Clinical Infectious Diseases Advance Access published January 29, 2015

EDITORIAL COMMENTARY

Severe Infections in Patients With Chronic Granulomatous Disease Andrew R. Gennery Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

Keywords.

chronic granulomatous disease; Aspergillus; Burkholderia cepacea; hematopoietic stem cell transplantation.

Received 30 November 2014; accepted 3 December 2014. Correspondence: Andrew R. Gennery, MD, Paediatric Immunology Dept, c/o Old Childrens’ Outpatients, Great North Children’s Hospital, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK ([email protected]). Clinical Infectious Diseases® © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected] DOI: 10.1093/cid/ciu1155

Most common are defects in X-linked gp91phox, whereas defects in the other 4 protein components are inherited in an autosomal fashion. The disease usually presents in early childhood, and is characterized by recurrent infection and inflammation. Infections caused by catalase-positive organisms are most common, particularly Staphylococcus aureus and Burkholderia cepacia as well as Aspergillus species. Since the first description of the disease as fatal granulomatous disease of childhood in 1954, life expectancy for patients has increased, aided by prophylactic antibiotics and, since the 1990s, azole antifungal prophylaxis. Although hematopoietic stem cell transplant (HSCT) remains the only curative treatment, in the pediatric population, survival with modern conservative treatment is equivalent to that following HSCT, although life quality is diminished [1]. A number of previous studies from different countries have documented infection frequency in chronic granulomatous disease cohorts [2–9]. Common themes emerge from these studies, which include the single most common infectious cause of death (Aspergillus species); an improving survival over time, with a later age at death; similar survival rates between X-linked and autosomal recessive disease, despite increased severity of complication onset and frequency in the X-linked disease; and severity of disease linked more strongly to lack of

superoxide production than mode of inheritance. In this edition of Clinical Infectious Diseases, Marciano and colleagues report the infectious complications of a large cohort of patients with chronic granulomatous disease, followed at the US National Institutes of Health [10]. Given the numerous preceding published reports, one might ask the value of yet another cohort series—how does this study differ from previous studies? First, this is a large cohort of >250 patients, followed at a single center of excellence, although data were collected and analyzed retrospectively. Therefore, some indication of infectious trends over time can be gained, accepting that there will be change in practice and introduction of new treatment strategies. Second, the follow-up is long, with patients followed at the center for >40 years, and the median age of patients is within the young adult range; many of the previous studies are of much shorter duration, and results are only applicable to the pediatric population. Third, the study used very strict criteria to define infection, and therefore results are more likely to be a conservative estimate of the problem. So, do we learn anything new, and, most important, what impact does this information have on patient care today? Almost one-fifth of the cohort had died at time of analysis, with infection accounting for 80% of the non-transplant-related

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Genetically inherited inborn errors of immunity impair immune function and leave affected individuals exposed to increased risks of infection, inflammation, and autoimmunity. These human primary immune deficiencies offer insights into the evolution of our host defences, and how particular components are critical for protection against an individual or specific range of pathogens. Detailed analysis of infectious episodes in disease-specific cohorts can inform geography-specific features, changing epidemiology—over time and with the introduction of new treatments—and aid choice of optimum treatment for patients today. Chronic granulomatous disease, a defect in the phagocyte respiratory burst, is one such example. Mutations in 1 of the 5 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes that code for protein subunits, which make up the enzyme responsible for the phagocyte respiratory burst and superoxide production, cause the disease.

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symptoms and the use of corticosteroids are not associated with infectious deaths. Chronic granulomatous disease remains a life-limiting condition, even in the era of modern antimicrobial prophylaxis. The risk of severe infection is lifelong, but given that fungal infections account for the highest infectious and mortality risk, greater emphasis on antifungal prophylaxis is required. Advances in the technique of HSCT mean that this is a much safer treatment option to consider than it was previously [11],and a successful procedure is not only curative, but restores the quality of life to normal [1]. Gene therapy is still an experimental treatment for chronic granulomatous disease, but is likely to have a more significant treatment role in the future [12]. Serious consideration should be given to offering curative treatment to these patients to abolish the ongoing infectious risk associated with the disease, particularly in those patients at highest risk of infectious mortality who have low superoxide production. For those patients presenting with infection, a fungal etiology should be first on the list of differential diagnoses, and aggressive measures to identify the causative microorganism are essential to direct the most appropriate treatment. For patients born today with this rare inborn error of immunity, the outlook has significantly improved, and patient-tailored personalized medicine is a reality. Note Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References 1. Cole T, Pearce MS, Cant AJ, Cale CM, Goldblatt D, Gennery AR. Clinical outcome in children with chronic granulomatous disease managed conservatively or with haematopoietic stem cell transplant. J Allergy Clin Immunol 2013; 132:1150–5. 2. Mouy R, Fischer A, Vilmer E, Seger R, Griscelli C. Incidence, severity, and prevention of infections in chronic granulomatous disease. J Pediatr 1989; 114:555–60. 3. Ahlin A, De Boer M, Roos D, et al. Prevalence, genetics and clinical presentation of chronic granulomatous disease in Sweden. Acta Paediatr 1995; 84:1386–94. 4. Hasui M. Chronic granulomatous disease in Japan: incidence and natural history. The Study Group of Phagocyte Disorders of Japan. Pediatr Int 1999; 41:589–93. 5. Liese J, Kloos S, Jendrossek V, et al. Longterm follow-up and outcome of 39 patients with chronic granulomatous disease. J Pediatr 2000; 137:687–93. 6. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000; 79:155–69. 7. Martire B, Rondelli R, Soresina 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; 126:155–64. 8. Jones LB, McGrogan P, Flood TJ, et al. Special article: chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry. Clin Exp Immunol 2008; 152:211–8. 9. van den Berg JM, van Koppen E, Ahlin A, et al. Chronic granulomatous disease: the European experience. PLoS One 2009; 4: e5234. 10. Marciano BE, Spalding C, Fitzgerald A, et al. Common severe infections in chronic granulomatous disease. Clin Infect Dis 2014; doi:10.1093/cid/ciu1154. 11. Güngör T, Teira P, Slatter M, et al. Reducedintensity conditioning and HLA-matched haematopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet 2014; 383:436–48. 12. Kaufmann KB, Chiriaco M, Siler U, et al. Gene therapy for chronic granulomatous disease: current status and future perspectives. Curr Gene Ther 2014; 14:447–60.

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deaths. Respiratory infections were most common, and respiratory fungal infections were the most common cause of infectious death. Despite this, median age at death had almost doubled over the time period, from 15.5 to 28.1 years. The residual superoxide production is the most important determinant of risk of mortality from infection, rather than the subunit of NADPH oxidase that is affected, although Burkholderia infections recurred more frequently in the p47phox cohort, and infection with Aspergillus species occurred at an earlier age in the gp91phox cohort. Perhaps the most surprising finding is that 30% of patients did not receive regular antifungal prophylaxis, although it is not clear from the data whether these patients were from an older cohort when prophylaxis was not so readily available. Given that the important role of regular antifungal prophylactic treatment at preventing serious or fatal fungal infection has been acknowledged for >30 years, and that fungal infection remains the leading cause of infectious death in this and other studies, urgent steps should be taken to ensure that this simple intervention is applied to all patients. Compliance may be a problem, particularly in older patients who are no longer under parental supervision; nevertheless, this single, relatively inexpensive intervention has the potential to improve results significantly in the modern era in this patient population. Other important confirmatory findings included the observation that severe invasive infections continue to occur after diagnosis, presumably while taking prophylactic antimicrobial medication, and that inflammatory gastrointestinal

Editorial commentary: severe infections in patients with chronic granulomatous disease.

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