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1 (32 - 42): The Clinical, Microbial, and Host Response Characteristics of the
The goal of this study was to provide new data regarding levels of inflammatory and growth factor
mediators and bacterial pathogens associated with failing implants, as compared to healthy
implants. Twenty-one patients with failing implant sites (group 1) and 8 patients with only healthy
implants (group 2) were included. Fifteen of the 21 failing implant patients (group 1) also
presented with at least one stable nondiseased implant. Plaque samples were examined, using DNA
oligonucleotide probes for 40 different microbes. Gingival crevicular fluid samples were collected
for the analyses of catabolic bone resorbing agonists prostaglandin E 2 (PGE2), interleukin-1ß
(IL-1ß) and IL-6 and anabolic bone-forming growth factors transforming growth factor ß (TGF-ß)
and platelet-derived growth factor (PDGF). Although positive trends were noted, there were no
significant differences in any of the microbial, inflammatory, or growth factors mediators
comparing failing to stable implants in group 1. This study found greater detection frequencies of
P. nigrescens, P. micros, F. nucleatum ss vincentii, and F. nucleatum ss nucleatum , as well as
significant elevations in GCF levels of PGE 2, IL-1ß, and PDGF in mouths with failing implant sites
as compared to mouths with healthy control implants. Risk appears to be primarily at a patient
level and secondarily at a site or implant level from a clinical, microbial (P. micros and P.
nigrescens), and biochemical (PGE2 and IL-1ß) perspective. Furthermore, the counts of P.
nigrescens and P. micros were found to correlate with concentrations of PGE2 at a site level.
(INT J ORAL MAXILLOFAC IMPLANTS 1997;12:32–42)
Key words: bacterial pathogen, failing implant, growth factor, inflammatory mediator, peri-implantitis
F or more than 30 years, the placement and restoration of endosseous dental implants has been shown to
be a successful treatment alternative for edentulous or partially edentulous patients.1-8 Despite the
long-term success of osseointegrated implants, clinicians report the occasional incidence of pathogenic
complications associated with the maintenance and retention of implants. Changes in clinical signs such
as soft tissue inflammation, bleeding on probing, suppuration, pain, increased probing depth, and
radiographic evidence of bone loss,9 as well as microbiologic alterations in the flora, are similar to those
signs associated with periodontal disease. The progressive loss of peri-implant bone, as well as soft tissue
inflammatory changes, is defined as peri-implantitis.10
The etiologic factors associated with peri-implantitis are reported to be bacterial infection and
biomechanical factors associated with occlusal overloading.1,3,11-13 Numerous studies have evaluated
the microbiota around implants associated with states of health and disease. The primary finding is that a
flora composed of gram-positive cocci and rods is seen associated with stable, nondiseased implants,
while a more gram-negative, anaerobic flora with high levels of spirochetes is associated with failing or
failed implants.12-23 The periodontopathogens commonly identified are P. intermedia and P. gingivalis.
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JOMI on CD-ROM (1997 © Quintessence Pub. Co.), 1997 Vol. 12, No. 1 (32 - 42): The Clinical, Microbial, and Host Response Characteristics of the
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JOMI on CD-ROM (1997 © Quintessence Pub. Co.), 1997 Vol. 12, No. 1 (32 - 42): The Clinical, Microbial, and Host Response Characteristics of the
1. Patient had at least one root-form implant that had been in function for at least 1 year.
2. Patient with one or more failing implants must have presented with evidence of peri-implant
radiolucency and/or vertical crestal bone loss greater than 2.0 mm after the first year of service.
3. Patients with one or more failing implants may have had at least one other stable implant that showed
no clinical signs of inflammation or radiographic evidence of crestal bone loss.
The exclusion criteria for the study were as follows:
1. Patient had taken any antibiotic within 6 weeks prior to the clinical examination and biologic
sampling.
2. Patient had taken any steroidal or nonsteroidal anti-inflammatory drug within 2 weeks prior to the
clinical examination and biologic sampling.
3. Patient had undergone any periodontal or peri-implant therapy within 21 days.
4. Patient has had a history of chronic illness, such as cardiovascular, hepatic, rheumatic fever, asthma,
diabetes, immune disorder, bleeding disorder, or any condition requiring prophylactic antibiotic
coverage.
5. Women who were pregnant or nursing.
Patients with one or more healthy implants (group 2) were also selected for inclusion into the study
as the control subjects. The same inclusion and exclusion criteria applied to these patients as well. Thus,
the three categories of patients seen were: (1) patients with only failing (diseased) implants (6 patients);
(2) patients with both failing and stable (nondiseased) implants (15 patients); and (3) patients with only
healthy implants and considered as the control subjects (8 subjects).
Clinical Measurements. The initial complete-mouth clinical measurements were for plaque and
redness (inflammation) by visual inspection. These scores were dicotomously evaluated (0 = absent, 1 =
present) at six sites per tooth and implant. Following these assessments, any supragingival plaque present
was removed around the implant where there was to be the collection of gingival crevicular fluid (GCF)
and subgingival plaque samples. Following the collection of the peri-implant GCF and the microbial
plaque sample, a complete-mouth recording of the probing depths was completed using the Florida Probe
(Florida Probe, Gainesville, FL) with a titanium insert. Clinical attachment levels were recorded with a
UNC15 probe from the cementoenamel junction on teeth and the suprastructure-abutment junction on
implants, where possible. Bleeding on probing was dicotomously recorded as present or absent. All
measurements and collection of GCF and microbial samples were completed by one investigator (JMS).
This investigator had been calibrated to a gold standard in the UNC Clinical Research Unit, as described
elsewhere.31
Gingival Crevicular Fluid Sampling. Gingival crevicular fluid samples were collected from failing,
stable, and control implants for analysis of the following mediators: PGE2; IL-1ß; IL-6; PDGF; and
TGF-ß. The tissues surrounding the implants were air dried, and supragingival plaque was removed.
Sterile periopaper strips were inserted into the sulcus surrounding the implant, and the peri-implant fluid
was collected. The volume was recorded on a Periotron 6000 (Periotron Flow, Amityville, NY; IDE
Intrastate Distributing, Newark, NJ). The strip was wrapped in aluminum foil and placed into a cryovial
for immediate storage in liquid nitrogen. Duplicate samples were collected for all mediators at each
implant at each site. Strips were consecutively placed around the circumference of the implant, so that
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one strip was placed facially, then lingually, then mesially, and finally distally until all samples were
collected. The order of mediator collection was as follows: PGE2; PDGF; IL-1ß; TGF-ß; and IL-6.
Sampling four sites twice provided first and second samples of GCF from each site, and these were each
assayed independently for the selected mediator for duplicate determinations. All samples were
transported and stored in liquid nitrogen vapor phase at –160ºC until analyses could be performed.
Microbial Sampling. Microbial sampling and analyses were performed following methods described
by Socransky et al.32 At each implant, a sterile plastic curet was gently inserted to the base of the
peri-implant sulcus, and the subgingival plaque was removed with one sweep of the curet. One sample
was collected for each implant to be included in the study. The sample was then placed into an individual
tube containing 0.1 mL of tromethamine EDTA (TE); 0.1 mL of 0.5-mol/L of sodium hydroxide was
added, and the tube was agitated. All samples were sent to Dr Sigmund Socransky for analysis by
checkerboard DNA–DNA hybridization technique to enumerate 40 organisms (including two
streptococcus).
Laboratory Procedures. All GCF and plaque analyses were performed by blinded technicians. All
samples were identified by accession numbers and merged with clinical data at the time of statistical
analysis.
Gingival Crevicular Fluid Analyses. Levels of PGE2 were determined by radioimmunoassay (RIA).
This procedure has been described previously by Offenbacher et al.25 Levels of IL-1ß, IL-6, PDGF, and
TGF-ß were determined by enzyme-linked immunosorbent assay (ELISA). An ELISA kit was purchased
for IL-1ß and IL-6 from Cistron Biotechnology (Pinebrook, NJ), and PDGF and TGF-ß kits were
purchased from R&D Systems (Minneapolis, MN); manufacturers’ directions were followed. The TGF-ß
samples were not acid treated because levels of free TGF-ß present in the GCF were sought. Gingival
crevicular fluid mediator concentrations are reported as the mean of duplicate samples assayed
independently for each mediator.
Microbial Analysis. The checkerboard DNA–DNA hybridization technique has been described by
Socransky et al.32 Plaque samples were probed for 40 microbes using 105 and 106 standards. A
representative checkerboard blot appeared, and the blot intensity for each organism was scored. Samples
were scored as 0, no signal detected; 1, equal to or less than 105 standard; 2, equal to approximately 105
standard; 3, equal to between 105 and 106 standard; 4, equal to approximately 106 standard; and 5, equal
to or greater than 106 standard. The DNA probes determined the presence of 40 different microbial
species (Table 1).
Data Analyses. Each variable was pooled for each implant category for each implant and then across
all three implant categories, based on case status: (1) healthy implants in healthy patients; (2) healthy
(referred to as stable) implants in patients with failing implants; and (3) failing implants. Mean values
were calculated for each of the mediator levels and clinical assessments, and detection frequency was
determined for each of the identified microbes. A P value was set at < .05 with the Bonferroni corrections
for multiple comparisons. A two-way analysis of variance was performed among and between each of the
categories.
Results
Patient Population. Twenty-one patients with failing implant sites (group 1) were included in the study.
Fifteen of these 21 patients presented with both a failing implant site, as well as at least one stable
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nondiseased implant site. There were eight patients who had only nondiseased implant sites (group 2).
These subjects were considered the control subjects. Of the 21 patients with failing implants in group 1,
14 were women (mean age 58.2 years, range 25 to 76), and 7 were men (mean age 71.1 years, range 61 to
77). Nine of the 14 women and 6 of the 7 men had additional implants that were considered stable. Of the
8 control implants in patients in group 2, 6 were in women (mean age 47.5 years, range 37 to 82) and 2
were in men (mean age 75 years, range 66 to 84).
Pooling all of the patients in the study, there was a total of 28 failing implant sites, 27 stable sites,
and 14 nondiseased, control sites. Failing and nondiseased implant sites were present in each of the four
quadrants of the mouth and therefore were not noted to be in only one arch. Although data were recorded
regarding the various root-form implant types and surfaces, there were no particular statistically
significant trends in the failing implant category.
Among the 15 patients with both stable and failing implants in group 1, three patients were
completely edentulous. In group 2, there were three completely edentulous patients as well. All of the
completely edentulous patients were restored with maxillary dentures and fixed detachable “high-water”
mandibular anterior frameworks. Any patient with mobile implants, ie, failed implants, were excluded
from the study. None of the clinical, microbial, or mediator values were significantly different for the
edentulous versus partially edentulous patients; therefore, these patients were not segregated for further
analyses.
Clinical Measurements. Table 2 presents the mean data for plaque, inflammation, and bleeding on
probing (BOP) scores of failing (group 1) versus control patients (group 2). Neither the mean plaque nor
BOP scores were significantly different; however, the mean inflammation scores of the failing sites (P =
.002) and stable sites (P = .019) in group 1 patients were significantly higher than the healthy control
sites in group 2.
The mean probing depths (PD) and clinical attachment levels (CAL) of failing (group 1) versus
control (group 2) patients are presented in Table 3. As noted, there was a statistically significant
difference in the mean PD of the group 1 complete-mouth sites (2.14 mm/site) and failing sites (3.79
mm/site) versus the group 2 complete-mouth sites (1.81 mm/site) and control sites (2.11 mm/site) at P =
.04 and P = .03, respectively. The mean CAL of the failing sites in group 1 (3.59 mm/site) was also
significantly different than the group 2 control sites (1.39 mm/site) at P = .003.
Gingival Crevicular Fluid Mediator Levels. Using commercially available assay techniques,
gingival crevicular fluid levels of IL-6 were detected in the group 2 control sites (59.7 ng/mL), and in
group 1 failing sites (48.4 ng/mL) and stable sites (44.8 ng/mL). However, these levels were not
significantly different among the three implant categories. The TGF-ß was not clinically detectable at the
sensitivity levels determined by the ELISA kit.
The mean levels of PGE2 were found to be significantly higher in the failing sites (74.2 ng/mL) and
stable sites (64.2 ng/mL) of group 1 patients versus the nondiseased control sites (36.1 ng/mL) of group 2
patients at P = .01 and P = .008, respectively (Fig 1). A similar trend was seen in the IL-1ß levels (Fig 2),
with the highest level among the failing sites (761.5 ng/mL) and stable sites (626.7 ng/mL) of group 1
patients versus the group 2 patients (255.4 ng/mL). These levels are also statistically significant at P =
.023 for the failing sites versus the control sites and P = .029 for the stable sites versus the control sites.
Figure 3 illustrates that the mean GCF PDGF levels were the highest as detected at the stable implant
sites (50.8 ng/mL). These GCF PDGF levels at both the stable and failing implant sites (33.3 ng/mL) in
group 1 patients were significantly higher than those of the nondiseased control sites (6.55 ng/mL) of
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group 2 at P = .01 and P = .041, respectively. There were no statistically significant within-mouth
differences in the mean PGE2, IL-1ß, or PDGF levels when the failing implant sites were compared to
the stable implant sites in group 1 patients.
Microbial Analyses. Of the 40 different microorganisms evaluated, based on detection frequency,
only four were found to be positively associated with failing implants versus nondiseased control
implants using a bivariate analysis (chi square or Fisher’S exact). These organisms were Prevotella
nigrescens, Peptostreptococcus micros, Fuso . nucleatum ss vincentii, and Fuso. nucleatum ss nucleatum
(Table 4). In no instance was there a significant difference between the frequency of detection or the
levels present comparing the flora of failing and stable sites within the same patient. Overall, 95.7% of
failing sites harbored either P. nigrescens or P. micros. F. nucleatum species may be pathogenic. It is
also seen as a commensal organism associated with P. nigrescens and P. micros . Our mediator data
would suggest that F. nucleatum is serving as a key commensal organism in this mixed infection, as will
be discussed.
Attendant risk is summarized in Table 5, with an overview of the crude (unadjusted) odds ratio,
overall risk, and kappa and P values for each of these organisms. For example, P. micros and P.
nigrescens would have a 26.7-fold and 13.7-fold increased chance, respectively, of being present in the
subgingival plaque of a failing implant site, and these are shown to be highly significant. There is also a
2- to 3-fold attendant risk that P. micros or P. nigrescens would be present in the flora of a failing
implant site versus a nondiseased control site.
Although not statistically significant, there was a tendency for a greater detection frequency of P.
gingivalis, B. forsythus, and T. denticola in the failing and stable implant sites of group 1 patients versus
the control patients (group 2). No levels of A. actinomycetemcomitans were detected in any of the
implant sites. Of the nondiseased control sites (group 2), there were also greater detection frequencies
noted with the Streptococcus species, especially S. gordonii and S. mitis, as well as P. intermedia , but
again these were not statistically significant.
When evaluating the flora of the six completely edentulous patients (three group 1 and three group 2
patients), there were no differences seen in the species or detection frequencies between or among the
completely edentulous patients and the partially edentulous patients. However, with the small number of
patients in these categories, differences cannot be excluded.
Microbial and Mediator Associations. The relationship between the four pathogens associated with
failing implants and the levels of mediators present in the local gingival crevicular fluid was examined.
There was no significant relationship seen between the four predominant organisms and the GCF
mediator levels of IL-1ß or IL-6. However, PGE 2 was highly correlated with the levels of P. nigrescens
and P. micros present when examined pairwise (Table 6). This suggests that F. nucleatum ss vincentii
and F. nucleatum ss nucleatum are commensal organisms and are associated with disease. However, the
quantitative relationship between the level of P. nigrescens and P. micros present and the level of GCF
PGE2 present suggests and is consistent with a causal relationship.
Discussion
In the present investigation, the clinical variables of inflammation, probing depths, and attachment levels
were shown to be significantly different with failing implants than with nondiseased control implants.
Microbially, we also found greater detection frequencies of two fairly uncommon species, P. nigrescens
and P. micros , in the subgingival plaque of patients with failing implants. This study has also shown
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JOMI on CD-ROM (1997 © Quintessence Pub. Co.), 1997 Vol. 12, No. 1 (32 - 42): The Clinical, Microbial, and Host Response Characteristics of the
increased gingival crevicular fluid levels of PGE2, IL-1ß, and PDGF associated with failing and stable
implant sites in group 1 patients compared to nondiseased control sites in group 2 patients.
Marginal tissue reactions at osseointegrated implant–tissue interfaces have been reviewed by Schou
et al.33 The general consensus appears to be that successfully osseointegrated implants exhibit low
amounts of plaque concomitant with the absence of marginal inflammation. However, plaque
accumulation may cause inflammatory reactions around the implants. Perspective may be gained by
analogy to gingivitis and periodontitis, in determining the reactions of host tissues to plaque on abutment
and prosthesis surfaces. A recent clinical study in humans by Pontoriero et al 34 on experimentally
induced peri-implant inflammation reaffirms the similar association between the accumulation of
bacterial plaque and the development of peri-implant mucositis, as established for the gingival units by
the experimental gingivitis model. In most of the implant studies reported, Plaque, Bleeding, and
Gingival indexes are used to evaluate the degree of health or disease present, as well as are
measurements of probing depth, attachment levels, mobility, and radiographic bone loss. The Plaque and
Gingival indexes, which are descriptive reflections of the patients’ compliance with their home care
regimen, may not correlate as well with osseous changes.
In the present study, there were no significant differences in the plaque or bleeding scores of control
patients or patients with failing implants. Therefore, this suggests that these clinical measures could not
be used as discriminators of a healthy or diseased peri-implant state. One clinical variable of significance
in this study was the marginal redness seen with the peri-implant tissues in patients with failing implants.
Unfortunately, however, marginal redness was seen around failing implant sites and within-mouth stable
implant sites, as well. This may be accounted for by the greater detection frequencies of the four
periodontopathogens seen in those sites. This suggests that redness may potentially identify patients at
risk but may not discriminate implants at risk. Given the lack of significant differences in clinical
measures of home care compliance (eg, plaque and BOP) in the patient groups, it seems reasonable to
assess patient response variables to identify high-risk patients.
As expected, other clinical variables found to be associated with failing implants in this study were
increased mean probing depths and attachment levels. Analogous to periodontitis, the loss of attachment
around an implant would be reflected clinically as deeper probing depths and increased levels of clinical
attachment. However, a recent report by Ericsson and Lindhe 35 questioned the significance of probing
around osseointegrated implants. In their experimental data, they observed that the resistance to probing
offered by the gingiva was greater than that offered by the peri-implant mucosa, and, consequently, the
probe penetration was more advanced at implants than at teeth. The tip of the probe terminated apically
of a laterally displaced junctional epithelium and close to the crest of the alveolar bone (0.2 mm).
Furthermore, probing depth measurements at clinically healthy gingivae failed to provoke bleeding,
whereas bleeding on probing was recorded from most of the nondiseased implant sites. They concluded
that the interaction of soft tissue and implants is less resistant to mechanical forces than the connective
tissue attachment to teeth, and that probing the peri-implant mucosa dislocates the mucosa and allows the
probe to penetrate beyond the apical termination of the junctional epithelium.
This hesitation in the diagnostic applicability of probe depth measurements is reiterated by Schou et
36
al. These authors state, “. . . the disparity between clinical and radiographic measurements indicates
that probing measurements around implants and teeth are not fully comparable, [and that] . . . the altered
probing depths of implants may be directly related to bone loss, whereas changes around teeth with
attached dentogingival fibers may rather be related to attachment loss and changes in inflammation.”
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Until long-term studies demonstrate the diagnostic applicability and significance of probing, careful
monitoring of probing depths and clinical attachment levels over time needs to be evaluated
concomitantly with radiographic examination. In the present study, the primary basis for patient selection
as a failing implant patient was the radiographic appearance of crestal bone loss generally greater than 2
mm. We did not include an analysis of occlusal loading, which is a recognized risk factor for implant
failure.37 Grieve et al31 have demonstrated that teeth under significant loading, secondary to orthodontic
forces, have significant increases in GCF levels of PGE2 and IL-1ß. These may serve to promote
inflammation, bacterial overgrowth, and attachment loss. This occlusal component may be a factor in the
failing implant data observed in the present study.
The microbial findings in this study highlight the significant detection of two rather unfamiliar
microbes associated with failing implants, P. nigrescens and P. micros , as well as the presence of F.
nucleatum ss vincentii and ss nucleatum, which are herein considered to be commensal organisms. As
reported earlier, the primary florae seen associated with failing or failed implants often contain high
numbers of gram-negative anaerobic rods and spirochetes. P. intermedia and Fusobabacterium spp,
which have been regularly found in elevated proportions in failing sites,15,38 are suspected periodontal
pathogens and are commonly associated with periodontitis lesions. Recently reported by Haffajee and
Socransky, 39 strains of P. intermedia expressing different phenotypic traits have been separated into two
species, P. intermedia and Prevotella nigrescens: “This distinction makes earlier studies of this species
difficult to interpret, since data from two different species may have been inadvertently pooled. However,
new studies that discriminate the species in subgingival plaque samples might strengthen the relationship
of one or both species to periodontal disease pathogenesis.” Until additional studies have been
completed, they rank P. nigrescens as a moderate contender in strength of the relationship to periodontal
disease. This has also been implicated in refractory periodontitis.40
P. micros is a gram-positive, anaerobic, small asaccharolytic coccus. Although this species has only
recently been implicated in destructive periodontal diseases, it has long been associated with mixed
anaerobic infections in the oral cavity and other parts of the body. 39 In the article by Haffajee and
Socransky, 39 it was noted that P. micros has been detected more frequently and in higher numbers at
sites of periodontal destruction, as compared with gingivitis or healthy sites, and was elevated in active
sites. With additional studies, this microorganism may become a key player in the microbial diagnosis
and pathogenesis of failing implants.
In our study, there were greater detection frequencies of four microbes—P. nigrescens, P. micros, F.
nucleatum ss vincentii and F. nucleatum ss nucleatum —present in patients who had both failing and
stable implants versus patients who had only nondiseased implants. The presence of these
periodontopathogens in the peri-implant subgingival flora of patients with both failing and
radiographically nondiseased stable implants are consistent with other studies that demonstrate the
overall site-to-site consistency of the florae within subjects. The fact that an organism, if present, is
generally located at many other sites affecting most teeth is consistent with intraoral spread or site-to-site
translocation of organisms. It is possible that translocation could potentially occur from surrounding
periodontally involved teeth to an implant site. The suspicion that teeth serve as an important source of
bacteria for the colonization of implants has recently been investigated by Mombelli et al.41 These
investigators evaluated the presence of suspected periodontal pathogens in the peri-implant microflora of
osseointegrated implants exposed 3 and 6 months to the oral environment of patients previously treated
for periodontal disease. The patients in this study showed a high peri-implant prevalence of anaerobic
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JOMI on CD-ROM (1997 © Quintessence Pub. Co.), 1997 Vol. 12, No. 1 (32 - 42): The Clinical, Microbial, and Host Response Characteristics of the
Jeanne M. Salcetti
John D. Moriarty
Lyndon F.Cooper
Frances W. Smith
Footnotes 10
Laboratory Research Specialist, Dental Research
Center, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina.
John G. Collins
Sigmund S. Socransky
Steven Offenbacher
FIGURES
Footnotes 11
Figure 1
Figure 2
Figures 12
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Figure 3
TABLES
Figures 13
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Table 1
Tables 14
JOMI on CD-ROM (1997 © Quintessence Pub. Co.), 1997 Vol. 12, No. 1 (32 - 42): The Clinical, Microbial, and Host Response Characteristics of the
Table 2
Table 3
Tables 15
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Table 4
Table 5
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Table 6
The Clinical, Microbial, and Host Response Characteristics of the Failing Imp
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