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A Comprehensive Approach to the Management of Children and Adults with Chronic Granulomatous Disease

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A Comprehensive Approach to the Management of Children and Adults with Chronic Granulomatous Disease Clinical Commentary Review A Comprehensive Approach to the Management of Children and Adults with Chronic Granulomatous Disease Isaac P. Thomsen, MD, MSCIa, Meaghan A. Smith, MPHa, Steven M. Holland, MDb, and C. Buddy Creech, MD, MPHa Nashville, Tenn; and Bethesda, Md Chronic granulomatous disease (CGD), a disease characterized of affected tissue. Since its original description, and due in part to by inadequate neutrophil killing of microbial pathogens, affects successful antimicrobial prophylaxis, fatal granulomatous disease 4 to 5 per million live births. For many decades following its has now become a disease in which careful management leads to description, CGD was a fatal disease in childhood. With the survival well into adulthood. Therefore, the purpose of this re- development of effective preventive therapies and the early view was to highlight the challenges in the management of not recognition of infectious complications, 90% of children with only children with CGD but also adults with CGD. CGD now survive into adulthood. The management of CGD in adults includes unique challenges and potential disease manifestations. In this article, the authors discuss the current CGD PATHOGENESIS, INHERITANCE, AND approach to the management of CGD in both children and DIAGNOSIS adults. This includes a focus on the importance of a The genetic basis for CGD lies in any of the 5 structural genes comprehensive multidisciplinary approach in the care of CGD encoding the phagocytic oxidase (phox) subunits of the nicotin- and its potential complications. In addition, a novel approach to amide adenine dinucleotide phosphate oxidase complex. When improving education about CGD, and subsequently improving CGD was initially discovered, the disease was observed only in adherence to preventive therapies, is discussed. Ó 2016 males and was believed to be exclusively an X-linked disease. In fi American Academy of Allergy, Asthma & Immunology (J Allergy 1968, CGD was identi ed in a female patient, leading to the 3 Clin Immunol Pract 2016;4:1082-8) discovery of autosomal-recessive forms of the disease. Approxi- mately two-third of CGD cases in the United States are caused Key words: Chronic granulomatous disease; Multidisciplinary by mutations in CYBB, which is present on the X chromosome care; IFN-g and encodes the heme-containing Nox2 subunit (also known as gp91phox). Biallelic mutations in the other 4 genes (CYBA, neutrophil cytosolic factor 1 [NCF1], NCF2, and NCF4) are fi fi Chronic granulomatous disease (CGD) was rst identi ed as a associated with autosomal-recessive CGD.4 Mutations in NCF1 fi 1,2 distinct immunode ciency in the 1950s. The disease was are the second most common cause of CGD.5 Table I presents “ ” initially termed fatal granulomatous disease of childhood and the genetic defects of CGD and the relative frequency of each was characterized by chronic suppurative lymphadenitis, hep- mutation in North America. fi atosplenomegaly, pneumonia and diffuse pulmonary in ltrates, The incidence of CGD in the United States is estimated at and eczema. The disease was initially described in boys (and approximately 4 to 5 cases per million live births.6 Before the therefore considered to be exclusively X-linked inheritance) and introduction of oral antifungals, mortality rates ranged from 2% was characterized by hypergammaglobulinemia (as opposed to per year among those with autosomal-recessive CGD to 5% per ’ Bruton s agammaglobulinemia) and granulomatous involvement year among those with X-linked CGD.7 Further understanding of CGD along with utilization of a more comprehensive treat- aDivision of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt ment regimen allows the vast majority of individuals with CGD Vaccine Research Program, Vanderbilt University School of Medicine, Nashville, to live into adulthood. Although long-term survival is dependent Tenn on several factors, overall survival into adulthood with CGD is b Laboratory of Clinical Infectious Diseases, National Institute of Allergy and In- now around 90%, although significant morbidity due to frequent fectious Diseases, National Institutes of Health, Bethesda, Md fl 7 This work was supported in part by an educational grant from Horizon Pharma, plc. infectious and in ammatory complications remains common. Conflicts of interest: I. P. Thomsen has received research support from Horizon Female CYBB mutation carriers are often phenotypically Pharmaceuticals. C. B. Creech has received research support from Horizon normal. Nearly half, however, report various symptoms Pharmaceuticals, Novartis, and Pfizer and has provided expert witness testimony including aphthous ulcers, cutaneous photosensitivity, or ar- for various entities unrelated to chronic granulomatous disease. The rest of the thralgias.8,9 In addition, there are reports of women with het- authors declare that they have no relevant conflicts of interest. Received for publication October 14, 2015; revised March 11, 2016; accepted for erozygous mutations who have the X-linked CGD phenotype publication March 24, 2016. due to skewed inactivation of the normal X chromosome by Available online May 10, 2016. lyonization. This highlights the fact that the population of Corresponding author: Isaac P. Thomsen, MD, MSCI, D-7235 MCN, 1161 21st Ave normal neutrophils required for immune function is not 100%; South, Nashville, TN 37232. E-mail: [email protected]. 2213-2198 however, when the number of neutrophils capable of a normal Ó 2016 American Academy of Allergy, Asthma & Immunology oxidative burst falls below approximately 15%, classic CGD 4 http://dx.doi.org/10.1016/j.jaip.2016.03.021 symptoms may be seen. 1082 J ALLERGY CLIN IMMUNOL PRACT THOMSEN ET AL 1083 VOLUME 4, NUMBER 6 TABLE I. Genetic defects of CGD Abbreviations used Frequency CGD- chronic granulomatous disease Protein Characteristic Subunit Gene locus (%) CT- computed tomography phox MRI- magnetic resonance imaging Cytochrome Membrane-bound gp91 CYBB, Xp21.1 65 NCF- neutrophil cytosolic factor b558 components SCT- stem cell transplantation p22phox CYBA, 16q24.3 5-10 TMP-SMX- trimethoprim-sulfamethoxazole Cytosolic p47phox NCF1, 7q11.23 25 components p67phox NCF2, 1q25.3 5-10 Chronic granulomatous disease is phenotypically diagnosed by p40phox NCF4, 22q13.1 Rare measurement of the neutrophil oxidative burst, which in the current era is done most commonly via the dihydrorhodamine prophylactic antibacterial agents, antifungal agents, and IFN-g assay. Dihydrorhodamine is a nonfluorescent compound that is therapy. oxidized by activated neutrophils into the fluorescent compound fl fl rhodamine. The detection of uorescence by ow cytometry Antibiotic therapy provides a reliable indicator of normal neutrophil activation; Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis has inadequate fluorescence is most consistent with CGD, but can been used routinely for the prevention of infections in patients also be seen in myeloperoxidase deficiency. Other diagnostic with CGD since the 1970s. Gallin et al14 showed that patients modalities may be used, such as nitroblue tetrazolium reduction, with CGD, on average, suffered 1 life-threatening episode every but the dihydrorhodamine assay’s ability to distinguish X-linked 10 months; however, with TMP-SMX prophylaxis, this was from autosomal patterns of CGD, as well as its ease of use, makes reduced to 1 life-threatening episode every 40 months. Similarly, it the preferred modality at most centers. Regelman et al15 reported that only 5% of patients with CGD remained infection-free for more than 1 year without TMP-SMX INFECTIOUS COMPLICATIONS OF CGD prophylaxis, but more than 40% were infection-free for more “ ” Common pathogens: The big 5 than 1 year while taking TMP-SMX prophylaxis. Further evi- Early clinical manifestations of CGD include recurrent upper dence to support the use of TMP-SMX prophylaxis was reported and lower respiratory tract infections, failure to thrive, visceral in 1990 by Margolis et al,16 who demonstrated that prophylaxis abscesses, cellulitis, lymphadenitis, and granulomatous lesions in decreased the incidence of nonfungal infections from 7.1 to 2.4 hollow viscera without apparent organisms. Sites of infection per 100 patient-months in patients with autosomal-recessive 5 most often include the lungs, lymph nodes, skin, and liver. CGD and from 15.8 to 6.9 infections per 100 patient-months Most infections in patients with CGD living in North America in patients with X-linked CGD. Importantly, there was no are caused by 5 organisms: Staphylococcus aureus, Burkholderia concomitant increase in the incidence of fungal infections in cepacia complex, Serratia marcescens, Nocardia species, and patients with CGD while on TMP-SMX prophylaxis. 10 Aspergillus species. The pathogenicity of organisms was once Although TMP-SMX therapy is generally well tolerated, it thought to be due to their production of catalase, an enzyme that does have various potential toxicities. Hematologic (eg, agranu- ’ degrades the organism s own hydrogen peroxide, thus depriving locytosis, hemolysis, and thrombocytopenia), renal (interstitial 8 the phagocyte of additional reactive oxygen species. Although nephritis), metabolic (hyperkalemia), gastrointestinal (abdominal the precise mechanisms underlying the pathogenicity of these pain, diarrhea, and pancreatitis), and dermatologic (photosensi- organisms are unclear, deletion of bacterial or fungal catalase tivity, Stevens-Johnson syndrome) adverse effects are well production does not affect virulence,
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