Incidence, relevance and response for ralstonia respiratory infections.
The impact of gram negative rods on clinical disease is well known. For example, it has been noted that gram negative rods (i.e., Burkholderia cepacia) have significant impact on patients (decline of lung function) with cystic fibrosis. Ralstonia is a lesser known member of the group. The Centers for Disease Control has published occasional reports over the past few decades of patients colonized or infected with Ralstonia bacteria. (1-3)
The Ralstonia genus is an aerobic, non-fermentative, oxidase-positive, Gram-negative bacillus commonly found in water and soil. (4) It may exist under harsh conditions; for example, it is able to survive disinfectants such as chlorhexidine (5) and ethacridine lacatate (6), but it thrives best in moist environments. The Ralstonia genus includes R. pickettii and R. solanacearum (formerly Burkholderia pickettii and B. solanacearum), R. insidiosa (7), and R. mannitolilytica. (8) In CF patients, the prominent species detected via PCR is R. mannitolilytica. (9) However, its role in affecting disease/symptom severity is unknown. Recently in a review by Ryan et al, it was concluded that, "R. pickettii is still regarded as the main pathogenic species of this strain." (10)
Recently, the 2005 recall of a respiratory gas humidification device thought to be associated with cases of Ralstonia (15% R. mannitolilytica, 1% other Ralstonia spp.) colonization reported by hospitals in several states has generated increased interest in an organism previously little known to most clinicians. (1) The FDA Preliminary Public Health Notification regarding the Vapotherm respiratory device (Oct. 21, 2005) made the following recommendation, "Clinicians must continue to weigh the potential risks of Ralstonia spp. contamination of Vapotherm[R] devices against the benefits of using the device in patients requiring humidified oxygen therapy." (1) The device has been approved for return to market so clinicians need information on the potential risks of Ralstonia to patients, of which there is little, to follow this recommendation. Given this conclusion it is worth noting that this was not the strain identified in the Vapotherm recall. Our goal was to determine the incidence of respiratory colonizations and infections involving Ralstonia including (primary and secondary infections) and the association of mechanical ventilation (secondary infection defined as that which occurs because some initial primary infection has weakened the host). We limited our review to reports on occurrences in the USA.
The majority of results from an Internet search on " Ralstonia" would yield information on occurrences in plant nurseries rather than neonatal units. In that context Ralstonia is referred to by names such as "Bacterial Wilt" or "Geranium Wilt." Prior to 1995, this genus was typically identified as a species of Burkholderia or Pseudomonas and, depending on the assay used, there may still be misidentification. (4) Most of the reported human Ralstonia cases resulted from use of contaminated solutions such as distilled water11 or injectable water (12), injectable saline (12-13) or purified respiratory ampules. (14)
The presence of Ralstonia spp. isolated from patients has led to confusion for many clinicians as to whether it is appropriate to treat the bacteria or to regard it as colonization. Another difficulty arises with properly identifying Ralstonia from other phylogenically similar organisms (i.e., Burkholderia sp. and Pseudomonas sp.). These factors have led to an aggressive treatment of the bacteria and this generalized "shotgun" approach to therapy has likely contributed to increasingly resistant strains, (15-17) which experts believe may be related to both constitutive and inducible mechanisms of the organism. This intensive therapy is quite unfortunate as most Ralstonia sp. lack the virulence factors seen in both Pseudomonas sp. and Burkholderia sp. (15,18-19)
It is often difficult to decide specific therapy for an organism without consideration of the host. If a host is immunocompromised (i.e. HIV infection or on immunosuppressive agents) or exhibits a long-term medical condition (i.e. cancer, cystic fibrosis), often a more aggressive therapy is enacted to treat a positive culture. (20-21) While there is some evidence pointing to this approach for the treatment in Ralstonia, a more complete examination of these host factors is certainly warranted.
To examine the impact of Ralstonia on patient clinical outcomes, we performed an analysis of published clinical reports of Ralstonia to determine the potential risks for respiratory colonization and infection in the USA. We specifically asked if being on mechanical ventilation (MV) had an influence on colonization and conversion to infection (symptomatic). These data would then lead to the generation of decision-making pathways for use in clinical respiratory care.
METHODS AND MATERIALS
Electronic databases searched included Medline/ PubMed, Web of Science[R], Embase[R], Scopus[R], and BIOSIS Previews[R] from January 1995 through January 2008. Embase (over 4600 journals) and Medline/ PubMed (over 5000 journals) each cover about 1800 journals that the other database does not. Web of Science searches 8100 multidisciplinary research journals and Scopus covers over 15,000 research journals that include science, technology and medicine. BIOSIS Previews draws from 5,500 life science journals plus items from international meetings, review articles, books, and other unique references. Retrospective and prospective cited reference searches of key articles were also performed using Scopus and Web of Science.
Our literature review identified four reports that include data on respiratory colonization that allowed for calculating an average odds ratio. (2,22-23,3) The definition of infection versus colonization was based on the establishment of clinical parameters of disease (i.e., purulent sputum, fever greater than 38. 8 C, impaired oxygenation, or elevated white blood cell count). (24)
Four reports (two of which also provided colonization data) contained sufficient data to calculate an average odds ratio for infection. (2-3,25) Due to the variability of clinical environments, procedures, surveillance and therapies used internationally, we limited our search to occurrences in the USA. All studies represented new cases of Ralstonia. We focused on occurrences that involved the respiratory tract because of the relationship to hospital equipment/procedures raised by the humidification device recall and the greater potential for serious complications. Immunocompromised population examined included individuals with HIV, common variable immunodeficiency (CVID), extensive burn injury, and those individuals with greater than 20 mg of prednisone per day; patients with bronchiectatic conditions such as cystic fibrosis (CF) and idiopathic bronchiectasis were also examined as compromised populations.
Our analysis sought to determine what the odds of becoming colonized or infected with Ralstonia between patients' receiving mechanical ventilation and those on other types of therapies. We performed a meta-analysis for these published multiple incidences of Ralstonia cultured in patients with respiratory infections in the USA. A meta-analysis seeks to systematically review all pertinent evidence, provide quantitative summaries, integrate results across studies, and provide an overall interpretation of these studies (National Library of Medicine Glossary). The results of each study included in the analysis were summarized as counts in a 2-by-2 table. The treatment group was patients on MV and the control group consisted of patients not on MV. We developed two different analyses; one for colonization with Ralstonia and the other for infection with Ralstonia based on reported constitutional and respiratory symptoms with isolation of bacteria. This analysis was carried out using the Fixed-effects model with NCSS Software (NCSS, Kaysville, UT, 2006). This analysis involved the calculation of a set of two-group, binaryevent studies summarized from the published studies. In addition to limiting our search to reports of Ralstonia respiratory infections in the USA, our analysis required that case controls were reported (Jhung, 2001, used matched case controls).
Selection of Reports for Meta-Analysis
Four of the six published reports in this analysis contained colonization data and four of the reports contained infection data. A Morbidity and Mortality Weekly Report (MMWR) document from 1983 reported on an outbreak (multiple cases of culture-positive Ralstonia regardless of patient status, e.g., infection or colonization) in a special-care nursery traced to a contaminated respiratory therapy solution (no colonization detected in the prior 15 months). (2,14) The single dose vials of normal saline were under recall because of intrinsic bacterial contamination and were used in both infant and adult patients; no colonization was found in the adults under surveillance. Of the 12 reported infant patients, 11 were on mechanical ventilation and five of those were positive for Ralstonia colonization (one positive colonization without mechanical ventilation). Six of the seven control patients had endotracheal tubes. None of the 12 patients developed symptomatic Ralstonia infection.
An outbreak of multi-drug resistant Pseudomonas pickettii (now Ralstonia pickettii) in an 81-bed neonatal intensive care unit over a 26 month period was reported by Timm, et al, in 1995. (22) The ten premature infants with respiratory colonization had no extrapulmonary infections
and all were intubated, had multiple intravascular catheters, and patent ductus arterioses. Six of the ten patients developed P. pickettii pneumonia (one associated death). This particular P. pickettii was resistant to aminoglycosides, several extended spectrum beta-lactams and cephalosporins (some isolates were also resistant to ceftazidime and ticaricillin/clavulanate). The source of contamination was thought to be a vinegar cleaning solution used on the exterior of the infant isolettes.
Burns et al, reported on specimens from 595 patients with stable, non-exacerbated cystic fibrosis of which 559 were tested for gram negative pathogens as part of a phase III national collaborative study of aerosolized tobramycin from July 1995 through September 1996. (23) Only two (0.3%) of the specimens were positive for R. pickettii colonization and one was highly tobramycin-resistant.
A report of R. pickettii colonization associated with intrinsically contaminated normal saline solution (used for respiratory therapy) was published in MMWR (April 1998). (3) Seventeen patients (age range 4 days to 11 years) were culture positive for Ralstonia pickettii. The outbreak was associated with a contaminated saline solution used for endotracheal suctioning. Responding to the 1998 MMWR article request to report R. pickettii colonization or infection, Labraca and colleagues reported a total of 34 patients from four hospitals (three pediatric and one adult) colonized with R. pickettii over a three month period in 1999. (25) Twenty-six percent of these patients developed an infection and all had received mechanical ventilation. The source of contamination was identified as the intrinsically contaminated "sterile" normal saline solution identified in the prior MMWR report.
Jhung, et al, (26) reported both a case control cohort of 5 individuals at a single center and 38 patients nationally who were confirmed with culture positive R. mannitolilytica, many of whom had been previously on a respiratory device made by Vapotherm, Inc. These findings led to a recall of the product in 2005.
Results of meta-analyses
The summary results for colonization are shown in Table 1 and Figure 1 and the infection results are shown in Table 2 and Figure 2. The data indicate that the risk of infection or colonization is higher in the Treatment Group (mechanical ventilation group) compared to the control group (no mechanical ventilation). The wide 95% confidence intervals (CI) are due to the fact that the individual studies have small numbers. The overall average from combining all the studies is the statistic of interest. The first odds ratio was the ratio of the odds of Ralstonia colonization occurring in the pooled group of patients with MV to the odds of it occurring in the pooled group without MV. The second odds ratio was the odds of Ralstonia infection occurring in the pooled group of patients with MV to the odds of it occurring in the pooled group without MV. The odds of developing colonization with Ralstonia was eight times higher in those mechanically ventilated compared to those not mechanically ventilated. The patients in the pooled group who were on mechanical ventilation had 6 times the likelihood of developing Ralstonia infection compared to the rest of the cohort that didn't receive mechanical ventilation.
The current meta-analysis was conducted to examine one specific host factor, mechanical ventilation, and its associated risk for Ralstonia colonization and infection. These results suggest that patients receiving mechanical ventilation may be at increased risk for Ralstonia colonizations and infections. Our examination of these data offers the possibility that individuals who are being mechanically ventilated are more likely to develop Ralstonia-related infection. These findings have logical implications for treatment response.
It is well-accepted that, over time, the presence of endotracheal tubes for mechanical ventilation increases the risk for bacterial colonization and development of ventilator-associated pneumonias (VAP). Similarly, it is conceivable that Ralstonia, a water-borne bacteria cultured from respiratory devices, may have the capacity to colonize the airways; their capacity to generate biofilms, similar to Pseudomonas sp., have been recently reported. (21-28) While not specifically reviewed in this manuscript, it is worth speculating if intraspecies antibiotic resistance patterns may apply to the ongoing Ralstonia resistance, as is seen in other bacteria. Our data does hint at increased infection from Ralstonia in those individuals who are mechanically ventilated, although this may be associated with mechanical ventilation as a marker of overall health status of these individuals.
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Despite the results from our meta-analysis and other studies to help in clarifying Ralstonia status of patients, many clinicians continue to treat all of these bacterial isolates. Standard microbiological examination of biologic specimens (blood, urine, sputum) does not efficiently identify Ralstonia and may lead to misidentification of the organism. Therefore high clinical suspicion in susceptible populations may serve as a trigger for more in-depth examination for Ralstonia. In order to aid these caregivers, we have created a possible approach to the culture-positive Ralstonia patient (see Figures 3 and 4). Given an emerging concern for increased incidence of both Ralstonia and phylogenically similar (i.e., Pseudomonas sp., Burkholderia sp.) bacterial infection in immune-compromised hosts, (29-30) these decision trees start by dividing patients into either immunocompetent or immunecompromised. For immunocompetent patients, if there are clinical signs of infection, respiratory devices and IVs are replaced and antibiotics are started. In those individuals who demonstrate no signs of infection but are being mechanically ventilated, respiratory devices should be changed but no antibiotics should be started. In immunocompromised patients, it is crucial to correctly identify organisms by species-specific polymerase chain reaction (PCR) testing and to treat immediately upon the first signs of symptoms of infection (PCR specificity 99-100% for several Ralstonia species). (9-31) While this technique is not readily available throughout the USA, the importance of correct identification of the organism necessitates additional efforts for these results.
The small number of reports in the literature on respiratory colonizations and infections (those individuals who are culture-positive and exhibit signs of infection) associated with the Ralstonia organism is a limitation of this meta-analysis but it is a telling sign in itself. Respiratory infections due to Ralstonia do not appear to be common in the USA; at our university medical center there was no incidence of Ralstonia pickettii in microbiologic cultures over a ten year period (1991-2001). This may, in part, be due to the use of automated microbiological identification systems for identification of Ralstonia spp., which seem to have inadequate specificity. Ralstonia sp., are not common organisms in the clinical setting partly because surveillance in large scale should be performed to clarify the current position of the organism in various kinds of respiratory specimens. As previously mentioned, the patients suffering from Ralstonia infection in the available reports typically had weak/compromised immune responses, supporting the approach of utilizing this host factor as a means to stratify individuals in the appropriate identification and treatment of Ralstonia as an opportunistic organism. (10) To date there are only three reported cases of Ralstonia sepsis and they were in patients with immune insufficiency. (32)
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Our results suggest that individuals who are currently on mechanical ventilation and are Ralstonia culture-positive may have increased propensity to the development of infection. Here, we provide two logical decision trees, taking into account host factors, clinical signs of infection, and mechanical ventilation status to aid the healthcare provider in approaching diagnosis and therapy for this organism. While interpatient transmission has not been well documented, (29) a common reservoir among multiple patients may serve to foster outbreaks (a reason to screen other patients in proximity). This data is suggested by various outbreaks reported with exposure to respiratory devices in the ICU. Our findings also support that simply culturing the organism from respiratory care devices in a mechanically ventilated patient is an inadequate stimulus to consider Ralstonia-specific-therapy. Rather, these devices should be replaced (i.e., ventilator tubing, etc.) and the patient should be recultured. In addition, a low-threshold for therapy should be applied to individuals exposed to possible contaminated reservoirs with immunocompromised states.
In conclusion, our data suggest that although rare, the presence of Ralstonia in clinical culture correlated with the use of mechanical ventilation. There was a significant correlation between mechanical ventilation and colonization. Given the potential for both a missed diagnosis and misdiagnosis, we presented a novel approach to surveillance and treatment of Ralstonia pickettii in susceptible populations. These findings will hopefully assist clinicians in the efficient identification and treatment of this organism.
The authors would like to thank Lee Vucovich, MS, MLS, AHIP; Assistant Director for Reference Services at the Lister Hill Library of the Health Sciences of the University of Alabama at Birmingham; for her assistance with searching electronic databases and George A. Fritsma, MS, MT(ASCP); for his careful review of the manuscript, and Linda Waugh for assistance with figure artwork.
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Jonathan B. Waugh, PhD, Clinical and Diagnostic Sciences Department, University ofAlabama at Birmingham
Wesley M. Granger, PhD, Clinical and Diagnostic Sciences Department, University of Alabama at Birmingham
Amit Gaggar, MD, PhD, Department ofMedicine, Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham
Address for Correspondence: Jonathan B. Waugh, PhD, Clinical and Diagnostic Sciences Dept., University of Alabama at Birmingham, 1705 Univ Blvd, SHPB 455, Birmingham, AL 35294-1212, 205.934.7638, firstname.lastname@example.org
Table 1. Colonization in the Respiratory Tract with Ralstonia. The odds ratios shown are the odds of developing a Ralstonia colonization while on mechanical ventilation compared to non-mechanical ventilation. The 95% CIs are for the odds ratio and if it includes a value of 1.0 then the odds ratio is not significantly different from 1.0. The percent weight is the percent weight given by the meta-analysis when calculating the average values. The statistical procedures base this weight on sample sizes. Study Name Patients with Odds Ratio 95% 95% Ralstonia Lower CI Upper CI MMWR 1983 12 34.48 2.03 586.04 MMWR 1998 11 10.32 4.23 25.22 Burns et al. 2 125.25 1.40 11219.63 Jhung et al. * 5 0.46 0.20 1.02 Weighted Average -- 8.14 1.20 55.22 Study Name Percent Weight MMWR 1983 22.41 MMWR 1998 30.96 Burns et al. 15.31 Jhung et al. * 31.21 Weighted Average 100.00 (Total) * Only patients that included mechanical ventilation data were used from this multi-site report. Table 2. Infection in the Respiratory Tract with Ralstonia. The odds ratios shown are the odds of developing a Ralstonia infection while on mechanical ventilation compared to non-mechanical ventilation. The 95% CIs are for the odds ratio and if it includes a value of 1.0 then the odds ratio is not significantly different from 1.0. The percent weight is the percent weight given by the meta-analysis when calculating the weighted average values. The statistical procedures base this weight on sample sizes. Study Name Patients with Odds Ratio 95% 95% Ralstonia Lower CI Upper CI MMWR 1983 12 1.00 0.020 50.89 Timm et al. 10 1.49 0.029 76.82 Labraca et al. 15 72.67 4.36 1211.39 Weighted Average --- 6.38 0.34 118.53 Study Name Percent Weight MMWR 1983 29.82 Timm et al. 29.73 Labraca et al. 40.45 Weighted Average 100.00 (Total)
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|Title Annotation:||RESEARCH AND REPORTS|
|Author:||Waugh, Jonathan B.; Granger, Wesley M.; Gaggar, Amit|
|Publication:||Clinical Laboratory Science|
|Date:||Mar 22, 2010|
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