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      Editorial Commentary: Microbiologic Testing in Post–Solid Organ Transplant Diarrhea

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          Abstract

          (See the Major Article by Echenique et al on pages 729–37.) Up to 27% of recipients of solid organ transplant (SOT) experience diarrhea posttransplant, with some episodes being severe enough to require hospitalization [1–3]. Immunosuppressive medications are a common cause, but reduction of immunosuppression carries the risk of allograft rejection, making it necessary to rule out other causes, such as infection, before modifying the immunosuppressive regimen [3–7]. In this issue of Clinical Infectious Diseases, Echenique and colleagues report the frequency of infectious causes and diagnostic yield of microbiologic tests in a large retrospective cohort of hospitalized SOT patients with community- and hospital-onset diarrhea [8]. An implied goal of the study was to determine if a targeted approach to testing for infectious causes of diarrhea could be considered as an alternative to the more comprehensive testing strategies recommended at their facility and elsewhere [7, 8]. With this question in mind, it is striking that most diarrheal episodes in their study had no specific etiology identified, infectious or otherwise, and >90% resolved in the hospital before discharge. A potential infectious cause was identified in 30% of community-onset and 19% of hospital-onset diarrheal episodes overall. Most infections were limited to just 3 agents—Clostridium difficile, norovirus, or cytomegalovirus—which comprised >90% of the infectious cases identified. Other infectious causes of diarrhea, such as Campylobacter, Salmonella, rotavirus, adenovirus, astrovirus, Cryptosporidium, and Giardia, were rarely identified. In light of these findings, the authors suggest that initial testing for infectious causes of diarrhea in SOT recipients could potentially be limited to a few tests (eg, blood quantitative cytomegalovirus polymerase chain reaction [PCR], C. difficile PCR, norovirus reverse transcription PCR, bacterial stool culture) in most patients. Then, if symptoms persist, additional testing could be performed to diagnose or rule out less common infectious causes before modifying immunosuppressive regimens. An analogous tiered approach to testing has been used for decades in immunocompetent patients with diarrhea. However, there are several important points that should be considered before generalizing the results of this study to other centers. First, the frequencies of several potentially significant pathogens in immunocompromised hosts, such as Campylobacter and Cryptosporidium, were lower in this study than previous studies based in Europe (Table 1). Conversely, the rate of C. difficile among community-onset diarrheal episodes was higher than other studies and comparable to the rate of C. difficile in hospital-onset diarrheal episodes. This may be a manifestation of the changing epidemiology of C. difficile with more transmission and infection in the community or simply due to community onset of symptoms after hospitalization [11, 12]. Alternatively, it is possible that some of the C. difficile identified in community-onset diarrheal episodes were recurrent infections or lingering colonization with another cause of symptoms, as many patients had a history of prior C. difficile infection. In any case, the differences in the rates of individual diarrheal pathogens in this study vs previous studies suggests that the etiologies of infectious diarrhea in SOT recipients likely differ between transplant centers. Hence, the authors note in their discussion that the results of this study should not be generalized without verification of the local epidemiology and validation. Table 1. Frequency of Infectious Causes in Patients With Posttransplant Diarrhea, by Study Study Echenique, 2014 (This Issue) [8] Maes et al, 2006 [7] Roos-Weil et al, 2011 [9] Coste et al, 2013 [10] Test Methods Molecular and Classical Classical Molecular and Classical Multiplex Molecular Panels Country United States Belgium France France Population CO Diarrhea HO Diarrhea Diarrhea CO Diarrhea CO Diarrhea No Diarrhea Transplant type Mixed Mixed Renal Renal Renal Renal Positive (total) 30% 19% 28% 42% 56%–72% 20%–47% Bacteria   Clostridium difficile 13% 12% 2% 10% 2% 0%–3%   Campylobacter, Salmonella 1% 0% 12% 4% 30% 3%–7% Viruses  CMV 6% 3% 7% 0%–2% 0%–2% NT  Norovirus 9% 4% NT 17% 26% 10%–13%  Other GI viruses 0% 0% 1% 1% 6% 0% Parasites   Cryptosporidium, Giardia <1% 0% 2% 4% 4% 0%  Other 0%–<1% 0% 2% 3% 0% 0%–3% Abbreviations: CMV, cytomegalovirus; CO, community-onset; GI, gastrointestinal; HO, hospital-onset; NT, not tested. A more concerning explanation for the low frequency of traditional infectious causes of community-onset diarrhea in this study is underdiagnosis due to lack of testing. Most diarrheal episodes in this study included an abbreviated microbiologic workup in spite of a more complete institutional test protocol. Bacterial stool culture was performed in only 58% of community-onset diarrheal episodes, and testing for Cryptosporidium and Giardia was performed in only 27% of episodes, making it possible that infectious cases were missed due to lack of testing. Less than 1% of episodes had testing for gastrointestinal viruses other than norovirus. This is not the authors’ fault, as the study was a retrospective summary of real-world practice and not a prospective study designed to comprehensively define the infectious etiologies of diarrhea in SOT recipients. The testing strategies observed in this study may also have been reasonable and cost-effective medical practice because most diarrheal episodes appear to have had a relatively short duration. However, it is important to be aware of the limited workup for intestinal pathogens when interpreting the results of this study. The final point that should be made is that diagnostic test methods for gastrointestinal pathogens are rapidly and dramatically changing. Highly sensitive, multipathogen nucleic acid amplification test panels are poised to become the routine diagnostic test for gastrointestinal pathogens within the next few years. Two molecular test panels, each detecting multiple diarrheal pathogens, are already approved for in vitro diagnostic testing by the US Food and Drug Administration. Several other multiplex gastrointestinal pathogen panels are in various stages of clinical trials and regulatory review. Similar to what happened with the introduction of multiplex viral respiratory panels, it is likely that these multiplex gastrointestinal pathogen panels will replace traditional, less sensitive tests such as bacterial stool culture and viral and protozoal immunoassays in the near future. Moreover, whether it is cost effective or not, these multiplex molecular panels may obviate the need or choice to target testing to selected pathogens. Investigators in France recently demonstrated the dramatic potential of these panels to increase the detection of gastrointestinal pathogens in SOT recipients, leading them and others to question the dogma that most posttransplant diarrhea is noninfectious [10]. In this pilot study, the investigators retested stool from 54 episodes of severe diarrhea in recipients of SOT with several multiplex gastrointestinal pathogen panels and compared results with classical test methods (ie, culture, microscopic examinations, immunoassays, some molecular tests) [10]. Strikingly, the proportion of samples with 1 or more potential pathogens detected increased from 23% with classical tests to 72% after performance of the multiplex gastrointestinal pathogen panels. Similar results have been observed in nontransplant populations [13, 14]. However, it is worth noting that asymptomatic transplant patients can also have pathogens detected by these multiplex panels, making it essential to limit testing to symptomatic patients and correlate test results clinically [10]. A partial summary of results from this study using multiplex gastrointestinal pathogen panels are included in Table 1 (sixth and seventh columns) for comparison with the Echenique et al study [8] and previous studies published elsewhere [7, 9–10]. In summary, Echenique and colleagues provide valuable real-world data showing that the majority of diarrheal episodes in SOT recipients have no etiology identified, with infectious causes being limited to a few pathogens under existing test methods. Looking forward, clinical implementation of multiplex gastrointestinal pathogen test panels is likely to increase the proportion of diarrheal patients with a potential pathogen identified, changing the question from which test(s) to order, to when to test and when to treat.

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          Most cited references10

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          Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011.

          Clostridium difficile infection (CDI) has been increasingly reported among healthy individuals in the community. Recent data suggest that community-associated CDI represents one-third of all C difficile cases. The epidemiology and potential sources of C difficile in the community are not fully understood. To determine epidemiological and clinical characteristics of community-associated CDI and to explore potential sources of C difficile acquisition in the community. Active population-based and laboratory-based CDI surveillance in 8 US states. Medical records were reviewed and interviews performed to assess outpatient, household, and food exposures among patients with community-associated CDI (ie, toxin or molecular assay positive for C difficile and no overnight stay in a health care facility within 12 weeks). Molecular characterization of C difficile isolates was performed. Outpatient health care exposure in the prior 12 weeks among patients with community-associated CDI was a priori categorized into the following 3 levels: no exposure, low-level exposure (ie, outpatient visit with physician or dentist), or high-level exposure (ie, surgery, dialysis, emergency or urgent care visit, inpatient care with no overnight stay, or health care personnel with direct patient care). Prevalence of outpatient health care exposure among patients with community-associated CDI and identification of potential sources of C difficile by level of outpatient health care exposure. Of 984 patients with community-associated CDI, 353 (35.9%) did not receive antibiotics, 177 (18.0%) had no outpatient health care exposure, and 400 (40.7%) had low-level outpatient health care exposure. Thirty-one percent of patients without antibiotic exposure received proton pump inhibitors. Patients having CDI with no or low-level outpatient health care exposure were more likely to be exposed to infants younger than 1 year (P = .04) and to household members with active CDI (P = .05) compared with those having high-level outpatient health care exposure. No association between food exposure or animal exposure and level of outpatient health care exposure was observed. North American pulsed-field gel electrophoresis (NAP) 1 was the most common (21.7%) strain isolated; NAP7 and NAP8 were uncommon (6.7%). Most patients with community-associated CDI had recent outpatient health care exposure, and up to 36% would not be prevented by reduction of antibiotic use only. Our data support evaluation of additional strategies, including further examination of C difficile transmission in outpatient and household settings and reduction of proton pump inhibitor use.
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            Vital signs: preventing Clostridium difficile infections.

            (2012)
            Clostridium difficile infection (CDI) is a common and sometimes fatal health-care-associated infection; the incidence, deaths, and excess health-care costs resulting from CDIs in hospitalized patients are all at historic highs. Meanwhile, the contribution of nonhospital health-care exposures to the overall burden of CDI, and the ability of programs to prevent CDIs by implementing CDC recommendations across a range of hospitals, have not been demonstrated previously. Population-based data from the Emerging Infections Program were analyzed by location and antecedent health-care exposures. Present-on-admission and hospital-onset, laboratory-identified CDIs reported to the National Healthcare Safety Network (NHSN) were analyzed. Rates of hospital-onset CDIs were compared between two 8-month periods near the beginning and end of three CDI prevention programs that focused primarily on measures to prevent intrahospital transmission of C. difficile in three states (Illinois, Massachusetts, and New York). Among CDIs identified in Emerging Infections Program data in 2010, 94% were associated with receiving health care; of these, 75% had onset among persons not currently hospitalized, including recently discharged patients, outpatients, and nursing home residents. Among CDIs reported to NHSN in 2010, 52% were already present on hospital admission, although they were largely health-care related. The pooled CDI rate declined 20% among 71 hospitals participating in the CDI prevention programs. Nearly all CDIs are related to various health-care settings where predisposing antibiotics are prescribed and C. difficile transmission occurs. Hospital-onset CDIs were prevented through an emphasis on infection control. More needs to be done to prevent CDIs; major reductions will require antibiotic stewardship along with infection control applied to nursing homes and ambulatory-care settings as well as hospitals. State health departments and partner organizations have shown leadership in preventing CDIs in hospitals and can prevent more CDIs by extending their programs to cover other health-care settings.
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              Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality.

              Gastrointestinal complications after kidney transplantation are associated with inferior graft outcomes. We examined the incidence, risk factors, and outcomes of posttransplantation diarrhea. Historic cohort study. We examined first kidney transplant recipients in the United States from 1995 to 2002, with follow-up through December 2002. Recipients of multiple organs were excluded. We limited our study population to Medicare beneficiaries. Recipient, donor, and transplant characteristics were ascertained by means of US Renal Data System database inquiry. Incidence of diarrhea, graft loss, and death after transplantation. First episodes of diarrhea after transplantation were ascertained by using International Classification of Disease, Ninth Revision, Clinical Modification codes using Medicare billing data. Cause of diarrhea was classified as infectious or not and according to specific cause. Graft loss and death were ascertained from the date of the first diarrhea episode. We enrolled 41,442 patients. Mean follow-up was 758 +/- 399 days. We observed 7,103 diarrhea cases and 8,104 graft losses (4,201 deaths). The 3-year cumulative incidence of diarrhea was 22%, with 18% diagnosed as noninfectious diarrhea with an unspecified cause. Using multivariate Cox proportional hazards analysis, factors associated with increased risk of unspecified noninfectious diarrhea were female sex (hazard ratio [HR], 1.40; 95% confidence interval, 1.33 to 1.48), type 1 diabetes (HR, 1.20; 95% confidence interval, 1.06 to 1.37), and regimens containing tacrolimus and mycophenolate mofetil (HR, 1.37; 95% confidence interval, 1.28 to 1.46). Unspecified noninfectious diarrhea was associated with increased risk of graft failure (HR, 2.13; 95% confidence interval, 1.98 to 2.28) and patient death (HR, 2.04; 95% confidence interval, 1.85 to 2.24). Use of claims data to ascertain patient characteristics and events; inability to make causal inference based on retrospective designs. Regimens containing tacrolimus and mycophenolate mofetil were associated with increased risk of noninfectious diarrhea. Episodes of noninfectious diarrhea doubled the hazard of graft loss and patient death.
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                Author and article information

                Journal
                Clin Infect Dis
                Clin. Infect. Dis
                cid
                cid
                Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
                Oxford University Press
                1058-4838
                1537-6591
                01 March 2015
                03 November 2014
                03 November 2014
                : 60
                : 5
                : 738-740
                Affiliations
                [1 ]Department of Pathology and Laboratory Medicine
                [2 ]Department of Internal Medicine, Division of Infectious Diseases, University of California, Davis Medical Center , Sacramento
                Author notes
                Correspondence: Christopher R. Polage, MD, Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, 4400 V St, Sacramento, CA 95817 ( christopher.polage@ 123456ucdmc.ucdavis.edu ).
                Article
                ciu884
                10.1093/cid/ciu884
                4329923
                25371493
                ea533343-ef22-405e-b963-9d674f8d0b10
                © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com .

                History
                : 17 October 2014
                : 22 October 2014
                Categories
                Articles and Commentaries

                Infectious disease & Microbiology
                solid organ transplant,diarrhea,c. difficile,norovirus,testing
                Infectious disease & Microbiology
                solid organ transplant, diarrhea, c. difficile, norovirus, testing

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