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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 references 14

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          Reduced exposure to calcineurin inhibitors in renal transplantation.

          Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens. We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival. The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%). A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].). Copyright 2007 Massachusetts Medical Society.
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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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              Development and assessment of molecular diagnostic tests for 15 enteropathogens causing childhood diarrhoea: a multicentre study.

              Childhood diarrhoea can be caused by many pathogens that are difficult to assay in the laboratory. Molecular diagnostic techniques provide a uniform method to detect and quantify candidate enteropathogens. We aimed to develop and assess molecular tests for identification of enteropathogens and their association with disease.
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                Author and article information

                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 ).
                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
                ciu884
                10.1093/cid/ciu884
                4329923
                25371493
                © 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 .

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