Journal of Nematology 35(2):212–217. 2003. © The Society of Nematologists 2003. Burkholderia cepacia Complex as Human Pathogens1 John J. LiPuma2 Abstract: Although sporadic human infection due to Burkholderia cepacia has been reported for many years, it has been only during the past few decades that species within the B. cepacia complex have emerged as significant opportunistic human pathogens. Individuals with cystic fibrosis, the most common inherited genetic disease in Caucasian populations, or chronic granulomatous disease, a primary immunodeficiency, are particularly at risk of life-threatening infection. Despite advances in our understanding of the taxonomy, microbiology, and epidemiology of B. cepacia complex, much remains unknown regarding specific human virulence factors. The broad-spectrum antimicrobial resistance demonstrated by most strains limits current therapy of infection. Recent research efforts are aimed at a better appreciation of the pathogenesis of human infection and the development of novel therapeutic and prophylactic strategies. Key words: Burkholderia cepacia, cystic fibrosis, human infection. Until relatively recently, Burkholderia cepacia had been B. cepacia, possess other factors that remain to be elu- considered a phytopathogenic or saprophytic bacterial cidated that also mediate pathogenicity in this condi- species with little potential for human infection. How- tion (Speert et al., 1994). Fortunately, CGD is a rela- ever, reports of sporadic human infection have ap- tively rare disease, having an average annual incidence peared in the biomedical literature, generally describ- of approximately 1/200,000 live births in the United ing infection in persons with some underlying disease States; this means there are approximately 20 persons or debilitation (Dailey and Benner, 1968; Poe et al., with CGD born each year in the United States. 1977). Indeed, an early review of one medical center’s Cystic fibrosis: Cystic fibrosis (CF) is another inherited experience with B. cepacia infection during the years disorder in which B. cepacia can cause severe infection 1968–1969 indicated that essentially all infections oc- (LiPuma 1998a). In contrast to CGD, CF is relatively curred in patients with a chronic disease that predis- common. It is, in fact, the most common lethal genetic posed them to opportunistic infection (Ederer and disorder among Caucasians, affecting approximately Matsen, 1972). Other reports described “pseudo- 1/2,750 live births. One person in 25 is an asymptom- epidemics” among hospitalized patients, most often at- atic carrier. There are currently some 30,000 persons tributed to contamination of disinfectants used in the with CF in the United States, and an equal number can preparation of blood culture systems (Berkelman et al., be found in Europe. Cystic fibrosis is a multisystem dis- 1981; Craven et al., 1981; Sobel et al., 1982). Contami- ease that is believed to result primarily from a mutation nation of antiseptic and anesthetic solutions also has in the gene encoding the cystic fibrosis transmembrane resulted in true nosocomial infection and “mini- conductance regulator (CFTR), a cAMP-dependent epidemics,” particularly in intensive care units (Phillips chloride channel. The consequences of this defect are et al., 1971; Steere et al., 1977). complex (Larson and Cohen, 2000; Zeitlin, 1999), but Chronic Granulomatous Disease: In addition to hospital- the resultant altered respiratory epithelial surface fluid acquired infection, persons with certain chronic dis- in some way predisposes to chronic pulmonary infec- eases are susceptible to infection by B. cepacia. Among tion. Nearly 1,000 mutations have been identified in these disorders is chronic granulomatous disease the CF gene—the most common being a deletion of (CGD). In this inherited primary immunodeficiency phenylalanine at amino acid position 508 (⌬F508). De- disease, white blood cells are unable to kill some bac- spite the presence of this mutation among the majority terial and fungal species after phagocytosis (Winkel- of persons with CF, there is a wide spectrum of disease stein et al., 2000). The underlying defect is an inability of phagocytic cells to generate superoxide and reactive severity. Most persons have some degree of respiratory oxidants that are necessary for intracellular microbici- dysfunction and are prone to chronic respiratory tract dal activity. As a result of this defect, CGD patients suf- infection (Dinwiddie, 2000). Common bacterial patho- fer from recurrent life-threatening infections, such as gens in young CF patients include Staphylococcus aureus severe pneumonia and bacteremia caused by certain and Haemophilus influenzae. During adolescence Pseudo- catalase-positive species. The observation that not all monas aeruginosa infection becomes common, and by catalase-positive bacteria are capable of causing severe adulthood nearly 80% of CF patients are chronically infection in CGD suggests that some species, including infected with P. aeruginosa. Progressive lung deteriora- tion secondary to recurrent or chronic infection is the leading cause of death in CF; the median survival age is Received for publication 24 June 2002. approximately 32 years. Nevertheless, it is important to 1 Symposium paper presented at the 40th Annual Meeting of The Society of Nematologists, 25–29 August 2001, Salt Lake City, UT. point out that many persons with CF are in relatively 2 Department of Pediatrics and Communicable Diseases, University of Michi- good health, infrequently hospitalized, and lead pro- gan Medical School, Ann Arbor MI 48109. e-mail: [email protected] ductive and active lives. This paper was edited by B. C. Hyman. History of B. cepacia infection in CF: The first reports of 212 B. cepacia Complex as Human Pathogens: LiPuma 213 B. cepacia infection in persons with CF appeared in the established. There is increasing evidence that the lung late 1970s (Blessing et al., 1979; Laraya-Cuasay et al., damage seen with B. cepacia infection results from a 1977). Shortly thereafter, a report described severe marked host inflammatory response (Hughes et al., pneumonia, sepsis, and death due to B. cepacia inaCF 1997). For example, B. cepacia lipopolysaccharide is a patient (Rosenstein and Hall, 1980), and a study of potent stimulator of neutrophil respiratory burst re- prophylactic antibiotic use in CF from Toronto in 1982 sponses and induces significantly more production of reported that 45% of enrolled patients were infected tumor necrosis factor alpha from monocytes in vitro with B. cepacia (Nolan et al., 1982). The seminal report than does lipopolysaccharide from P. aeruginosa (Shaw by Isles et al. (1984) subsequently described in greater et al., 1995). The ability of B. cepacia to invade and detail the clinical significance of B. cepacia infection in survive within respiratory epithelial cells (Chiu et al., the Toronto CF center. In addition to documenting a 2001; Keig et al., 2001; Martin and Mohr, 2000) and steadily increasing prevalence of B. cepacia infection resist intracellular killing by phagocytic cells (Saini et during the previous decade, these investigators de- al., 1999) may play a role in evasion of host immune scribed a syndrome of severe progressive respiratory response and persistence of infection. Finally, N- failure with bacteremia that occurred in several pa- acylhomoserine lactone-dependent quorum-sensing tients. Soon thereafter, this so-called “cepacia syn- systems that most likely regulate biofilm production by drome” was also described in reports from other North B. cepacia in vivo have been described (Gotschlich et al., American CF treatment centers that had witnessed simi- 2001; Lewenza et al., 1999). lar increases in incidence of B. cepacia infection among Antimicrobial resistance: The broad-spectrum antibiotic their patients (Tablan et al., 1985; Thomassen et al., resistance demonstrated by most strains of B. cepacia 1985). A number of subsequent studies further defined severely limits effective therapy of human infection. In the impact of B. cepacia infection in CF and identified fact, identification of strains resistant to all currently several risk factors for infection, including hospitaliza- available antibiotics, particularly in CF patients, fre- tion and having an infected sibling (Goldmann and quently renders infection refractory to antimicrobial Klinger, 1986; Tablan et al., 1987). therapy. The sparse phosphorylation of B. cepacia lipo- Virulence of B. cepacia: Several case-controlled studies polysaccharide is believed to be responsible for intrin- have demonstrated an association between infection sic resistance to polycationic peptides including with B. cepacia and poor prognosis in CF (Brown et al., aminoglycoside antibiotics (Hancock, 1998). Inducible 1993; Ledson et al., 2002; Lewin et al., 1990; Taylor et chromosomal ␤-lactamases are present in the majority al., 1993; Whiteford et al., 1995). In fact, although of strains (Chiesa et al., 1986) as are antibiotic efflux many individuals may remain infected with B. cepacia pumps that mediate resistance to chloramphenicol, for prolonged periods, up to 20% succumb to a rapidly quinolone antibiotics, and trimethoprim (Burns et al., progressive necrotizing pneumonia soon after infection 1996). Altered dihydrofolate reductase is yet another is recognized (Isles et al., 1984; Tablan et al., 1987; mechanism by which some strains may exhibit tri- Simmonds et al., 1990). Despite this association, the methoprim resistance (Burns et al., 1989). precise role