity and mortality. The difficulty in considering high-risk yet curative treatments, such as allogeneic bone marrow transplantation, lies in the unpredictable courses of both CGD and bone marrow transplantation in different patients. Some patients with CGD can have frequent infections, granulomatous or autoimmune disorders necessitating immunosuppressive therapy, or both but also experience long periods of relative good health. However, the risk of death is clearly higher in patients with CGD of all types, and the complications of CGD short of death can still cause significant morbidity. Therefore, with recent developments and improvements, bone marrow transplantation, previously considered an experimental or high-risk procedure, has emerged as an important option for patients with CGD. We will discuss the complications of CGD that result in significant morbidity and mortality, particularly the most common infections and autoimmune/inflammatory complications, as well as their typical management. We will then discuss the status of bone marrow transplantation. Chronic granulomatous disease (CGD) still causes significant morbidity and mortality. The difficulty in considering high-risk yet curative treatments, such as allogeneic bone marrow transplantation, lies in the unpredictable courses of both CGD and bone marrow transplantation in different patients. Some patients with CGD can have frequent infections, granulomatous or autoimmune disorders necessitating immunosuppressive therapy, or both but also experience long periods of relative good health. However, the risk of death is clearly higher in patients with CGD of all types, and the complications of CGD short of death can still cause significant morbidity. Therefore, with recent developments and improvements, bone marrow transplantation, previously considered an experimental or high-risk procedure, has emerged as an important option for patients with CGD. We will discuss the complications of CGD that result in significant morbidity and mortality, particularly the most common infections and autoimmune/inflammatory complications, as well as their typical management. We will then discuss the status of bone marrow transplantation. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: June 2011. Credit may be obtained for these courses until May 31, 2013.Copyright Statement: Copyright © 2011-2013. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Elizabeth M. Kang, MD, Betty E. Marciano, MD, SukSee DeRavin, MD, PhD, Kol A. Zarember, PhD, Steven M. Holland, MD, and Harry L. Malech, MDActivity Objectives1.To recognize the mutations involved in the development and outcomes of chronic granulomatous disease (CGD).2.To identify the common bacterial pathogens that cause infections in patients with CGD.3.To understand the inflammatory and autoimmune complications of CGD.4.To identify transplantation and treatment options for patients with CGD.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The authors have declared that they have no conflict of interest.Chronic granulomatous disease (CGD) results from defects in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, resulting in an inability to produce the superoxide anion necessary for normal killing of bacterial and fungal microorganisms. In addition, this defect predisposes to granulomatous complications and autoimmune diseases. Mutations in at least 5 different genes involved in the assembly and activation of the NADPH oxidase can lead to CGD.1Segal B.H. DeCarlo E.S. Kwon-Chung K.J. Malech H.L. Gallin J.I. Holland S.M. Aspergillus nidulans infection in chronic granulomatous disease.Medicine (Baltimore). 1998; 77: 345-354Crossref PubMed Scopus (211) Google Scholar The gene encoding the enzymatic center of the NADPH oxidase, gp91phox, is on the X-chromosome and accounts for about two thirds of the cases. Autosomal forms occur from mutations in p47phox, p67phox, p22phox, or p40phox, with the latter being the most recently described.2Matute J.D. Arias A.A. Wright N.A. Wrobel I. Waterhouse C.C. Li X.J. et al.A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.Blood. 2009; 114: 3309-3315Crossref PubMed Scopus (303) Google Scholar In general, gp91phox-deficient patients (ie, those with X-linked CGD) are the most severely affected, whereas patients with mutations in p47phox seem to have the best outcomes overall. Deficiency in p40phox might predispose to more gastrointestinal disease and fewer infections.2Matute J.D. Arias A.A. Wright N.A. Wrobel I. Waterhouse C.C. Li X.J. et al.A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.Blood. 2009; 114: 3309-3315Crossref PubMed Scopus (303) Google Scholar Specific mutations affect the severity of disease through the amount of residual NADPH oxidase activity.3Kuhns D.B. Alvord W.G. Heller T. Feld J.J. Pike K.M. Marciano B.E. et al.Residual NADPH oxidase and survival in chronic granulomatous disease.N Engl J Med. 2010; 363: 2600-2610Crossref PubMed Scopus (372) Google Scholar However, even among patients with similar NADPH oxidase mutations, there can be widely different clinical outcomes. Therefore the genetic type of CGD, the specific mutation, the patient’s own infection history, the presence of inflammatory or autoimmune complications, and access to appropriate medical care all factor into what to expect from CGD in a particular patient’s case. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: June 2011. Credit may be obtained for these courses until May 31, 2013. Copyright Statement: Copyright © 2011-2013. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Elizabeth M. Kang, MD, Betty E. Marciano, MD, SukSee DeRavin, MD, PhD, Kol A. Zarember, PhD, Steven M. Holland, MD, and Harry L. Malech, MD Activity Objectives1.To recognize the mutations involved in the development and outcomes of chronic granulomatous disease (CGD).2.To identify the common bacterial pathogens that cause infections in patients with CGD.3.To understand the inflammatory and autoimmune complications of CGD.4.To identify transplantation and treatment options for patients with CGD. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The authors have declared that they have no conflict of interest. Despite the significant progress made in antibiotic and antifungal therapy and prophylaxis, patients with CGD still have serious infections. Most large studies have shown an infection rate of around 0.15 to 0.3 per year.4Martire B. Rondelli R. Soresina A. Pignata C. Broccoletti T. Finocchi A. et al.Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: an Italian multicenter study.Clin Immunol. 2008; 126: 155-164Crossref PubMed Scopus (246) Google Scholar, 5Kobayashi S. Murayama S. Takanashi S. Takahashi K. Miyatsuka S. Fujita T. et al.Clinical features and prognoses of 23 patients with chronic granulomatous disease followed for 21 years by a single hospital in Japan.Eur J Pediatr. 2008; 167: 1389-1394Crossref PubMed Scopus (65) Google Scholar, 6Marciano B.E. Rosenzweig S.D. Kleiner D.E. Anderson V.L. Darnell D.N. Anaya-O’Brien S. et al.Gastrointestinal involvement in chronic granulomatous disease.Pediatrics. 2004; 114: 462-468Crossref PubMed Scopus (292) Google Scholar The US National Institutes of Health (NIH) has followed more than 250 patients with CGD over almost 40 years, the majority of whom were given diagnoses after infections of the skin, lymph node, lung, or liver. A small group of patients (approximately 5%) were identified because of inflammatory lesions being their primary clinical event. The diagnosis was usually established early in life (median age of diagnosis, 5.4 years), although a small proportion were given diagnoses as adults. Notably, the majority of these later diagnoses were due to autosomal recessive forms of CGD. Isolation of the microorganism causing infection in patients with CGD is essential to rational and appropriate treatment but is not always feasible. In the last 10 years, 80% of patients with CGD at the NIH with a pulmonary infection underwent some type of diagnostic procedure, either needle biopsy or bronchial lavage. Of these procedures, 52% were successful in identifying a pathogen. Coinfection, such as fungal plus bacterial infection, was found in less than 10% of biopsy specimens. Viral infections appeared at similar rates as in the general population (unpublished data). The majority of infections in North American patients with CGD are due to 4 bacterial organisms (Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, and Nocardia species), as well as species of the fungus Aspergillus. Invasive aspergillosis has been a major cause of morbidity and mortality in patients with CGD, but the advent of the newer azole antifungal agents has dramatically changed the treatment and outcome of these infections and shifted the intractable fungal infections to non-fumigatus Aspergillus species, dematiaceous molds, and hyalohyphomycosis, such as paecilomyces.1Segal B.H. DeCarlo E.S. Kwon-Chung K.J. Malech H.L. Gallin J.I. Holland S.M. Aspergillus nidulans infection in chronic granulomatous disease.Medicine (Baltimore). 1998; 77: 345-354Crossref PubMed Scopus (211) Google Scholar, 7Winkelstein J.A. Marino M.C. Johnston Jr., R.B. Boyle J. Curnutte J. Gallin J.I. et al.Chronic granulomatous disease. Report on a national registry of 368 patients.Medicine (Baltimore). 2000; 79: 155-169Crossref PubMed Scopus (1216) Google Scholar, 8Vinh D.C. Shea Y.R. Jones P.A. Freeman A.F. Zelazny A. Holland S.M. Chronic invasive aspergillosis caused by Aspergillus viridinutans.Emerg Infect Dis. 2009; 15: 1292-1294Crossref PubMed Scopus (46) Google Scholar Patients with CGD might present without symptoms or with low-grade fevers and only mild constitutional symptoms inconsistent with the extent of disease seen by using imaging studies. Consequently, frequent imaging studies (eg, computed tomography and magnetic resonance imaging) are recommended for clinical monitoring. The paradoxically dampened inflammation in response to some serious infections and the exaggerated responses to some noninfectious stimuli (see below) remain perplexing. The lung was the most common site of disease in the NIH cohort, and Aspergillus species was responsible for approximately 40% of the culture-positive cases. Chest scans and markers of acute inflammation (eg, C-reactive protein and erythrocyte sedimentation rate) have proved useful in the diagnosis and monitoring of fungal disease (unpublished data). The role for serology, such as the β-D-glucan and galactomannan assays, are undefined in patients with CGD, but when results are positive, these assays might be helpful to follow in some cases. North American studies have identified a much higher incidence of Burkholderia and Nocardia species infections than in European reports, which in part might reflect the differences in diagnostic approaches and might also reflect environmental differences.4Martire B. Rondelli R. Soresina A. Pignata C. Broccoletti T. Finocchi A. et al.Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: an Italian multicenter study.Clin Immunol. 2008; 126: 155-164Crossref PubMed Scopus (246) Google Scholar, 9van den Berg J.M. van Koppen E. Ahlin A. Belohradsky B.H. Bernatowska E. Corbeel L. et al.Chronic granulomatous disease: the European experience.PLoS One. 2009; 4: e5234Crossref PubMed Scopus (494) Google Scholar Emerging pathogens in patients with CGD include gram-negative pathogens (eg, Granulibacter bethesdensis10Greenberg D.E. Ding L. Zelazny A.M. Stock F. Wong A. Anderson V.L. et al.A novel bacterium associated with lymphadenitis in a patient with chronic granulomatous disease.PLoS Pathog. 2006; 2: e28Crossref PubMed Scopus (65) Google Scholar), gram-positive pathogens (eg Actinomyces species11Reichenbach J. Lopatin U. Mahlaoui N. Beovic B. Siler U. Zbinden R. et al.Actinomyces in chronic granulomatous disease: an emerging and unanticipated pathogen.Clin Infect Dis. 2009; 49: 1703-1710Crossref PubMed Scopus (62) Google Scholar), and fungi (eg, Neosartorya udagawae12Vinh D.C. Shea Y.R. Sugui J.A. Parrilla-Castellar E.R. Freeman A.F. Campbell J.W. et al.Invasive aspergillosis due to Neosartorya udagawae.Clin Infect Dis. 2009; 49: 102-111Crossref PubMed Scopus (90) Google Scholar). Occurrence of these uncommon pathogens in patients with CGD might provide clues to the critical pathways and functions of the NADPH oxidase.13Messina C.G. Reeves E.P. Roes J. Segal A.W. Catalase negative Staphylococcus aureus retain virulence in mouse model of chronic granulomatous disease.FEBS Lett. 2002; 518: 107-110Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 14Dorman S.E. Guide S.V. Conville P.S. DeCarlo E.S. Malech H.L. Gallin J.I. et al.Nocardia infection in chronic granulomatous disease.Clin Infect Dis. 2002; 35: 390-394Crossref PubMed Scopus (74) Google Scholar, 15Segal B.H. Barnhart L.A. Anderson V.L. Walsh T.J. Malech H.L. Holland S.M. Posaconazole as salvage therapy in patients with chronic granulomatous disease and invasive filamentous fungal infection.Clin Infect Dis. 2005; 40: 1684-1688Crossref PubMed Scopus (131) Google Scholar, 16Huang Y.F. Liu S.Y. Yen C.L. Yang P.W. Shieh C.C. Thapsigargin and flavin adenine dinucleotide ex vivo treatment rescues trafficking-defective gp91phox in chronic granulomatous disease leukocytes.Free Radic Biol Med. 2009; 47: 932-940Crossref PubMed Scopus (16) Google Scholar, 17Brechard S. Tschirhart E.J. Regulation of superoxide production in neutrophils: role of calcium influx.J Leukoc Biol. 2008; 84: 1223-1237Crossref PubMed Scopus (153) Google Scholar Liver abscesses are common in patients with CGD.18Lublin M. Bartlett D.L. Danforth D.N. Kauffman H. Gallin J.I. Malech H.L. et al.Hepatic abscess in patients with chronic granulomatous disease.Ann Surg. 2002; 235: 383-391Crossref PubMed Scopus (105) Google Scholar Thirty percent of NIH patients have had liver abscesses, with 25% of these occurring more than once. S aureus was the organism most frequently cultured, and surgical resection was the usual treatment. Percutaneous drainage was usually not helpful because liver abscesses associated with CGD tend to develop multiple loculations. When resected, the lesions are a collection of microabscesses.18Lublin M. Bartlett D.L. Danforth D.N. Kauffman H. Gallin J.I. Malech H.L. et al.Hepatic abscess in patients with chronic granulomatous disease.Ann Surg. 2002; 235: 383-391Crossref PubMed Scopus (105) Google Scholar Corticosteroids have been reported to be helpful in 2 cases of liver abscess.19Yamazaki-Nakashimada M.A. Stiehm E.R. Pietropaolo-Cienfuegos D. Hernandez-Bautista V. Espinosa-Rosales F. Corticosteroid therapy for refractory infections in chronic granulomatous disease: case reports and review of the literature.Ann Allergy Asthma Immunol. 2006; 97: 257-261Abstract Full Text PDF PubMed Scopus (33) Google Scholar Other staphylococcal infections are typically confined to the skin or lymph nodes.20Segal B.H. Leto T.L. Gallin J.I. Malech H.L. Holland S.M. Genetic, biochemical, and clinical features of chronic granulomatous disease.Medicine (Baltimore). 2000; 79: 170-200Crossref PubMed Scopus (718) Google Scholar Patients compliant with prophylaxis still have skin infections, but these infrequently spread. Skin and soft tissue infections are caused by S aureus, Klebsiella species, S marcescens, B cepacia complex, and some fungi. Lymph node and skin infections have decreased overall and constitute only about 20% of the infections seen in NIH patients. Antibacterial (trimethoprim/sulfamethoxazole) and antifungal (itraconazole) prophylaxis has significantly reduced the rates and severity of infections in patients with CGD, but breakthrough infections still occur.21Gallin J.I. Alling D.W. Malech H.L. Wesley R. Koziol D. Marciano B. et al.Itraconazole to prevent fungal infections in chronic granulomatous disease.N Engl J Med. 2003; 348: 2416-2422Crossref PubMed Scopus (289) Google Scholar, 22Beaute J. Obenga G. Le Mignot L. Mahlaoui N. Bougnoux M.E. Mouy R. et al.Epidemiology and outcome of invasive fungal diseases in patients with chronic granulomatous disease: a multicenter study in France.Pediatr Infect Dis J. 2010; ([Epub ahead of print])Google Scholar, 23Mouy R. Veber F. Blanche S. Donadieu J. Brauner R. Levron J.C. et al.Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease.J Pediatr. 1994; 125: 998-1003Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Prophylactic antibiotics were used in 93% of NIH patients with CGD, with trimethoprim/sulfamethoxazole the most frequent. Intolerance to sulfamethoxazole or other adverse events typically led to use of trimethoprim alone, cephalosporins, or quinolones. Fungal prophylaxis was used by only 68% of the patients, although it was recommended for all patients with CGD. Of these, 55% were receiving itraconazole, 30% were receiving posaconazole, and 15% were receiving voriconazole. Typically, patients receiving the latter 2 agents were receiving them after having been treated for an invasive fungal infection. There are no data on patients with CGD comparing voriconazole, posaconazole, or itraconazole. A single-center transplantation study did show better outcomes with posaconazole compared with itraconazole; however, direct extrapolation to patients with CGD might not be appropriate.24Sanchez-Ortega I. Patino B. Arnan M. Peralta T. Parody R. Gudiol C. et al.Clinical efficacy and safety of primary antifungal prophylaxis with posaconazole vs itraconazole in allogeneic blood and marrow transplantation.Bone Marrow Transplant. 2010; ([Epub ahead of print])PubMed Google Scholar Mild toxicity related to drugs was recorded in 36% of the overall NIH cohort, 15% of whom had photosensitivity, most likely caused by voriconazole or trimethoprim/sulfamethoxazole. Severe photosensitivity leading to squamous cell carcinoma and melanoma has been reported with long-term voriconazole.25Cowen E.W. Nguyen J.C. Miller D.D. McShane D. Arron S.T. Prose N.S. et al.Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole.J Am Acad Dermatol. 2010; 62: 31-37Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 26Miller D.D. Cowen E.W. Nguyen J.C. McCalmont T.H. Fox L.P. Melanoma associated with long-term voriconazole therapy: a new manifestation of chronic photosensitivity.Arch Dermatol. 2010; 146: 300-304Crossref PubMed Scopus (107) Google Scholar Patients receiving voriconazole should use aggressive sun protection. For patients with severe voriconazole-induced photosensitivity despite sun avoidance, posaconazole causes less photoreactivity. IFN-γ was shown in 1991 to be effective prophylaxis for CGD.27A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group.N Engl J Med. 1991; 324: 509-516Crossref PubMed Scopus (682) Google Scholar However, use in Europe has been less than in the United States because nonrandomized European data suggested less benefit from IFN-γ.28Mouy R. Seger R. Bourquin J.P. Veber F. Blanche S. Griscelli C. et al.Interferon gamma for chronic granulomatous disease.N Engl J Med. 1991; 325: 1516-1517Crossref PubMed Scopus (34) Google Scholar Even in our own cohort, with the advent of better antifungal agents and more active oral antibiotics, the percentage receiving IFN-γ is only 36% because of intolerance or lack of access. Fevers, myalgias, and irritability were reported as reasons for stopping the IFN-γ in 13% of patients in 1 study.29Marciano B.E. Wesley R. De Carlo E.S. Anderson V.L. Barnhart L.A. Darnell D. et al.Long-term interferon-gamma therapy for patients with chronic granulomatous disease.Clin Infect Dis. 2004; 39: 692-699Crossref PubMed Scopus (180) Google Scholar Renal failure or severe dysfunction occurred in 3.5% of our patients, probably because of long-term amphotericin exposure before the advent of newer agents. Dysregulated inflammation in patients with CGD typically occurs in response to a trigger and might be due to either increased proinflammatory or decreased anti-inflammatory mediators. Patients with CGD frequently experience inflammatory complications, and some might have autoimmune problems.30De Ravin S.S. Naumann N. Cowen E.W. Friend J. Hilligoss D. Marquesen M. et al.Chronic granulomatous disease as a risk factor for autoimmune disease.J Allergy Clin Immunol. 2008; 122: 1097-1103Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Other than infection, a characteristic feature of CGD is granulomatous inflammation. CGD granulomas are typically noncaseating, are composed of multinucleated giant cells, and can be found in multiple organs, including the brain, lungs, liver, spleen, and gastrointestinal tract. When present in hollow viscera, they can lead to obstruction, such as obstruction of the gastric outlet or ureteral obstruction, which are relatively common in patients with X-linked CGD. For most of these granulomas, no pathogen is identified, and they respond rapidly to steroids, suggesting that the inciting event is not an invasive infectious one. Surgical intervention should be avoided, and corticosteroids, when used, are usually started at doses of 1 mg/kg/d and then tapered after 1 week. In many patients the symptoms recur when the steroid dose is reduced, and thus our current practice is to taper the corticosteroid dose gradually to around 0.1 mg/kg/d on alternate days. Patients with recurring problems can be kept on low-dose prednisone for years, which does not appear to increase infection rates or impair growth.6Marciano B.E. Rosenzweig S.D. Kleiner D.E. Anderson V.L. Darnell D.N. Anaya-O’Brien S. et al.Gastrointestinal involvement in chronic granulomatous disease.Pediatrics. 2004; 114: 462-468Crossref PubMed Scopus (292) Google Scholar A unique presentation in CGD is an acute pneumonitis caused by the inhalation of mulch or other decayed organic matter (eg, potting soil, hay, and leaves). Exposure to a large burden of fungal elements and spores triggers an acute inflammatory response, leading to fever, hypoxia, and diffuse infiltrates, usually beginning within 1 week of the exposure.31Ameratunga R. Woon S.T. Vyas J. Roberts S. Fulminant mulch pneumonitis in undiagnosed chronic granulomatous disease: a medical emergency.Clin Pediatr (Phila). 2010; 49: 1143-1146Crossref PubMed Scopus (18) Google Scholar Similar responses are seen in mice with CGD exposed to live or even dead fungi,32Morgenstern 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 (295) Google Scholar indicating that some of this pathology is due to dysregulated inflammation rather than infection per se. Bronchoscopy and lung biopsy specimens might yield 1 or more fungal pathogens, especially Aspergillus species. In addition to rapid institution of antifungal agents, moderately high doses of prednisone (1 mg/kg/d) help prevent respiratory failure and might facilitate more successful healing.31Ameratunga R. Woon S.T. Vyas J. Roberts S. Fulminant mulch pneumonitis in undiagnosed chronic granulomatous disease: a medical emergency.Clin Pediatr (Phila). 2010; 49: 1143-1146Crossref PubMed Scopus (18) Google Scholar, 33Siddiqui S. Anderson V.L. Hilligoss D.M. Abinun M. Kuijpers T.W. Masur H. et al.Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease.Clin Infect Dis. 2007; 45: 673-681Crossref PubMed Scopus (113) Google Scholar Inflammatory lesions without demonstrated pathogens have also been noted in the lungs of patients with CGD and are characterized by discrete infiltrates on chest computed tomography that wax and wane without intervention. In some patients diffuse pulmonary inflammation can progress to hypoxia and functional limitation.34Brown K.L. Bylund J. MacDonald K.L. Song-Zhao G.X. Elliott M.R. Falsafi R. et al.ROS-deficient monocytes have aberrant gene expression that correlates with inflammatory disorders of chronic granulomatous disease.Clin Immunol. 2008; 129: 90-102Crossref PubMed Scopus (59) Google Scholar It is difficult to exclude infection despite negative cultures, cytology, nucleic acid testing, and the lack of improvement in response to antibacterial or antifungal agents. However, in some cases empiric treatment beyond corticosteroids has included methotrexate. Progressive lung inflammation with augmented nuclear factor κB activation and increased proinflammatory cytokine levels has been recently demonstrated in mice with CGD (p47 and gp91phox deficient) after intratracheal challenge with zymosan or LPS.35Segal B.H. Han W. Bushey J.J. Joo M. Bhatti Z. Feminella J. et al.NADPH oxidase limits innate immune responses in the lungs in mice.PLoS One. 2010; 5: e9631Crossref PubMed Scopus (148) Google Scholar Inflammatory bowel disease characterized by granulomatous involvement of the bowel, especially in the perirectal area, is hard to distinguish pathologically from Crohn disease. However, the inflammatory bowel disease seen in patients with CGD is typically limited to the bowel and unassociated with any of the extraintestinal manifestations often seen in patients with Crohn disease. In the NIH series 43% of X-linked and 11% of p47phox-deficient patients had biopsy-proved symptomatic bowel disease.6Marciano B.E. Rosenzweig S.D. Kleiner D.E. Anderson V.L. Darnell D.N. Anaya-O’Brien S. et al.Gastrointestinal involvement in chronic granulomatous disease.Pediatrics. 2004; 114: 462-468Crossref PubMed Scopus (292) Google Scholar How many had active subclinical disease remains unknown. Other autoimmune diseases in patients with CGD and carriers have included IgA nephropathy, antiphospholipid syndrome, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, and juvenile idiopathic arthritis.7Winkelstein J.A. Marino M.C. Johnston Jr., R.B. Boyle J. Curnutte J. Gallin J.I. et al.Chronic granulomatous disease. Report on a national registry of 368 patients.Medicine (Baltimore). 2000; 79: 155-169Crossref PubMed Scopus (1216) Google Scholar An estimated 10% of the patients with CGD followed at the NIH have some autoimmune manifestation other than inflammatory bowel disease. The underlying cause for this predisposition to autoimmunity remains unknown. Polymorphisms in a few genes have been loosely associated with inflammatory complications in patients with CGD (MPO; mannose-binding lectin; Fc receptors IIa, IIIa, and IIIb; TNF-α; and IL-1 receptor).36Foster M.H. Fitzsimons M.M. Lupus-like nephrotropic autoantibodies in non-autoimmune mice harboring an anti-basement membrane/anti-DNA Ig heavy chain