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ARTICLE IN PRESS Digestive and Liver Disease xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
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Review Article
The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis Karn Wijarnpreecha a,∗ , Suthanya Sornprom a , Charat Thongprayoon a,b , Parkpoom Phatharacharukul c , Wisit Cheungpasitporn b , Kiran Nakkala a a
Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA c Department of Internal Medicine, University of Minnesota, Minneapolis, MN, USA b
a r t i c l e
i n f o
Article history: Received 19 January 2016 Accepted 26 January 2016 Available online xxx Keywords: Clostridium difficile associated diarrhea Clostridium difficile infection Meta-analysis Nasogastric tube
a b s t r a c t Background/objectives: Clostridium difficile-associated diarrhea (CDAD) is a major concern of public health worldwide. The risk of CDAD in patients with nasogastric tube (NGT) insertion is controversial. The aim of this study was to assess the risk of incidence of CDAD in patients with NGT insertion. Methods: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception through August 2015. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risk of CDAD in patients with NGT insertion versus those who did not were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Results: Eleven observational studies were included in our analysis to assess the association between NGT insertion and risk of CDAD. The pooled RR of CDAD in patients with NGT insertion was 1.87 (95% CI, 1.06–3.28, I2 = 73). When meta-analysis was limited only to cohort and case-control studies, the pooled RR of CDAD was 1.99 (95% CI, 1.05–3.77, I2 = 76). Conclusions: Our study demonstrated a statistically significant association between NGT insertion and risk of CDAD. This finding may impact clinical management and primary prevention of CDAD. © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Clostridium difficile-associated diarrhea (CDAD) is a common cause of nosocomial diarrhea and one of the most serious public health problems worldwide [1–3]. Antibiotic use is the most recognized and modifiable risk factor for CDAD [4]. A number of studies have previously identified risk factors for CDAD including advanced age, severe illness, prolonged hospitalization, gastric acid suppression, chemotherapy, chronic kidney disease and obesity [4–11]. Despite the effort to prevent CDAD, its increased prevalence has been reported and The Center for Disease Control and Prevention emphasized the need for urgent and aggressive prevention of CDAD [1]. The reported risk of CDAD in patients with nasogastric tube (NGT) insertion is still conflicting. It has recently been demonstrated that NGT insertion could be a risk factor for CDAD [12–16]. However, several studies demonstrated no significant association
∗ Corresponding author at: One Atwell Road, Cooperstown, NY 13326, USA. E-mail address: [email protected] (K. Wijarnpreecha).
between NGT insertion and CDAD [17–19]. Thus, to assess the association between NGT insertion and risk of CDAD, we conducted this systematic review and meta-analysis of observational studies that compared the risk of CDAD in patients who did have NGT insertion versus patients who did not.
2. Methods 2.1. Search strategy Two investigators (K.W. and W.C.) independently searched published studies indexed in MEDLINE, EMBASE and the Cochrane database from inception through August 2015 using the search strategy described in Item S1 in online supplementary data. A manual search for additional relevant studies using references from retrieved articles was also performed. Two reviewers independently screened all titles, abstracts and assessed the full texts using the inclusion criteria and a standard form. We retrieved the full text of any publications marked for inclusion by reviewers and contacted with authors if could not accessed to full text. To assess the
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Please cite this article in press as: Wijarnpreecha K, et al. The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.01.012
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Table 1 Main characteristics of the studies included in this meta-analysis. Brown et al. [12]
Bliss et al. [7]
Moshkowitz et al. [25]
Jamal et al. [16]
Country Study design Year Total number Study sample
USA Case–control study 1990 74 Hospitalized patients in a single center
USA Cohort study 1998 152 Hospitalized adult ≥18 years
Israel Cohort study 2006 72 Hospitalized patient with PMC in a single center
Exposure definition Exposure measurement Outcome definition Outcome ascertainment
Nasogastric tube insertion Medical record review
Tube feeding Medical record review
Nasogastric tube insertion Medical record review
Kuwait Case–control study 2010 112 Hospitalized patients from all the government hospital in Kuwait Nasogastric tube insertion Medical record review
CDAD Positive C. difficile cytotoxicity assay and clinical correlation of diarrhea at the time of diagnosis
CDAD Positive C. difficile toxin by Toxin A and B or toxigenic strain from stool culture and clinical correlation of diarrhea at the time of diagnosis
Recurrence of PMC Yellow-white plaques loosely adherent to the inflamed mucosa from sigmoidoscopy
Adjusted OR or relative risk
23.0 (4.5, 215)
1.24 (0.31, 4.95)
Confounder adjusted
None
None
Matched for age, sex and stool testing date
Quality assessment (Newcastle-Ottawa scale)
Selection: 2 Comparability: 0 Exposure: 3
Tube feeding 9.0 (1.02, 79.8) Prepyloric tube feeding 3.52 (0.19, 66.5) Postpyrolic tube feeding 11.41 (1.3,103.7) Age, diagnosis, type of unit, abdominal surgery during the study, duration of surveillance, duration of hospitalization before the study, severity of illness index score, antibiotic, metoclopramide hydrochloride, antacids, H2-receptor antagonists, sucralfate Selection: 3 Comparability: 2 Outcome: 3
Selection: 2 Comparability: 0 Outcome: 3
Selection: 3 Comparability: 1 Exposure: 2
CDAD Positive C. difficile toxin by Toxin A and B or toxigenic strain from stool culture and/or endoscopic evidence of PMC and clinical correlation of diarrhea at the time of diagnosis 3.73 (1.25, 11.13)
Kim et al. [18]
Thipmontree et al. [19]
Goorhuis et al. [14]
Ali et al. [24]
Country Study design Year Total number Study sample
South Korea Cohort study 2010 125 Hospitalized patients with CDAD in a single center
Thailand Case–control study 2011 186 Hospitalized patients with hospital-acquired diarrhea in a single center
Netherlands Case–control study 2011 330 Hospitalized patients in a single center
Exposure definition Exposure measurement Outcome definition Outcome ascertainment
Nasogastric tube insertion Medical record review
Nasogastric tube insertion Medical record review
Nasogastric tube insertion Medical record review
USA Cross-sectional study 2012 Not reported Hospitalized patients between 2004 and 2008 identified from HCUP-NIS inpatient discharge database Nasogastric tube insertion ICD-9-CM codes 96.07
Recurrence of CDAD Positive stool testing by EIA for C. difficile toxin A and B and clinical correlation of diarrhea at the time of diagnosis
CDAD Positive stool testing by EIA for C. difficile toxin A and B and clinical correlation of diarrhea at the time of diagnosis
C. difficile infection ICD-9-CM codes 008.45
1.25 (0.91, 2.65)
CDAD Positive C. difficile toxin by Toxin A and B or visualization of pseudomembrane of colon on colonoscopy/sigmoidoscopy or pathologic diagnosis of CDAD or typical finding of PMC and clinical correlation of diarrhea at the time of diagnosis 0.36 (0.17, 0.74)
2.73 (1.07, 6.99)
1.36 (1.29,1.42)
Age, low serum albumin, PPI use
Number of recent antibiotics, PPI, hematologic malignancy
Matched for ward, age, sex, admission period, duration of hospitalization
Age, sex, race, liver/kidney transplant, mechanical ventilation, any infection, inflammatory bowel disease and Charlson index
Adjusted OR or relative risk Confounder adjusted
Quality assessment (Newcastle-Ottawa scale)
Selection: 3 Comparability: 1 Outcome: 3
Selection: 3 Comparability: 1 Exposure: 3
Adjusted for comorbidities and medication Selection: 3 Comparability: 2 Exposure: 3
Selection: 4 Comparability: 2 Outcome: 3
Please cite this article in press as: Wijarnpreecha K, et al. The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.01.012
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Table 1 (Continued)
Country Study design Year Total number Study sample Exposure definition
Exposure measurement Outcome definition
Outcome ascertainment
Adjusted OR or relative risk
Confounder adjusted
Quality assessment (Newcastle-Ottawa scale)
Doh et al. [13]
Huang et al. [15]
Bouza et al. [17]
South Korea Cohort study 2014 120 Hospitalized patients with CDAD in a single center Nasogastric tube insertion
China Case-control study 2014 270 Hospitalized patients in a single center Nasogastric tube insertion in the 3 months preceding the onset of diarrhea Medical record review
Spain Case-control study 2015 200 ICU patients with diarrhea in a single center Nasogastric tube insertion
CDAD
CDAD
Positive C. Difficile toxin by Toxin A and B or toxigenic strain from stool culture and/or endoscopic evidence of PMC and clinical correlation of diarrhea or toxic megacolon at the time of diagnosis 3.32 (1.53,7.20)
Positive C. Difficile toxin by Toxin A and B or toxigenic strain from stool culture and clinical correlation of diarrhea at the time of diagnosis
Matched for time and place of hospitalization
None
Medical record review Recurrence of CDAD; within (early) or after (delayed) 8 weeks of the initial successful treatment Positive C. Difficile toxin by Toxin A and B or toxigenic strain from stool culture and/or endoscopic evidence of PMC and clinical correlation of diarrhea at the time of diagnosis Early recurrence: 8.73 (1.29,59.15) Delayed recurrence: 40.11 (2.65,608.14) Sex, Age, Malignancy, Anti-gastric acid agent, number of antibiotics use
Selection: 3 Comparability: 2 Outcome: 3
Adjusted for malignancy, prior antibiotics treatment, chemotherapy, length of stay, intra-abdominal surgery, laxative use and serum creatinine Selection: 3 Comparability: 2 Exposure: 3
Medical record review
0.86 (0.48,1.55)
Selection: 3 Comparability: 0 Exposure: 3
Abbreviation: HCUP-NIS, The Healthcare Cost and Utilization Project-Nationwide Inpatient Sample; CDAD, Clostridium Difficile associated diarrhea; PMC, Pseudomembranous colitis; EIA, Enzyme immunoassay.
quality and publication bias of all studies, conference abstracts, and unpublished studies were excluded. 2.2. Inclusion criteria The inclusion criteria were as follows: (1) randomized controlled trials (RCTs) or observational studies (case-control, cross-sectional or cohort studies) published as original studies to evaluate the risk of CDAD in patients with NGT insertion, (2) odds ratios, relative risks, hazard ratios or standardized incidence ratio with 95% confidence intervals (CI) were provided, and (3) a reference group composed of participants who did not have NGT insertion. No limits were applied to language. Study eligibility was independently determined by the two investigators noted above. Differing decisions were resolved by mutual consensus. The quality of each study was independently evaluated by each investigator using the Newcastle-Ottawa quality assessment scale [20].
2.4. Statistical analysis Review Manager 5.3 software from the Cochrane Collaboration was used for data analysis. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird [21]. Given the high likelihood of between-study variances, we used a random-effect model rather than a fixed-effect model. Statistical heterogeneity was assessed using the Cochran’s Q test. This statistic is complemented with the I2 statistic, which quantifies the proportion of the total variation across studies that is due to heterogeneity rather than chance. A value of I2 of 0–25% represents insignificant heterogeneity, 26–50% low heterogeneity, 51–75% moderate heterogeneity, and >75% high heterogeneity [22]. The presence of publication bias was assessed by funnel plots of the logarithm of odds ratios versus their standard errors [23].
3. Results 2.3. Data extraction A standardized data collection form was used to extract the following information: last name of the first author, study design, year of study, country of origin, year of publication, sample size, characteristics of included participants, definition of NGT insertion, method used to diagnose CDAD, confounder adjustment and adjusted effect estimates with 95% CI. The two investigators mentioned above independently performed this data extraction.
Our search strategy yielded 298 potentially relevant articles. 245 articles were excluded based on title and abstract for not fulfilling inclusion criteria on the basis of the type of article, study design, population, or outcome of interest. 53 articles underwent full-length article review. 42 articles were excluded (8 articles were not observational studies or RCTs and 34 articles did not report the outcomes of interest). Eleven articles were identified and included in the data analysis [7,12–19,24,25]. Item S2 outlines our search
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Fig. 1. Forest plot of the included studies comparing risk of CDI in patients with NGT insertion and those who did not; square data markers represent risk ratios (RRs); horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. IV, inverse variance; SE, standard error.
Fig. 2. Forest plot of only cohort and case-control studies comparing risk of CDI in patients with NGT insertion and those who did not; square data markers represent risk ratios (RRs); horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. IV, inverse variance; SE, standard error.
methodology and selection process. Table 1 describes the detailed characteristics and quality assessment of the included studies. 3.1. The risk of Clostridium difficile infection in patients with nasogastric tube insertion Eleven studies (six case–control studies [12,14–17,19], four cohort studies [7,13,18,25], and one cross-sectional study [24]) with 1641 patients were included in the data analysis for the risk of CDAD. The pooled risk ratio (RR) of CDAD in individuals who has NGT insertion was 1.87 (95% CI, 1.06–3.28). The statistical heterogeneity was moderate with I2 of 73%. Fig. 1 shows the forest plot of the included studies. The risk of CDAD remained significant in a sensitivity analysis that included only cohort [7,13,18,25] and case-control studies [12,14–17,19] with a pooled RR of 1.99 (95% CI, 1.05–3.77, I2 = 76), as shown in Fig. 2. 3.2. Evaluation of publication bias Funnel plot to evaluate publication bias for the risk of CDAD in patients with NGT insertion is summarized in Figure S1. The graph provides a suggestion for insignificant publication bias of the risk of CDAD in patients with NGT insertion. 4. Discussion This study is the first systematic review and meta-analysis of published studies assessing the association between NGT insertion and risk of incident CDAD. We demonstrated a statistically
significant association between NGT insertion and risk of incident CDAD, with 1.87-fold increased risk of developing CDAD compared to those who did not have NGT insertion. There are several plausible explanations for the increased risk of CDAD in patients with NGT insertion. Firstly, NGT insertion requires the manipulation of the feeding tube system leading to acquiring CDAD from the hands of the staff or health care providers [7,25]. Second, the contamination of the formula and instrument were associated with hospital-acquired infection and can transfer C. difficile from hospital environments [26]. Third, it has been proposed that lack of dietary fiber in the formula might play a role in the growth of C. difficile. It caused less acidic pH in colonic fluid and can contribute to colonization of C. difficile [7]. The finding from this study demonstrated a significant increase in risk of incidence of CDAD among patients with NGT insertion. Physician should be aware and minimize the use of NGT insertion as appropriate in order to decrease the incidence of CDAD. Limited use of antibiotics, shorter hospital stays, if possible, and minimizing the use of PPI and NGT would play a major role to decrease the incidence of CDAD. Although most of the included studies have good quality, there are some limitations of this study. First, there were no RCTs included in the analysis, which could be from the difficulty of study design and ethical issues. However, the meta-analysis of cohort and case–control studies could help remove potential publication bias. Second, this is a meta-analysis of observational studies which can demonstrate an association but not a causal relationship. Third, there were moderate statistical heterogeneities in the complete analysis. The possible sources of these heterogeneities include the
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differences in the confounder adjustment methods, differences in the sample in each study, definition of outcome, and outcome ascertainments. However, there was no significant publication bias in our final analysis. In summary, this meta-analysis clearly demonstrated a significant association between NGT insertion and risk of CDAD. The finding of this study may impact clinical management and primary prevention of CDAD. NGT insertion is a modifiable risk factor that might be associated with the risk of CDAD. Appropriate use of NGT not only reduces its complications but may also decrease the risk of CDAD. Conflict of interest None declared. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2016.01.012. References [1] Evans CT, Safdar N. Current trends in the epidemiology and outcomes of clostridium difficile infection. Clinical Infectious Diseases 2015;60(Suppl. 2):S66–71. [2] Fenner L, Frei R, Gregory M, et al. Epidemiology of clostridium difficileassociated disease at university hospital basel including molecular characterisation of the isolates 2006–2007. European Journal of Clinical Microbiology & Infectious Diseases 2008;27:1201–7. [3] Vindigni SM, Surawicz CM. C. difficile infection: changing epidemiology and management paradigms. Clinical and Translational Gastroenterology 2015;6:e99. [4] Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for clostridium difficile infection and colonization. New England Journal of Medicine 2011;365:1693–703. [5] Bartlett JG. Narrative review: the new epidemic of clostridium difficileassociated enteric disease. Annals of Internal Medicine 2006;145: 758–64. [6] Bishara J, Farah R, Mograbi J, et al. Obesity as a risk factor for Clostridium difficile infection. Clinical Infectious Diseases 2013;57:489–93. [7] Bliss DZ, Johnson S, Savik K, et al. Acquisition of clostridium difficile and clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding. Annals of Internal Medicine 1998;129:1012–9. [8] Kamthan AG, Bruckner HW, Hirschman SZ, et al. Clostridium difficile diarrhea induced by cancer chemotherapy. Archives of Internal Medicine 1992;152:1715–7.
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[9] Kyne L, Sougioultzis S, McFarland LV, et al. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infection Control and Hospital Epidemiology 2002;23:653–9. [10] Phatharacharukul P, Thongprayoon C, Cheungpasitporn W, et al. The risks of incident and recurrent clostridium difficile-associated diarrhea in chronic kidney disease and end-stage kidney disease patients: a systematic review and meta-analysis. Digestive Diseases and Sciences 2015;60:2913–22. [11] Thongprayoon C, Cheungpasitporn W, Phatharacharukul P, et al. Chronic kidney disease and end-stage renal disease are risk factors for poor outcomes of Clostridium difficile infection: a systematic review and meta-analysis. International Journal of Clinical Practice 2015;69:998–1006. [12] Brown E, Talbot GH, Axelrod P, et al. Risk factors for Clostridium difficile toxin-associated diarrhea. Infection Control and Hospital Epidemiology 1990;11:283–90. [13] Doh YS, Kim YS, Jung HJ, et al. Long-term clinical outcome of Clostridium difficile infection in hospitalized patients: a single center study. Intestinal Research 2014;12:299–305. [14] Goorhuis A, Debast SB, Dutilh JC, et al. Type-specific risk factors and outcome in an outbreak with 2 different clostridium difficile types simultaneously in 1 hospital. Clinical Infectious Diseases 2011;53:860–9. [15] Huang H, Wu S, Chen R, et al. Risk factors of Clostridium difficile infections among patients in a University Hospital in Shanghai, China. Anaerobe 2014;30:65–9. [16] Jamal W, Rotimi VO, Brazier J, et al. Analysis of prevalence, risk factors and molecular epidemiology of Clostridium difficile infection in Kuwait over a 3-year period. Anaerobe 2010;16:560–5. [17] Bouza E, Rodriguez-Creixems M, Alcala L, et al. Is Clostridium difficile infection an increasingly common severe disease in adult intensive care units? A 10-year experience. Journal of Critical Care 2015;30:543–9. [18] Kim JW, Lee KL, Jeong JB, et al. Proton pump inhibitors as a risk factor for recurrence of Clostridium difficile-associated diarrhea. World Journal of Gastroenterology 2010;16:3573–7. [19] Thipmontree W, Kiratisin P, Manatsathit S, et al. Epidemiology of suspected Clostridium difficile-associated hospital-acquired diarrhea in hospitalized patients at siriraj hospital. Journal of the Medical Association of Thailand = Chotmaihet thangphaet 2011;94(Suppl. 1):S207–16. [20] Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European Journal of Epidemiology 2010;25:603–5. [21] DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7:177–88. [22] Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in metaanalyses. British Medical Journal 2003;327:557–60. [23] Easterbrook PJ, Berlin JA, Gopalan R, et al. Publication bias in clinical research. Lancet 1991;337:867–72. [24] Ali M, Ananthakrishnan AN, Ahmad S, et al. Clostridium difficile infection in hospitalized liver transplant patients: a nationwide analysis. Liver Transplantation 2012;18:972–8. [25] Moshkowitz M, Ben-Baruch E, Kline Z, et al. Risk factors for severity and relapse of pseudomembranous colitis in an elderly population. Colorectal Disease 2007;9:173–7. [26] Thurn J, Crossley K, Gerdts A, et al. Enteral hyperalimentation as a source of nosocomial infection. Journal of Hospital Infection 1990;15:203–17.
Please cite this article in press as: Wijarnpreecha K, et al. The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.01.012
ARTICLE IN PRESS Digestive and Liver Disease xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Review Article
The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis Karn Wijarnpreecha a,∗ , Suthanya Sornprom a , Charat Thongprayoon a,b , Parkpoom Phatharacharukul c , Wisit Cheungpasitporn b , Kiran Nakkala a a
Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA c Department of Internal Medicine, University of Minnesota, Minneapolis, MN, USA b
a r t i c l e
i n f o
Article history: Received 19 January 2016 Accepted 26 January 2016 Available online xxx Keywords: Clostridium difficile associated diarrhea Clostridium difficile infection Meta-analysis Nasogastric tube
a b s t r a c t Background/objectives: Clostridium difficile-associated diarrhea (CDAD) is a major concern of public health worldwide. The risk of CDAD in patients with nasogastric tube (NGT) insertion is controversial. The aim of this study was to assess the risk of incidence of CDAD in patients with NGT insertion. Methods: A literature search was performed using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from inception through August 2015. Studies that reported relative risks, odds ratios, or hazard ratios comparing the risk of CDAD in patients with NGT insertion versus those who did not were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. Results: Eleven observational studies were included in our analysis to assess the association between NGT insertion and risk of CDAD. The pooled RR of CDAD in patients with NGT insertion was 1.87 (95% CI, 1.06–3.28, I2 = 73). When meta-analysis was limited only to cohort and case-control studies, the pooled RR of CDAD was 1.99 (95% CI, 1.05–3.77, I2 = 76). Conclusions: Our study demonstrated a statistically significant association between NGT insertion and risk of CDAD. This finding may impact clinical management and primary prevention of CDAD. © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Clostridium difficile-associated diarrhea (CDAD) is a common cause of nosocomial diarrhea and one of the most serious public health problems worldwide [1–3]. Antibiotic use is the most recognized and modifiable risk factor for CDAD [4]. A number of studies have previously identified risk factors for CDAD including advanced age, severe illness, prolonged hospitalization, gastric acid suppression, chemotherapy, chronic kidney disease and obesity [4–11]. Despite the effort to prevent CDAD, its increased prevalence has been reported and The Center for Disease Control and Prevention emphasized the need for urgent and aggressive prevention of CDAD [1]. The reported risk of CDAD in patients with nasogastric tube (NGT) insertion is still conflicting. It has recently been demonstrated that NGT insertion could be a risk factor for CDAD [12–16]. However, several studies demonstrated no significant association
∗ Corresponding author at: One Atwell Road, Cooperstown, NY 13326, USA. E-mail address: [email protected] (K. Wijarnpreecha).
between NGT insertion and CDAD [17–19]. Thus, to assess the association between NGT insertion and risk of CDAD, we conducted this systematic review and meta-analysis of observational studies that compared the risk of CDAD in patients who did have NGT insertion versus patients who did not.
2. Methods 2.1. Search strategy Two investigators (K.W. and W.C.) independently searched published studies indexed in MEDLINE, EMBASE and the Cochrane database from inception through August 2015 using the search strategy described in Item S1 in online supplementary data. A manual search for additional relevant studies using references from retrieved articles was also performed. Two reviewers independently screened all titles, abstracts and assessed the full texts using the inclusion criteria and a standard form. We retrieved the full text of any publications marked for inclusion by reviewers and contacted with authors if could not accessed to full text. To assess the
http://dx.doi.org/10.1016/j.dld.2016.01.012 1590-8658/© 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wijarnpreecha K, et al. The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.01.012
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Table 1 Main characteristics of the studies included in this meta-analysis. Brown et al. [12]
Bliss et al. [7]
Moshkowitz et al. [25]
Jamal et al. [16]
Country Study design Year Total number Study sample
USA Case–control study 1990 74 Hospitalized patients in a single center
USA Cohort study 1998 152 Hospitalized adult ≥18 years
Israel Cohort study 2006 72 Hospitalized patient with PMC in a single center
Exposure definition Exposure measurement Outcome definition Outcome ascertainment
Nasogastric tube insertion Medical record review
Tube feeding Medical record review
Nasogastric tube insertion Medical record review
Kuwait Case–control study 2010 112 Hospitalized patients from all the government hospital in Kuwait Nasogastric tube insertion Medical record review
CDAD Positive C. difficile cytotoxicity assay and clinical correlation of diarrhea at the time of diagnosis
CDAD Positive C. difficile toxin by Toxin A and B or toxigenic strain from stool culture and clinical correlation of diarrhea at the time of diagnosis
Recurrence of PMC Yellow-white plaques loosely adherent to the inflamed mucosa from sigmoidoscopy
Adjusted OR or relative risk
23.0 (4.5, 215)
1.24 (0.31, 4.95)
Confounder adjusted
None
None
Matched for age, sex and stool testing date
Quality assessment (Newcastle-Ottawa scale)
Selection: 2 Comparability: 0 Exposure: 3
Tube feeding 9.0 (1.02, 79.8) Prepyloric tube feeding 3.52 (0.19, 66.5) Postpyrolic tube feeding 11.41 (1.3,103.7) Age, diagnosis, type of unit, abdominal surgery during the study, duration of surveillance, duration of hospitalization before the study, severity of illness index score, antibiotic, metoclopramide hydrochloride, antacids, H2-receptor antagonists, sucralfate Selection: 3 Comparability: 2 Outcome: 3
Selection: 2 Comparability: 0 Outcome: 3
Selection: 3 Comparability: 1 Exposure: 2
CDAD Positive C. difficile toxin by Toxin A and B or toxigenic strain from stool culture and/or endoscopic evidence of PMC and clinical correlation of diarrhea at the time of diagnosis 3.73 (1.25, 11.13)
Kim et al. [18]
Thipmontree et al. [19]
Goorhuis et al. [14]
Ali et al. [24]
Country Study design Year Total number Study sample
South Korea Cohort study 2010 125 Hospitalized patients with CDAD in a single center
Thailand Case–control study 2011 186 Hospitalized patients with hospital-acquired diarrhea in a single center
Netherlands Case–control study 2011 330 Hospitalized patients in a single center
Exposure definition Exposure measurement Outcome definition Outcome ascertainment
Nasogastric tube insertion Medical record review
Nasogastric tube insertion Medical record review
Nasogastric tube insertion Medical record review
USA Cross-sectional study 2012 Not reported Hospitalized patients between 2004 and 2008 identified from HCUP-NIS inpatient discharge database Nasogastric tube insertion ICD-9-CM codes 96.07
Recurrence of CDAD Positive stool testing by EIA for C. difficile toxin A and B and clinical correlation of diarrhea at the time of diagnosis
CDAD Positive stool testing by EIA for C. difficile toxin A and B and clinical correlation of diarrhea at the time of diagnosis
C. difficile infection ICD-9-CM codes 008.45
1.25 (0.91, 2.65)
CDAD Positive C. difficile toxin by Toxin A and B or visualization of pseudomembrane of colon on colonoscopy/sigmoidoscopy or pathologic diagnosis of CDAD or typical finding of PMC and clinical correlation of diarrhea at the time of diagnosis 0.36 (0.17, 0.74)
2.73 (1.07, 6.99)
1.36 (1.29,1.42)
Age, low serum albumin, PPI use
Number of recent antibiotics, PPI, hematologic malignancy
Matched for ward, age, sex, admission period, duration of hospitalization
Age, sex, race, liver/kidney transplant, mechanical ventilation, any infection, inflammatory bowel disease and Charlson index
Adjusted OR or relative risk Confounder adjusted
Quality assessment (Newcastle-Ottawa scale)
Selection: 3 Comparability: 1 Outcome: 3
Selection: 3 Comparability: 1 Exposure: 3
Adjusted for comorbidities and medication Selection: 3 Comparability: 2 Exposure: 3
Selection: 4 Comparability: 2 Outcome: 3
Please cite this article in press as: Wijarnpreecha K, et al. The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.01.012
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Table 1 (Continued)
Country Study design Year Total number Study sample Exposure definition
Exposure measurement Outcome definition
Outcome ascertainment
Adjusted OR or relative risk
Confounder adjusted
Quality assessment (Newcastle-Ottawa scale)
Doh et al. [13]
Huang et al. [15]
Bouza et al. [17]
South Korea Cohort study 2014 120 Hospitalized patients with CDAD in a single center Nasogastric tube insertion
China Case-control study 2014 270 Hospitalized patients in a single center Nasogastric tube insertion in the 3 months preceding the onset of diarrhea Medical record review
Spain Case-control study 2015 200 ICU patients with diarrhea in a single center Nasogastric tube insertion
CDAD
CDAD
Positive C. Difficile toxin by Toxin A and B or toxigenic strain from stool culture and/or endoscopic evidence of PMC and clinical correlation of diarrhea or toxic megacolon at the time of diagnosis 3.32 (1.53,7.20)
Positive C. Difficile toxin by Toxin A and B or toxigenic strain from stool culture and clinical correlation of diarrhea at the time of diagnosis
Matched for time and place of hospitalization
None
Medical record review Recurrence of CDAD; within (early) or after (delayed) 8 weeks of the initial successful treatment Positive C. Difficile toxin by Toxin A and B or toxigenic strain from stool culture and/or endoscopic evidence of PMC and clinical correlation of diarrhea at the time of diagnosis Early recurrence: 8.73 (1.29,59.15) Delayed recurrence: 40.11 (2.65,608.14) Sex, Age, Malignancy, Anti-gastric acid agent, number of antibiotics use
Selection: 3 Comparability: 2 Outcome: 3
Adjusted for malignancy, prior antibiotics treatment, chemotherapy, length of stay, intra-abdominal surgery, laxative use and serum creatinine Selection: 3 Comparability: 2 Exposure: 3
Medical record review
0.86 (0.48,1.55)
Selection: 3 Comparability: 0 Exposure: 3
Abbreviation: HCUP-NIS, The Healthcare Cost and Utilization Project-Nationwide Inpatient Sample; CDAD, Clostridium Difficile associated diarrhea; PMC, Pseudomembranous colitis; EIA, Enzyme immunoassay.
quality and publication bias of all studies, conference abstracts, and unpublished studies were excluded. 2.2. Inclusion criteria The inclusion criteria were as follows: (1) randomized controlled trials (RCTs) or observational studies (case-control, cross-sectional or cohort studies) published as original studies to evaluate the risk of CDAD in patients with NGT insertion, (2) odds ratios, relative risks, hazard ratios or standardized incidence ratio with 95% confidence intervals (CI) were provided, and (3) a reference group composed of participants who did not have NGT insertion. No limits were applied to language. Study eligibility was independently determined by the two investigators noted above. Differing decisions were resolved by mutual consensus. The quality of each study was independently evaluated by each investigator using the Newcastle-Ottawa quality assessment scale [20].
2.4. Statistical analysis Review Manager 5.3 software from the Cochrane Collaboration was used for data analysis. Point estimates and standard errors were extracted from individual studies and were combined by the generic inverse variance method of DerSimonian and Laird [21]. Given the high likelihood of between-study variances, we used a random-effect model rather than a fixed-effect model. Statistical heterogeneity was assessed using the Cochran’s Q test. This statistic is complemented with the I2 statistic, which quantifies the proportion of the total variation across studies that is due to heterogeneity rather than chance. A value of I2 of 0–25% represents insignificant heterogeneity, 26–50% low heterogeneity, 51–75% moderate heterogeneity, and >75% high heterogeneity [22]. The presence of publication bias was assessed by funnel plots of the logarithm of odds ratios versus their standard errors [23].
3. Results 2.3. Data extraction A standardized data collection form was used to extract the following information: last name of the first author, study design, year of study, country of origin, year of publication, sample size, characteristics of included participants, definition of NGT insertion, method used to diagnose CDAD, confounder adjustment and adjusted effect estimates with 95% CI. The two investigators mentioned above independently performed this data extraction.
Our search strategy yielded 298 potentially relevant articles. 245 articles were excluded based on title and abstract for not fulfilling inclusion criteria on the basis of the type of article, study design, population, or outcome of interest. 53 articles underwent full-length article review. 42 articles were excluded (8 articles were not observational studies or RCTs and 34 articles did not report the outcomes of interest). Eleven articles were identified and included in the data analysis [7,12–19,24,25]. Item S2 outlines our search
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Fig. 1. Forest plot of the included studies comparing risk of CDI in patients with NGT insertion and those who did not; square data markers represent risk ratios (RRs); horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. IV, inverse variance; SE, standard error.
Fig. 2. Forest plot of only cohort and case-control studies comparing risk of CDI in patients with NGT insertion and those who did not; square data markers represent risk ratios (RRs); horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. IV, inverse variance; SE, standard error.
methodology and selection process. Table 1 describes the detailed characteristics and quality assessment of the included studies. 3.1. The risk of Clostridium difficile infection in patients with nasogastric tube insertion Eleven studies (six case–control studies [12,14–17,19], four cohort studies [7,13,18,25], and one cross-sectional study [24]) with 1641 patients were included in the data analysis for the risk of CDAD. The pooled risk ratio (RR) of CDAD in individuals who has NGT insertion was 1.87 (95% CI, 1.06–3.28). The statistical heterogeneity was moderate with I2 of 73%. Fig. 1 shows the forest plot of the included studies. The risk of CDAD remained significant in a sensitivity analysis that included only cohort [7,13,18,25] and case-control studies [12,14–17,19] with a pooled RR of 1.99 (95% CI, 1.05–3.77, I2 = 76), as shown in Fig. 2. 3.2. Evaluation of publication bias Funnel plot to evaluate publication bias for the risk of CDAD in patients with NGT insertion is summarized in Figure S1. The graph provides a suggestion for insignificant publication bias of the risk of CDAD in patients with NGT insertion. 4. Discussion This study is the first systematic review and meta-analysis of published studies assessing the association between NGT insertion and risk of incident CDAD. We demonstrated a statistically
significant association between NGT insertion and risk of incident CDAD, with 1.87-fold increased risk of developing CDAD compared to those who did not have NGT insertion. There are several plausible explanations for the increased risk of CDAD in patients with NGT insertion. Firstly, NGT insertion requires the manipulation of the feeding tube system leading to acquiring CDAD from the hands of the staff or health care providers [7,25]. Second, the contamination of the formula and instrument were associated with hospital-acquired infection and can transfer C. difficile from hospital environments [26]. Third, it has been proposed that lack of dietary fiber in the formula might play a role in the growth of C. difficile. It caused less acidic pH in colonic fluid and can contribute to colonization of C. difficile [7]. The finding from this study demonstrated a significant increase in risk of incidence of CDAD among patients with NGT insertion. Physician should be aware and minimize the use of NGT insertion as appropriate in order to decrease the incidence of CDAD. Limited use of antibiotics, shorter hospital stays, if possible, and minimizing the use of PPI and NGT would play a major role to decrease the incidence of CDAD. Although most of the included studies have good quality, there are some limitations of this study. First, there were no RCTs included in the analysis, which could be from the difficulty of study design and ethical issues. However, the meta-analysis of cohort and case–control studies could help remove potential publication bias. Second, this is a meta-analysis of observational studies which can demonstrate an association but not a causal relationship. Third, there were moderate statistical heterogeneities in the complete analysis. The possible sources of these heterogeneities include the
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differences in the confounder adjustment methods, differences in the sample in each study, definition of outcome, and outcome ascertainments. However, there was no significant publication bias in our final analysis. In summary, this meta-analysis clearly demonstrated a significant association between NGT insertion and risk of CDAD. The finding of this study may impact clinical management and primary prevention of CDAD. NGT insertion is a modifiable risk factor that might be associated with the risk of CDAD. Appropriate use of NGT not only reduces its complications but may also decrease the risk of CDAD. Conflict of interest None declared. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2016.01.012. References [1] Evans CT, Safdar N. Current trends in the epidemiology and outcomes of clostridium difficile infection. Clinical Infectious Diseases 2015;60(Suppl. 2):S66–71. [2] Fenner L, Frei R, Gregory M, et al. Epidemiology of clostridium difficileassociated disease at university hospital basel including molecular characterisation of the isolates 2006–2007. European Journal of Clinical Microbiology & Infectious Diseases 2008;27:1201–7. [3] Vindigni SM, Surawicz CM. C. difficile infection: changing epidemiology and management paradigms. Clinical and Translational Gastroenterology 2015;6:e99. [4] Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for clostridium difficile infection and colonization. New England Journal of Medicine 2011;365:1693–703. [5] Bartlett JG. Narrative review: the new epidemic of clostridium difficileassociated enteric disease. Annals of Internal Medicine 2006;145: 758–64. [6] Bishara J, Farah R, Mograbi J, et al. Obesity as a risk factor for Clostridium difficile infection. Clinical Infectious Diseases 2013;57:489–93. [7] Bliss DZ, Johnson S, Savik K, et al. Acquisition of clostridium difficile and clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding. Annals of Internal Medicine 1998;129:1012–9. [8] Kamthan AG, Bruckner HW, Hirschman SZ, et al. Clostridium difficile diarrhea induced by cancer chemotherapy. Archives of Internal Medicine 1992;152:1715–7.
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