Common Severe Infections in Chronic Granulomatous Disease

Beatriz Marciano

Christine Spalding

Alan Fitzgerald

Daphne Mann

Lisa Barnhart+20 authors

^{Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda}

^{Clinical Research Directorate/Clinical Monitoring Research Program}

^{Clinical Services Program, Applied Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research}

^{Department of Laboratory Medicine, NIH Clinical Center, Bethesda}

^{Laboratory of Host Defenses, National Institute for Allergy and Infectious Diseases, NIH, Rockville}

^{Liver Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland}

Correspondence: Steven M. Holland, MD, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, CRC B3-4141, MSC 1684, Bethesda, MD 20892-1684 (vog.hin@hms).

Received 2014 Jul 30; Accepted 2014 Nov 6.

Copyright Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Abstract

Background. Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades.

Methods. All patients had confirmed diagnoses of CGD, and genotype was determined where possible. Medical records were excerpted into a standard format. Microbiologic analyses were restricted to Staphylococcus, Burkholderia, Serratia, Nocardia, and Aspergillus.

Results.Aspergillus incidence was estimated at 2.6 cases per 100 patient-years; Burkholderia, 1.06 per 100 patient-years; Nocardia, 0.81 per 100 patient-years; Serratia, 0.98 per 100 patient-years, and severe Staphylococcus infection, 1.44 per 100 patient-years. Lung infection occurred in 87% of patients, whereas liver abscess occurred in 32%. Aspergillus incidence was 55% in the lower superoxide-producing quartiles (quartiles 1 and 2) but only 41% in the higher quartiles (rate ratio, <0.0001). Aspergillus and Serratia were somewhat more common in lower superoxide producing gp91^phox deficiency. The median age at death has increased from 15.53 years before 1990 to 28.12 years in the last decade. Fungal infection carried a higher risk of mortality than bacterial infection and was the most common cause of death (55%).Gastrointestinal complications were not associated with either infection or mortality.

Conclusions. Fungal infections remain a major determinant of survival in CGD. X-linked patients generally had more severe disease, and this was generally in those with lower residual superoxide production. Survival in CGD has increased over the years, but infections are still major causes of morbidity and mortality.

Keywords: bacterial infection, fungal infection, CGD, superoxide production, survival

Abstract

(See the Editorial Commentary by Gennery on pages 1184–5.)

Chronic granulomatous disease (CGD) is a genetic immunodeficiency characterized by recurrent infections and inflammatory complications. It is caused by defective function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the enzyme responsible for the phagocyte respiratory burst and superoxide production. Defects in the NADPH complex can be inherited through mutations in any of 5 phagocyte oxidase (phox) genes: X-linked gp91^phox (cytochrome b-245 beta polypeptide), autosomal recessive p22^phox (cytochrome b-245 alpha polypeptide), autosomal recessive p47^phox (neutrophil cytosolic factor 1), autosomal recessive p67^phox (neutrophil cytosolic factor 2), and autosomal recessive p40^phox (neutrophil cytosolic factor 4) [1–3]. A minimal US rate is approximately 1 per 250 000 live births; rates in other countries are similar but differ in the prevalence of recessive mutations, depending on the rates of consanguinity [4, 5].

Since the first cases described in 1954, prophylactic antibiotics, antifungals, and interferon (IFN)–γ, along with aggressive surgical and medical management, have improved outcomes, but infections still cause significant morbidity and mortality [6–9]. The genetic type of CGD and superoxide production are clearly linked to overall survival, but the reasons are unclear [10]. Currently, bone marrow transplant is the only cure.

While some infections are harder to treat than others, it is unclear whether all infections are equally deleterious or equally distributed by CGD genotype. Furthermore, it remains unclear whether different infections affect survival differently. To understand the relative roles of genetics and superoxide generation in susceptibility to specific infections and to determine the relative roles of specific infections on morbidity and mortality, we examined the infections of a large cohort of CGD subjects followed at a single center over 4 decades.

Notes

Financial support. This project was supported by Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) and the National Cancer Institute, NIH (contract number HHSN261200800001E) and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH.

Disclaimer. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Potential conflicts of interest. All authors: No reported conflicts.

All authors have 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.

Notes

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