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Indian Journal of Medical Sciences, Vol. 61, No. 7, July, 2007, pp. 422-429 Practitioners section Burkholderia cepacia complex: Virulence characteristics, importance and relationship with cystic fibrosis Melo Coutinho HenriqueDouglas Departamento de Ciências Físicas e Biológicas- DCFB, Centro de Ciências Biológicas e da Saúde -CCBS, Universidade Regional do Cariri - URCA Code Number: ms07071 Abstract Background : Burkholderia cepacia has been described as a cause of opportunist infections in patients with immune deficiency because of the high transmission rates. Actually the B. cepacia is subdivided in nine different genomic species that show morphological similarity, called genomovars. High mortality rates have been associated with infections caused by genomovars in susceptible patients; antibiotics are not efficient because of the high resistance level and genomic mutability. Little is known about the epidemiological traits of this bacterium; therefore, their isolation remains a relevant technical problem.Aims : The objective of this review is to describe Burkholderia cepacia as a bacterial complex with high pathogenicity and variability of habitats. Materials and Methods : A systematic search was realized using the international bibliographic databanks SCIELO, HIGHWIRE, PUBMED, SCIRUS and LILACS to provide a useful and practical review for the health workers that do not know this microorganism. Conclusions : Today, B. cepacia complex is a very important problem for the acquired immunodeficiency syndrome and cystic fibrosis patients. The immunodeficiency caused by these diseases is a positive factor for this microorganism to infect and kill these patients. Therefore, this opportunistic pathogen should be pointed out as a risk to these patients, and hospitals all over the world must be prepared to detect and combat this bacterium. Keywords: Burkholderia cepacia, genomovars, immune deficiency, opportunist infections Burkholderia cepacia is a bacterial complex composed of opportunistic pathogens with high pathogenicity, living in various environments. Being aerobic and chemoorganotrophic with optimal temperature similar to the human body, this bacterium shows fast growth on immune-depleted patients - like cystic fibrosis patients (CFPs). Cystic fibrosis is an autosomal recessive disease, more severe when accompanied by this infection. The risk factors of this bacterium are due its capacity of direct transmission (as nosocomial infection or social contact with infected patients), but new information shows the possibility of indirect transmission. [1] Cystic fibrosis is the most common autosomal genetic disease in North America, affecting 1 in 2,000 individuals among Caucasians. [2] This disease is caused by mutations affecting the cystic fibrosis transmembrane conductance regulator protein - CFTR - and is characterized by chronic malfunction of lung, pancreatic insufficiency and high levels of chloride in sweat. Its high mortality index is evident when lung and spleen are affected, but other organs can also be affected. The persons affected die by progressive bronchiectasis and chronic respiratory insufficiency. [3],[4] This disease can affect persons without distinction of age or sex but can be asymptomatic in a great number of cases. [3] Lungs of CFPs are apparently normal at birth. The development of chronic and recurrent infections in the airways can be observed during the first years of life, reflecting problems with the innate defense mechanisms of lungs against bacteria. Correlation between the epithelial transport of ions and airways′innate defense against these pathogens was demonstrated. [5] In normal conditions, mucus clearance provides the mechanical remotion of airways bacteria in 6 h. It is necessary due to the specific height and viscosity of the periciliar liquid layer (PLL) to lubricate and clean the cellular surface of airways by ciliary beating. In CFPs it does not occur; and because of the continuous mucin production on PLL, the mucus plates and a microaerophilic environment may be formed next to the cellular surface. In this situation, bacteria such as P. aeruginosa, S. aureus and B. cepacia complex can grow. Moreover, the macrophages and antibiotics cannot penetrate the mucus plates. [5] The lack of mucocilliar clearance in the airways stimulates the installation and the recurrence of bacterial infections; and, in this way, the blockage of airways, the inflammation and chronic infections. [6] The inflammatory process in CFPs is apparently important for the bacterial infection, since an increase in the production of certain pro-inflammatory cytokines is a good prognostic against the recurrent bacterial infections. [7] Fast and precise detection is essential to evaluate the prognosis and risks of this infection. The clinical evidence is not clear; so laboratory tests (mainly biochemical and genetic tests) are important tools to detect this pathogen. Oncological or nosocomial patients, like CFPs, associated with lung infections by B. cepacia presented higher mortality rates when compared with patients having normal immune system. The use of new drugs, such as immunosuppressive drugs with antimicrobial activity, has reduced the difference between these rates. On the other hand, the antibiotic therapy was not efficient due to the high level of resistance and mutability of this bacterium. [8] Historical Background and Microbiological Facts of the Bacterium Burkholderia cepacia is a gram-negative rod with 1.6-3.2µm, aerobic and chemoorganotrophic Its optimal growth temperature is 30-35°C. It was first described by Burkholder in 1950. Burkholder isolated these bacteria from putrefactive onions. [9],[10] The isolation of B. cepacia is very difficult because of very slow growth under natural conditions. [11] Burkholderia cepacia is a bacterial complex with nine genomic species with similar phenotypical traits and different genetic ones, called genomovars. [12],[13] The complex is constituted by B. cepacia genomovar I (cepacia); B. cepacia genomovar II (multivorans); B. cepacia genomovar III (cenocepacia); B. cepacia genomovar IV (stabilis); B. cepacia genomovar V (vietnamiensis); B. dolosa genomovar VI; B. ambifaria genomovar VII; B. anthina as genomovar VIII; and B. pyrrocinia as genomovar IX. [3],[12],[14] The genomovars can live in several different environments such as soil, water and plants. These microorganisms have a high mutation rate, with a very plastic genome, being opportunistic pathogens to humans and plants. [4],[11],[15] The ancient denomination of B. cepacia was P. cepacia. The epidemiological, virulence and molecular biology studies showed that these bacteria differ in some biological traits, and Burkholderia has been classified as a different genus. [3],[16] Patient Populations at Risk , Epidemiology and Nosocomial Transmission The first epidemiological outbreak of the B. cepacia complex was associated with lung infections disseminated by Portuguese people between 1995 and 1997. [17] The epidemiology of this complex is unknown because the identification and the genomovars analysis are very difficult. [18] Therefore, the identification of outbreaks without the identification of the specific pathogenic agent little contributed to the epidemiology of B. cepacia complex. [19] The infection by this complex could be disseminated between infected nosocomial patients or by social contact with asymptomatic persons. This disease has a great impact on the morbidity and mortality of infected persons; therefore, the patients must be informed about the transmission risks of these bacteria by social contact. [4],[13] High levels of B. cepacia were detected in the salivary fluid of infected patients. This fact may indicate the possibility of indirect transmission by kisses or sexual activity. [20] The genetic identification of this bacterium is essential to understand the transmission and pathogenic potential of genomovars. The presence of pilum at the surface of B. cepacia strains can be related with a higher adherence to the airway epithelial cells, affecting the transmission and pathogenicity of this microorganism. [4] On the other hand, higher transmission of B. cenocepacia is related with a low adherence of its pilum. [21] The transmission between patients is most frequent in case of B. cepacia genomovar III (B. cenocepacia), compared to the others. [18] The incidence of B. cepacia complex is related with the incidence of cystic fibrosis causing immunosuppression. So this infection is more common among Caucasians, sex or age not being important [22] ; but in the countries where the infection by B. cepacia is uncontrolled, the ethnic factor is not relevant and this microorganism has a higher incidence. Prognosis of B. Cepacia Infection B. cepacia was identified in the 80 th decade, causing infections in CFPs. [23],[24] Cunha et al.,[17] who studied the Portuguese population infected by B. cepacia during a period of 7 years, observed the effect of genomovars on the infections in CFPs, capacity of transmission and the possibility to cause infections and diseases in other persons. Oncological, nosocomial and cystic fibrosis patients with lung infection present the B. cepacia complex as one of the more important opportunistic pathogens. [25] These patients can be colonized long before the infection begins. [26] The colonization by only one strain is more common. [20] The bacterial infection causes a loss of lung function, resulting in necrosis and pneumonia (cepacia syndrome), septicemia, reduction of body mass index and the life prognostic. [19],[20] Specific transmission forms were observed during the infectious process caused by this pathogen. As a result of this fact, the incidence of new infections was reduced but not eradicated. Evaluating the risk of environmental transmission of genomovars remains difficult, mainly for the genomovar III, making the control of transmission more difficult. [25] B. multivorans is characterized by a short time of infection and a good prognostic. On the other hand, the genomovar III is associated with high mortality level. [18] The complete eradication of infections caused by this complex is very difficult but not impossible. [21] The lung disease caused by cystic fibrosis generates a failure of the immune system and problems mainly in lung and spleen, making possible repetitive infections. [3] As a result, mortality levels of patients infected by B. cepacia are higher among those affected by cystic fibrosis than among those not affected. The use of modified therapeutic strategies with antimicrobial and immunosuppressive drugs has been useful to reduce these levels. [4] Associated with the loss of respiratory function, this disease reduced the life prognostic of lung-transplanted patients. [13] The different survival levels observed in lung-transplanted patients infected by B. cepacia indicate differences in virulence and transmission of the complex. [15] Soni et al.[13] compared the prognostic after infection of different genomovars of the B. cepacia complex. The results showed a difference in the prognostics between different genomovars, indicating specific traits of virulence and transmission in each genomovar. It is therefore very important to identify the infecting genomovar to determine the prognostic. All of B. cepacia complex genomovars were isolated from the lung of CFPs, although B. multivorans (genomovar II) and B. cenocepacia (genomovar III) were associated with a more severe clinical state. [21] Thus lung transplanted patients infected by genomovar I have a good prognostic; and with the genomovar II, this prognostic is reduced but still good. But the prognostic is not good when infected with genomovar III. [13],[21] Soni et al.[13]showed that all CFPs infected by genomovar III ST 040 died, but only 1 out of 5 infected with genomovar III ST 010 died (20%). This fact indicates a variable pathogenicity in the strains of the same genomovar. The prognostic cannot be unique to all patients infected by B. cepacia complex; it depends on several factors such as genomovar, the strain of genomovar, the virulence and the transmission capacity of the strain. [15] The classical clinical traits of CFPs infected by B. cepacia are reduction and stabilization of respiratory function, which becomes more severe with time; hypoxemia; fever; neutrophily; lung noises with crackles; higher production of mucus and lung-condensed areas. All these traits contribute to the fulminating cepacia syndrome. [20] Options for Microbiological Diagnostics The reduced taxonomic diversity and unique genomic characteristics make easier the identification of several diseases caused by microorganisms belonging to the B. cepacia complex. The diagnosis of a genomovar of B. cepacia is made by phenotypic and genotypic characterization. To simplify the identification process, genetic methods based on polymorphisms of the nucleotide sequence of rRNA 16S or the gene recA have been developed. [27],[28],[29] The accuracy and fast detection of this bacterium are essential to evaluate risks, prognostics and epidemiology of cystic fibrosis. Polymerase Chain Reaction - Random Fragments of length Polymorphism (PCR-RFLP) of the rDNA 16S gene is a very useful identification method, which contributes to the better evaluation of the clinical risks of each species of Burkholderia or genomovar in cystic fibrosis patients. [19],[30] When the work is based on strains isolated from transplanted patients, the PCR may be used to confirm the presence of the B. cepacia complex and to identify the genomovar. [31] The isolating of bacteria belonging to the B. cepacia complex from lung secretions of CFPs should be done on several basic culture media: P. cepacia (PC) agar, oxidative - fermentative base, Polymixin B, bacitracim and lactose (OFPBL) agar and B. cepacia selective agar (BCSA). [14] The isolation on selective media should be associated with the identification of this pathogen by biochemical tests and standard identification kits to prevent misidentification. The identification of other bacteria associated with CFPs, such as S. aureus and P. aeruginosa, is also important in the airways of CFPs. [21] All components of B. cepacia complex can be detected in the airways of CFPs, mainly genomovars II and III. [4],[21] The microbiological evaluation of airway mucus on specific medium for B. cepacia complex and other bacteria is an important diagnostic test to identify their presence and prognostic for CFPs. [13] Options for Antimicrobial Chemotherapy B. cepacia is very resistant to antibiotic therapy because its genome is very plastic and suffers several mutations and adapts itself, making it a hard challenge for treatment. Its resistance is mainly due the production of enzymes with capacity to inactivate the substances used in the treatment. [15],[21],[26] The resistance of these bacteria can be related with other factors such as selective permeability of cell wall, cellular alterations, enzymatic degradation of antibiotics and efflux pump. [21] Infection Control measures for the Prevention of Transmission of B. Cepacia Several factors affect transmission, such as the type of bacterial strain, the immune state of the patient and the use of contaminated medical equipment. Therefore, all patients infected or colonized with the complex B. cepacia must be isolated in a single room because they represent sources for nosocomial transmission of the microorganism to other patients during the treatment. [18],[32] In the last 15 years, Burkholderia cepacia has been a very important pathogen for patients with cystic fibrosis, affecting the mortality of these patients and making possible the transmission between ′infected - healthy - infected′persons. [33] Therefore, the isolation of infected patients and control of infection are very important to prevent the transmission of these bacteria between patients with cystic fibrosis. [12],[21] Conclusions On the basis of what has been said in this paper, it can be concluded that the study of the B. cepacia complex presents a large variety of questions to be answered with regard to the physiology, ecology, pathogenicity and possibilities for use of this microorganism in biocontrol or bioindication. Hence new research must be encouraged on several lines such as specific mechanisms of resistance to antibiotics and the discovery of new anti-Burkholderia drugs, genetic analysis and evaluation of genes and proteins produced by these bacteria against fungi and other plant pathogens.References
Copyright 2007 - Indian Journal of Medical Sciences |
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