RecurrentGranulibacter bethesdensisInfections and Chronic Granulomatous Disease

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

“…Francisella philomiragia causes sepsis in CGD and is also found in brackish waters, such as the Chesapeake Bay, Long Island Sound and around Nova Scotia (32). Granulibacter bethesdensis is a novel Gram negative rod that causes chronic necrotizing lymphadenitis and can cause sepsis in CGD (33). It can have latent and active phases, similar to tuberculosis and has been identified from the United States, Panama, and Spain, suggesting wide distribution.…”

Serologic Reactivity to the Emerging Pathogen Granulibacter bethesdensis

“…Given the recognized genetic differences between the Granulibacter isolates to date [10] and the small number of isolates that had been found, we pooled soluble Granulibacter extracts from 4 NIH isolates to better represent this diversity for immunoblot screening purposes. Although sera from our patients known to be culture positive [7,8,13] showed a variety of bands when tested against these pooled extracts, we consistently detected 11 distinct bands with apparent molecular weights of approximately 150, 140, 100, 80, 75, 70, 62, 51, 45, 38, and 28 kDa.…”

“…bethesdensis National Institutes of Health (NIH) strains NIH1.1 (strain CGDNIH1 T ; ATCC BAA-1260), NIH2.1, NIH2.2, NIH3.1, and NIH4.1 [10] were cultured in yeast peptone glucose (YPG) medium (5 g of yeast extract, 3 g of peptone, and 10 g of glucose per liter of water). Single colonies were inoculated into 5 mL YPG, shaken overnight (at 180 rpm and 37°C), and subcultured into 150 mL of YPG for 48 hours.…”

“…CGD patients get recurrent infections that are typically caused by Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia complex, Nocardia species, and Aspergillus species [2][3][4][5][6]. Granulibacter bethesdensis was originally isolated from a CGD patient with fever and lymphadenopathy and has since been isolated from at least 6 CGD patients [7][8][9][10]. Of interest, only 1 patient is known to have died from this organism [9].…”

Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease

“…The clinical presentation of Granulibacter infection generally includes fever, weight loss, fatigue, severe lymphadenitis, ascites, and bacteremia. However, in some subjects, long-term seropositivity prior to the isolation of the pathogen has been noted (7). Serologic testing of larger cohorts of CGD patients suggests that the observed prevalence of G. bethesdensis infections in CGD may be underestimated (9).…”