Recurrent Granulibacter bethesdensis Infections | CDC EID

Volume 16, Number 9–September 2010
MEDSCAPE CME ACTIVITY
Recurrent Granulibacter bethesdensis Infections and Chronic Granulomatous Disease
Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://cme.medscape.com/viewpublication/30063; (4) view/print certificate.

Learning Objectives
Upon completion of this activity, participants will be able to:

•Identify infectious organisms in cases of chronic granulomatous disease (CGD).
•Distinguish the clinical presentation of Granulibacter bethesdensis infection in CGD.
•Diagnose G. bethesdensis infection in CGD effectively.
•Plan effective treatment for G. bethesdensis infection in CGD.


Medscape CME Editor
Thomas J. Gryczan, MS, Copyeditor, Emerging Infectious Diseases. Disclosure: Thomas J. Gryczan, MS, has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

Authors
Disclosures: David E. Greenberg, MD; Adam R. Shoffner, BS; Adrian M. Zelazny, PhD; Michael E. Fenster, MD; Kol A. Zarember, PhD, BSc; Frida Stock, BS; Li Ding, MD; Kimberly R. Marshall-Batty, PhD, MS, BS; Kishore Kanakabandi; Dan E. Sturdevant, PhD; Kimmo Virtaneva; Stephen F. Porcella, PhD; Patrick R. Murray, PhD; Harry L. Malech, MD; and Steven M. Holland, MD, have disclosed no relevant financial relationships. Richard L. Wasserman, MD, has disclosed the following relevant financial relationships: served as an advisor or consultant for Baxter Healthcare, CSL Behring, Talecris Biotherapeutics; served as a speaker or a member of a speakers bureau for Baxter Healthcare, CSL Behring, Talecris Biotherapeutics; received grants for clinical research from Baxter Healthcare, CSL Behring, Talecris Biotherapeutics, Nabi Biopharmaceuticals. David F. Welch, PhD, has disclosed the following relevant financial relationships: received grants for clinical research from Prodesse (Gen-Probe); owns stock, stock options, or bonds from Cepheid, Luminex Corporation, Merck & Co., Inc., Eli Lilly and Company, Boston Scientific Corporation, Becton, Dickinson and Company.



EID Journal Home > Volume 16, Number 9–September 2010

Volume 16, Number 9–September 2010
Synopsis
Recurrent Granulibacter bethesdensis Infections and Chronic Granulomatous Disease
David E. Greenberg , Adam R. Shoffner, Adrian M. Zelazny, Michael E. Fenster, Kol A. Zarember, Frida Stock, Li Ding, Kimberly R. Marshall-Batty, Richard L. Wasserman, David F. Welch, Kishore Kanakabandi, Dan E. Sturdevant, Kimmo Virtaneva, Stephen F. Porcella, Patrick R. Murray, Harry L. Malech, and Steven M. Holland

Author affiliations: National Institutes of Health, Bethesda, Maryland, USA (D.E. Greenberg, A.R. Shoffner, A.M. Zelazny, M.E. Fenster, K.A. Zarember, F. Stock, L. Ding, K.R. Marshall-Batty, P.R. Murray, H.L. Malech, S.M. Holland); University of Texas Southwestern Medical Center, Dallas, Texas, USA (R.L. Wasserman, D.F. Welch); Children's Medical Center, Dallas (D.F. Welch); Medical City Dallas Hospital, Dallas (D.F. Welch); and National Institutes of Health, Hamilton, Montana, USA (K. Kanakabandi, D.E. Sturdevant, K. Virtaneva, S.F. Porcella)

Suggested citation for this article

Abstract
Chronic granulomatous disease (CGD) is characterized by frequent infections, most of which are curable. Granulibacter bethesdensis is an emerging pathogen in patients with CGD that causes fever and necrotizing lymphadenitis. However, unlike typical CGD organisms, this organism can cause relapse after clinical quiescence. To better define whether infections were newly acquired or recrudesced, we use comparative bacterial genomic hybridization to characterize 11 isolates obtained from 5 patients with CGD from North and Central America. Genomic typing showed that 3 patients had recurrent infection months to years after apparent clinical cure. Two patients were infected with the same strain as previously isolated, and 1 was infected with a genetically distinct strain. This organism is multidrug resistant, and therapy required surgery and combination antimicrobial drugs, including long-term ceftriaxone. G. bethesdensis causes necrotizing lymphadenitis in CGD, which may recur or relapse.

Chronic granulomatous disease (CGD) is a rare genetic disease caused by mutations in any of the 4 structural genes of the NADPH oxidase system and leads to defective production by phagocytes of superoxide and downstream oxygen metabolites (1). Infections in patients with CGD are caused by a narrow spectrum of pathogens, including Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, Nocardia spp., and Aspergillus spp. (2–4). Although lymphadenitis is commonly encountered, a pathogen is isolated in only »60% of cases (5).

Most human bacterial infections, even those that are severe, are transient and curable. Bacteria such as Mycobacterium tuberculosis are unique human pathogens in part because of their ability to persist in a dormant state and reactivate later. The recurrent infections observed in patients with CGD, even when caused by the same species of organism, are the result of reinfection rather than relapse (3,6). Granulibacter bethesdensis is a recently described gram-negative bacterium in the family Acetobacteraceae; it has been isolated from 6 patients with CGD from North and Central America and Spain (7–10). The initial case was in an adult who had prolonged fever, necrotizing lymphadenitis, and multiple disease recurrences culminating in cure 2 years after seeking treatment. Persons with subsequent cases in the Americas had shorter periods before diagnosis and more rapid responses to therapy. A fatal case reported in Spain involved a patient with CGD in whom G. bethesdensis was the only pathogen identified. Given the increasing cases of this emerging pathogen, we present in greater detail the clinical course of these patients and molecular epidemiologic evidence to support the recurrent infections we have diagnosed for some of these patients.

Five patients were followed up at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA) under protocol 93-I-0119. Patients 2, 3, and 5 had been actively followed up at NIH for at least 8 years before receiving a diagnosis of G. bethesdensis infection. Patient 1 had been sent to NIH for evaluation of his lymphadenopathy and Granulibacter infection was diagnosed shortly thereafter. Patient 4 was referred to NIH for treatment and follow-up after his Granulibacter infection was diagnosed at an outside hospital (by R.L.W. and D.F.W.).

The G. bethesdensis high-density microarray platform, DNA microarray hybridization, and comparative genomic hybridization analysis used for typing of the G. bethesdensis isolates have been described (9). Bacterial DNA was isolated by using the NucliSens Kit (bioMβrieux, Durham, NC, USA), and 16S rRNA genes from the 5 patient isolates were sequenced and analyzed as described (8). DNA was isolated from human tissue by using the Maxwell 16 Tissue DNA Purification Kit (Promega, Madison, WI, USA) according to the manufacturer’s protocol. DNA concentrations were measured by using a UV spectrophotometer (NanoDrop, Wilmington, DE, USA).

The 16S rRNA and methanol dehydrogenase subunit 1 (GeneID YP_744165.1) genes of G. bethesdensis were analyzed by using a PCR and primer sequences 16S-forward: 5'-TCGGGTGGGCACTCTAAAGG-3', 16S-reverse: 5'-GCATCACTGCCTAGCTTCCC-3', MDH-forward: 5'-CCGCAATACGGTCAATTCG-3', and MDH-reverse: 5'-GCCGATCTTCCAGGTTTCTTC-3'. Each reaction mixture contained 47 μL of Platinum Blue PCR SuperMix (Invitrogen, Carlsbad, CA, USA) and 1.5 μL of each primer at a final concentration of 0.75 μmol/L, and the PCR was performed in a thermocycler (Eppendorf, Hauppauge, NY, USA). The PCR amplification conditions were 94°C for 10 min; 40 cycles at 94°C for 30 s, 60°C for 30 s, and 72°C for 30 s; and a final extension at 72°C for 5 min. PCR fragments were visualized by electrophoresis on a 2% agarose gel and showed the expected sizes of 137 bp (16SrRNA) and 63 bp (methanol dehydrogenase subunit 1).

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