Clostridium difficile Infections after Blunt Trauma: a Different Patient Population?
Erin Vanzant, MD1, Huazhi Liu, MS1, Tezcan O. Baslanti, PhD2, Lawrence Lottenberg MD1, Alex G. Cuenca, MD1, Lori
F. Gentile, MD1, Makesha V. Miggins, MD1, Bruce McKinley, PhD1, Frederick A. Moore, MD1, Lyle L. Moldawer, PhD1,
Darwin N. Ang, MD, PhD, MPH1, Azra Bihorac, MD2, Philip A. Efron, MD1,4.
Departments of Surgery1 and Anesthesiology2, University of Florida College of Medicine, Gainesville, FL
Introduction: The identification of Clostridium difficile infection (C. diff.) as a significant cause of
infectious diarrhea and pseudomembranous colitis has been well recognized1. Although the
disease has classically had minimal impact on mortality (<2%), the health care burden from
management and complications attributed to the disease is quite high 2-5. Much effort over the years
has been made to describe the epidemiology and risk factors for C. diff-associated diarrhea
(CDAD). Historically, well-accepted risk factors for development of CDAD included antibiotic use,
increased age (>65), as well as exposure to hospitals or nursing home facilities. Nevertheless, a
significant percentage of hospitalized patients are colonized with the bacteria and the majority of
patients receiving antibiotics do not become infected2,6.
In recent years, the epidemiology of C. diff has changed dramatically. Since 2001, there have
been increasing reports of rising incidence, severity, resistance, mortality and complications of
CDAD2-4. Additionally, a new, more virulent strain was identified3, and the CDC released a
statement as well, describing incoming reports characterizing a new population of patients afflicted
by CDAD that was younger, with little to no antibiotic exposure and hospitalization3,7,8. Little
evidence to date has been able to associate the new strain with this evolving clinical picture9.
It is becoming increasingly evident that susceptibility to CDAD is related not only to environmental
exposures and bacterial potency, but host factors as well. Preliminary evidence that would support
this include several reports of the role of immunosuppression3 in increasing susceptibility in
populations without previous antibiotic exposure4,7. In addition, certain individuals with a specific
genetic polymorphism have been shown to be at increased risk for primary infection with C. diff as
well as recurrences6-8,10,11.
We recently determined that an individual’s genetic profile and subsequent response on the
individual’s immune system and inflammation may play a role in the development of disease (Efron
et al. in press). Using the TRDB database from the “Inflammation and Host Response to Injury”
(Glue Grant), to look at the microarray analysis we found the genomic profile of circulating
leukocytes early in the patient’s hospital course could predict which patients were going to develop
C. diff, although this data still requires prospective validation. Many of the genes that differentiated
the C. diff patients prior to infection were related to inflammation and host adaptive immunity,
supporting the hypothesis that inherent host factors may indeed play a role in infection 12.
To date, there have been very few studies looking at C. diff in the trauma population and those that
have, report only a small sample size. The trauma population is a relatively younger population,
often with minimal previous antibiotic exposure and exposure to health care facilities. Severe
trauma is also recognized to induce relative immune suppression. Lumpkins et al. reported a
significantly younger population of patients diagnosed with C. diff as well as an associated
increased hospital/ICU length of stay (LOS). In addition, they also reported CDAD in trauma
patients without significant antibiotic exposure, supporting hypothesis C. diff after trauma may be
(Philip.Efron@surgery.ufl.edu) University of Florida College of Medicine
Room 6116, Shands Hospital, 1600 SW Archer Road, Gainesville, Florida 32610
associated with a different patient phenotype. The purpose of this study was to examine and
describe the epidemiologic factors associated with C. diff in blunt non-traumatic brain injury trauma
patients using the TRDB.
Methods: In the initial analysis, 2,006 blunt trauma patients (entry criteria for the Glue Grant
included that they had an ISS >15, require a blood transfusion and did not have TBI) were
analyzed looking for reported nosocomial infections. A total of 48 patients, with one patient with
two reported episodes, were identified by RT-PCR testing to have C. diff. After univariate analysis
screened for risk factors between C.diff and non-C. diff patients they were matched and adjusted
by multivariate regression to test for significance. Subsequently, we compared C. diff patients with
the 384 trauma patients identified to have had both an uncomplicated clinical course and no
reported C. diff infection. Uncomplicated patients were defined by those patients whose baseline
genomic profile recovered by 5 to 7 after their injury13. We compared outcomes of death, hospital
LOS, ventilator dependent days, PaO2/FiO2 ratio, Marshall Score, Denver score, blood
chemistries, albumin, total and differential leukocyte counts, and INR between these two cohorts.
Outcomes for the C. diff patients were recorded as those occurring at days 7, 14, 21 and worst
value over the patient’s hospital course, and compared with the uncomplicated patient’s worst
value over their hospital course. Univariate methods of the cohorts provided the descriptive
analysis. A t-test or Wilcoxon rank-sum test, depending on the data distribution, was used to
compare means. Statistical analysis was performed with SAS
Results: Reported in the initial analysis, 48 patients (2.4%) developed CDAD during their
hospitalization, similar to previously reported prevalence. Interestingly, no C.diff patient had an
uncomplicated hospital course. The age of both C.diff and all non-C.diff patients in the database
were not statistically different, and the mean of both sets was under 65 years old. Although, this
mean age is typical for trauma patients, but uncommon for the general CDAD population7,11,14,15.
Of the baseline characteristics, only Apache II and NISS were significantly greater in the patients
who developed CDAD. The dose, administration and timing of antibiotics were not recorded in the
database making it impossible at this time to determine the relation between antibiotic use and
infection. However, it was determined that CDAD was associated with pneumonia, and the
majority of these pneumonias followed CDAD, meaning their prolonged pneumonia antibiotic
treatment was after C. diff. was diagnosed.
In our analysis of uncomplicated versus CDAD and their clinical outcomes, our data supported
similar previous reports that patients who developed CDAD had significantly greater hospital length
of stays and time on the ventilator compared with all patients. C. diff patients had significantly
higher Marshall Score, Denver Score, creatinine, bilirubin, alkaline phosphatase, WBC, and
neutrophil count, INR and lower P/F ratio, platelet count and albumin compared with uncomplicated
non-C. diff patients looking at worst value over stay. Similar significance was seen at day 7 with
exclusion of bilirubin, alkaline phosphatase, WBC, neutrophil count, and INR and day 14 with
exclusion of bilirubin and neutrophil count (see Table 1).
Conclusion: Although C.diff. has been reviewed in the trauma population11,16-18, we believe this is
the largest current review of prospectively obtained data of CDAD after severe blunt. As reported
earlier, our data are consistent with Lumpkins et al’s description of increased prevalence in a
younger age group of patients not previously thought to be at risk. We also observed that CDAD
2
patients had thrombocytopenia, neutrophilia, lymphocytosis, some indication of worsened kidney
injury and lower albumen levels compared to non-C. diff patients on their worst day values. This
may not be surprising given that there has been suggestion that infection with C. diff, in general,
represents a marker for poor outcome2, though several of these markers continued to be
significantly abnormal out to seven and 14 days compared with uninfected patients. Our data also
demonstrates that a significant percentage of those who develop C. diff have a higher NISS score
which is associated with worsening immune dysfunction14,15,17,18. This coupled with the fact that C.
diff. infection is associated with high Denver and Marshall Scores, hospital length of stay, days on
the ventilator and clinical complications supports the hypothesis that other factors may play a more
important role than previously realized. In conclusion, blunt trauma patients who develop CDAD
appear to be a unique population who may have specific genomic and/or inflammation related risk
factors that make them susceptible to the disease. Further prospective analysis may allow early
identification of at risk patients, as well as a better understanding of how/why C.diff. colonization
transforms into infection after severe trauma, and hopefully lead to the creation of novel
therapeutics.
Table 1: Clinical Outcomes Stratified by Hospital Day
Uncomplicated Patients
N=384
Clostridium difficile
(N=48)
P1
Worse Value Over Stay
Value at Hospital
Day 7
P2
P3
Value at Hospital Day 14
Outcomes
Hospital Day of Diagnosis
N/A
11.3 + 4.8
Hospital Length of Stay
Mean (min, max)
Median (25th, 75th percentile)
Mortality (%)
10.0 (1.0, 60.0)
7.0 (7.0, 15.0)
34.1 (8.0, 187.0)
27.0 (19.0, 38.5)
<0.0001
3 (0.01)
4 (0.08)
<0.0001
Days on Ventilator
Mean (min, max)
Median (25th, 75th percentile)
1.7 (0.0, 17.0)
2.0 (1.0, 2.0)
13.1 (0.0, 28.0)
10.5 (5.5, 20.0)
<0.0001
Marshall Score (mean + SD)
2.5 + 1.2
6.8 + 3.3
6.6 + 3.6
Denver Score (mean + SD)
0.6 + 1.0
2.9 + 2.5
Creatinine (mg/dl) (mean +
SD)
0.8 + 0.3 (N=354)
Bilirubin (per unit)
Mean (min, max)
Median (25th, 75th percentile)
Alkaline Phosphatase (per
unit)
Mean (min, max)
Median (25th, 75th percentile)
Albumin (per unit) (mean +
SD)
<0.0001
<0.0001
<0.0001
3.2 + 2.5
(N=19)
5.6 + 2.9
(N=31)
2.7 + 2.3
(N=14)
<0.0001
0.0011
0.0146
1.5 + 1.3
1.0 + 0.7
(N=43)
1.2 + 1.2
(N=30)
<0.0001
0.0085
<0.0001
1.1 (0.4, 2.9)
1.0 (0.7, 1.1)
(N=33)
70.8 (23.0, 198.0)
55.0 (47.0, 79.0)
(N=31)
10.5 (0.3, 138.0)
1.8 (0.9, 2.8)
(N=25)
149.9 (32.0, 539.0)
113.0 (85.0, 194.0)
(N= 25)
7.3 (0.7, 37.8)
1.4 (0.8, 5.8)
(N=9)
106.7 (32.0, 214.0)
95.5 (80.0, 123.0)
(N=6)
1.3 (0.6, 2.6)
1.0 (0.8, 1.4)
(N=5)
174.3 (92.0, 254.0) 175.5
(124.5, 224.0)
(N=4)
0.0059
0.0676
0.7628
0.0009
0.1038
0.0095
2.3 + 0.4
(N=48)
1.6 + 0.4
(N=33)
1.8 + 0.5
(N=8)
1.7 + 0.42
(N=6)
<0.0001
0.0056
0.0033
WBC (1000/ul) (mean + SD)
13.9 + 5.8
22.3 + 8.8
14.5 + 6.0
(N=42)
17.7 + 7.7
(N=31)
<0.0001
0.4499
0.0013
Neutrophil Count (1000/ul)
(mean + SD)
11.5 + 4.3
(N=111)
15.4 + 6.9
(N=15)
9.1 + 2.0
(N=7)
11.7 + 4.9
(4=N)
0.0162
0.0822
0.9640
Lymphocyte Count (1000/ml)
Mean (min, max)
Median (25th, 75th percentile)
1.0 (0.2, 4.6)
0.9 (0.7, 1.2)
(N=111)
0.8 (0.1, 1.6)
0.8 (0.4, 1.2)
(N=15)
1.4 (0.6, 3)
1.2 (1.0, 1.6)
(N=10)
2.1 (1.1, 3)
2.2 (1.5, 2.7)
(N=4)
0.1393
0.0210
0.0100
Platelet Count (1000/mm3)
(mean + SD)
134.5 + 39.2
94.6 + 37.3
250.4 + 146.1
(N=41)
618.0 + 371.3
(N=29)
<0.0001
<0.0001
<0.0001
INR (per unit) (mean + SD)
1.2 + 0.2
1.7 + 0.9
1.3 + 0.3
(N=26)
1.3 + 0.3
(N=18)
<0.0001
0.0684
0.0098
P/F Ratio (per unit change)
Mean (min, max)
Median (25th, 75th percentile)
305.8 (114.0, 557.0) 312.5
(325.0, 360.0) (N=70)
163.5 (21.0, 375.0)
156.0 (92.0, 215.0)
225.4 (69.0, 436.0)
223.5 (152.0, 285.0)
(N=30)
223.1 (53.0, 517.0)
208.0 (170.0, 290.0) (N=17)
<0.0001
0.0006
0.0119
P1 = comparing worse values over hospital course of C. diff patients with uncomplicated patients, P2 = comparing values of C. diff patients at
hospital day 7 with uncomplicated patients, P3 = comparing values of C. diff patients at hospital day 14 with uncomplicated patients
3
1.
Barbut F, Petit JC. Epidemiology of Clostridium difficile-associated infections.
Clinical microbiology and infection : the official publication of the European
Society of Clinical Microbiology and Infectious Diseases. Aug 2001;7(8):405410.
Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality
associated with nosocomial diarrhea due to Clostridium difficile. Clinical
infectious diseases : an official publication of the Infectious Diseases Society of
America. Feb 1 2002;34(3):346-353.
Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever. The New
England journal of medicine. Oct 30 2008;359(18):1932-1940.
Efron PA, Mazuski JE. Clostridium difficile colitis. The Surgical clinics of North
America. Apr 2009;89(2):483-500, x.
Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for
Clostridium difficile infection in adults: 2010 update by the society for
healthcare epidemiology of America (SHEA) and the infectious diseases
society of America (IDSA). Infection control and hospital epidemiology : the
official journal of the Society of Hospital Epidemiologists of America. May
2010;31(5):431-455.
Jiang ZD, DuPont HL, Garey K, et al. A common polymorphism in the
interleukin 8 gene promoter is associated with Clostridium difficile diarrhea.
The American journal of gastroenterology. May 2006;101(5):1112-1116.
Lumpkins K, Bochicchio GV, Joshi M, et al. Clostridium difficile infection in
critically injured trauma patients. Surg Infect (Larchmt). Oct 2008;9(5):497501.
Chernak Eea. Severe Clostridium Difficile-associated disease in populations
previously at low risk -- four states. Morbidity and Mortality Weekly Report.
2005;54(47):1201-1205.
McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant
strain of Clostridium difficile. The New England journal of medicine. Dec 8
2005;353(23):2433-2441.
Jiang ZD, Garey KW, Price M, et al. Association of interleukin-8 polymorphism
and immunoglobulin G anti-toxin A in patients with Clostridium difficileassociated diarrhea. Clinical gastroenterology and hepatology : the official
clinical practice journal of the American Gastroenterological Association. Aug
2007;5(8):964-968.
Garey KW, Jiang ZD, Ghantoji S, Tam VH, Arora V, Dupont HL. A common
polymorphism in the interleukin-8 gene promoter is associated with an
increased risk for recurrent Clostridium difficile infection. Clinical infectious
diseases : an official publication of the Infectious Diseases Society of America.
Dec 15 2010;51(12):1406-1410.
Efron PA. An Epidemiologic and Genomic Anaylis of Clostridium difficile
Infections in Blunt Trauma Patients. Journal of Trauma and Acute Care
Surgery. 2012.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
4
13.
Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured
humans. The Journal of experimental medicine. Dec 19 2011;208(13):25812590.
Walsh DS, Siritongtaworn P, Pattanapanyasat K, et al. Lymphocyte activation
after non-thermal trauma. The British journal of surgery. Feb
2000;87(2):223-230.
Menges T, Engel J, Welters I, et al. Changes in blood lymphocyte populations
after multiple trauma: association with posttraumatic complications. Critical
care medicine. Apr 1999;27(4):733-740.
Glance LG, Stone PW, Mukamel DB, Dick AW. Increases in mortality, length of
stay, and cost associated with hospital-acquired infections in trauma
patients. Archives of surgery. Jul 2011;146(7):794-801.
Brun-Buisson C. The epidemiology of the systemic inflammatory response.
Intensive care medicine. 2000;26 Suppl 1:S64-74.
Dewar D, Moore FA, Moore EE, Balogh Z. Postinjury multiple organ failure.
Injury. Sep 2009;40(9):912-918.
14.
15.
16.
17.
18.
5