Abstract
Background
Diarrhea is a common complication of hematopoietic stem cell transplantation (HSCT) and is associated with substantial morbidity, but its etiology is often unknown. Etiologies of diarrhea in this population include infectious causes, chemotherapy- or medication-induced mucosal injury and graft-versus-host disease (GVHD). Distinguishing these potential causes of diarrhea is challenging since diarrheal symptoms are often multifactorial, and the etiologies often overlap in transplant patients. The objectives of this study were to evaluate whether the FilmArray gastrointestinal (GI) panel would increase diagnostic yield and the degree to which pre-transplantation colonization predicts post-transplantation infection.
Methods
From November 2019 to February 2021, a total of 158 patients undergoing HSCT were prospectively included in the study. Stool specimens were obtained from all HSCT recipients prior to conditioning therapy, 28 ± 7 days after transplantation and at any new episode of diarrhea. All stool samples were tested by the FilmArray GI panel and other clinical microbiological assays.
Results
The primary cause of post-transplantation diarrhea was infection (57/84, 67.86%), followed by medication (38/84, 45.24%) and GVHD (21/84, 25.00%). Ninety-five of 158 patients were colonized with at least one gastrointestinal pathogen before conditioning therapy, and the incidence of infectious diarrhea was significantly higher in colonized patients (47/95, 49.47%) than in non-colonized patients (10/63, 15.87%) (P < 0.001). Fourteen of 19 (73.68%) patients who were initially colonized with norovirus pre-transplantation developed a post-transplantation norovirus infection. Twenty-four of 62 (38.71%) patients colonized with Clostridium difficile developed a diarrheal infection. In addition, FilmArray GI panel testing improved the diagnostic yield by almost twofold in our study (55/92, 59.78% vs. 30/92, 32.61%).
Conclusions
Our data show that more than half of pediatric patients who were admitted for HSCT were colonized with various gastrointestinal pathogens, and more than one-third of these pathogens were associated with post-transplantation diarrhea. In addition, the FilmArray GI panel can increase the detection rate of diarrheal pathogens in pediatric HSCT patients, but the panel needs to be optimized for pathogen species, and further studies assessing its clinical impact and cost-effectiveness in this specific patient population are also needed.
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Introduction
Diarrhea is a common complication of hematopoietic stem cell transplantation (HSCT), occurring in 43% to 91% of patients, and is associated with substantial morbidity [1,2,3]. Etiologies of diarrhea in this population include infectious causes, chemotherapy- or medication-induced mucosal injury and graft-versus-host disease (GVHD). Distinguishing these potential causes of diarrhea is challenging since diarrheal symptoms are often multifactorial, and the etiologies often overlap in transplant patients [4, 5]. Positive results from microbiologic tests in stool samples may improve antimicrobial stewardship, improve infection prevention, and decrease the use of other diagnostic modalities, although they do not rule out other clinically important causes of gastrointestinal (GI) symptoms. However, conventional stool testing methods (e.g., stool culture, serology tests, ova and parasite examination) are unable to detect most diarrheagenic Escherichia coli (E. coli) and have limited sensitivity for detecting other pathogens [6, 7]. Compared to conventional stool testing, multiplexed polymerase chain reaction (PCR) panels have shown increased sensitivity for detecting GI pathogens in the general population [8, 9], but studies focused on transplant patients are scarce and limited to adults [10]. The clinical diagnostic application of multiplexed PCR panels in children undergoing HSCT remains to be evaluated.
Asymptomatic colonization with GI pathogens is well reported in the literature, and most studies have focused on asymptomatic colonization with Clostridium difficile (C. difficile) [11,12,13]. For vulnerable populations, such as patients undergoing HSCT, GI carriage of microbial pathogens may be a reservoir from which pre-transplantation colonization may develop to post-transplantation infection. Determining the predictive value of GI pathogen colonization before HSCT on the development of diarrhea with certain infectious pathogens post-transplantation can provide a positive effect on infection control. However, the significance of certain studies has been underestimated. The only study from Kubiak et al. reported that 37% of adult patients were colonized with at least one pathogen before transplantation, and 48.9% of those colonized patients developed a post-transplantation diarrhoeal infection [14]. In pediatric HSCT patients, there are no related data yet.
In this study, we used a BioFire FilmArray GI panel (bioMérieux, Marcy l’Etoile, France) to evaluate whether the introduction of the FilmArray GI panel would increase diagnostic yield and improve the understanding of the epidemiology of diarrhea and the degree to which pre-transplantation colonization predicts post-transplantation infection in pediatric HSCT patients.
Methods
Study population
This prospective study of patients undergoing either allogeneic or autologous HSCT was performed at Shanghai Children’s Medical Center between November 2019 and February 2021. A total of 158 patients were included in the study, according to our inclusion/exclusion criteria (Fig. 1). Patient demographics, underlying diseases, and transplant types were obtained from the medical records. The study was approved by the Institutional Review Board and the Ethics Committee of Shanghai Children’s Medical Center (SCMCIRB-K2018109), and written informed consent was obtained from each patient and/or their parents.
Study design
Stool specimens were obtained from all HSCT recipients prior to conditioning therapy and 28 ± 7 days after transplantation. In addition, stool specimens were also obtained at any new episode of diarrhea. All these specimens were tested with the FilmArray GI panel within 24 hours after collection. Post-transplantation diarrhea was defined as ≥ 3 unformed stools per day [15]. Infectious diarrhea was defined as the detection of the pathogen or toxin in diarrhea episodes during transplantation admission by several methods indicated below. The diagnosis of noninfectious causes of diarrhea, including GVHD and medication-induced diarrhea, as well as infection-causing pathogens were determined by retrospective, in-depth chart review performed independently by two physicians with expertise in HSCT, according to established criteria [16].
FilmArray GI panel testing
The FilmArray GI panel targets 22 pathogens, including 13 bacterial pathogens: Campylobacter spp. (jejuni, coli, and upsaliensis), Plesiomonas shigelloides, Salmonella spp., Yersinia enterocolitica, Vibrio spp. (parahaemolyticus, vulnificus, and cholerae), enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), Shiga toxin-producing E. coli, Shigella/enteroinvasive E. coli, and C. difficile; five viral pathogens: adenovirus F40/41, astrovirus, norovirus GI/GII, rotavirus A, and sapovirus (I, II, IV, and V); and four protozoan pathogens: Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica, and Giardia lamblia. The FilmArray GI assay was performed according to the manufacturer’s instructions. Comprehensive results were available within approximately 1 hour after a 2-minute operating time.
Microbiological evaluation
In diarrhea episodes, other clinical microbiological assays were also performed as requested by the treating physician. Routine microbiological assays included stool culture (for the presence of pathogenic bacteria), stool microscopic examination (for the presence of parasites), stool antigen tests (for rotavirus, adenovirus, and norovirus), stool real-time quantitative PCR (RT‒qPCR) test [for cytomegalovirus (CMV), Epstein–Barr virus (EBV), BK virus, human herpesvirus 6 (HHV6), adenovirus, norovirus, and human parvovirus B19], and metagenomic next-generation sequencing (mNGS) for intestinal mucosa specimens.
Statistical analyses
For each patient who developed diarrhea after transplantation, we first analyzed the proportion of diarrhea due to different causes, including GVHD-, infection-, and medication-induced diarrhea. We then determined the proportions of patients who tested positive with the FilmArray GI panel prior to conditioning therapy and 28 ± 7 days after transplantation. Next, we assessed the proportions of patients who developed diarrheal infections due to their pre-transplantation colonizing pathogens detected by the FilmArray GI panel. The proportions of patients with different underlying diseases and who developed diarrheal infection due to colonizing pathogens were compared using the Chi-square test when the expected number of events was five or more or using Fisher’s exact test when the expected number was less than five. Statistical analyses and figures were performed with GraphPad Prism, version 8.3.0 (GraphPad Software). A two-sided P < 0.05 was considered statistically significant.
Results
Clinical characteristics of patients
A total of 158 patients undergoing HSCT, aged from 9 months to 16 years, were enrolled in the present study between November 2019 and February 2021. The median patient age was 6.00 years, with 37.97% of patients being female and 96.84% being allogeneic HSCT recipients. The most common underlying diseases were hematological malignancies (40.51%), aplastic anemia (23.42%), primary immunodeficiency (17.72%), and inherited metabolic disorders (12.66%).
Ninety-five of the 158 (60.13%) patients tested positive for at least one GI pathogen before transplantation and were therefore classified as colonized patients. There were no significant differences regarding age, stem cell source or outcomes in colonized or non-colonized patients (Table 1).
Etiologies of diarrhea after transplantation
Eighty-four of the 158 (53.16%) patients developed diarrhea after transplantation (Fig. 1). In half of these patients, diarrhea was considered to be caused by a single factor, including infection (21/84, 25.00%), medication-induced diarrhea (14/84, 16.67%), GVHD (6/84, 7.14%), and engraftment syndrome (1/84, 1.19%). In the other 37 patients, diarrhea was due to multiple factors, including infection plus GVHD (13/84, 15.48%), infection plus medication-induced (22/84, 26.19%), infection plus GVHD plus medication-induced (1/84, 1.19%), and GVHD plus medication-induced (1/84, 1.19%) (Fig. 2a). In summary, the primary cause of post-transplantation diarrhea was infection (57/84, 67.86%), followed by medication (38/84, 45.24%) and GVHD (21/84, 25.00%) (Fig. 2b).
To determine whether pre-transplantation colonization with GI pathogens has an impact on post-transplantation diarrhea, we compared the proportion of diarrhea patients in the colonized and non-colonized groups. The incidence of diarrhea was higher in the colonized patients (56/95, 58.95%) than in the non-colonized patients (28/63, 44.44%), although the difference was not significant (P = 0.074). However, there was a significant increase in the incidence of infection-induced diarrhea in the colonized group (47/95, 49.47%) compared to the non-colonized group (10/63, 15.87%) (P < 0.001, Fig. 2c).
Pathogens detected by FilmArray GI panel
In total, 95 patients were colonized by at least one GI pathogen pre-transplantation, resulting in 124 pathogens being detected. The most commonly detected pathogen was C. difficile, present in 62 (65.26%) patients. Other pathogens detected included EPEC (21/95, 22.11%), norovirus (19/95, 20.00%), EAEC (7/95, 7.37%), etc. (Fig. 3, left column). Fifty-nine patients tested positive for at least one GI pathogen 28 ± 7 days after transplantation. The most commonly detected pathogen was C. difficile, present in 38 (64.41%) patients, followed by norovirus (21/59, 35.59%) (Fig. 3, right column). Interestingly, we found that EPEC was only present in 1 of the 59 patients. No other pathogenic E. coli, including EAEC and EPEC, were detected in the 59 patients. These results indicated that the conditioning therapy as well as other medications used during the transplantation period may eliminate most colonizing bacterial pathogens, with the exception of C. difficile. In another way, viral pathogens were almost unaffected.
Risk of post-transplantation diarrhea due to colonizing pathogens
We next assessed the proportions of patients who developed a diarrheal infection due to their colonized pathogens pre-transplantation. Overall, 45 of the 124 (36.29%) colonized pathogens detected in 39 patients led to post-transplantation diarrhea. In detail, 14 of 19 (73.68%) patients who were initially colonized with norovirus pre-transplantation developed a post-transplantation norovirus infection. Twenty-four of 62 (38.71%) patients colonized with C. difficile developed a diarrheal infection. Only 2 of 21 (9.52%) patients colonized with EPEC and 1 of 7 (14.29%) patients colonized with EAEC developed post-transplantation EPEC and EAEC infections, respectively. In addition, four patients were colonized with ETEC, and three patients were colonized with Giardia lamblia, astrovirus and Vibrio cholerae, but none of them developed post-transplantation diarrhea due to their colonized pathogens (Fig. 3, left column).
We also assessed the proportions of patients with different underlying diseases who developed infectious diarrhea due to their colonized pathogens. Twenty-four of 28 (85.71%) patients with primary immunodeficiency were colonized by at least one GI pathogen pre-transplantation. In 14 patients who developed infectious diarrhea post-transplantation, 11 of them (11/14, 78.57%) had colonization by pathogens before transplantation. Similarly, 41 of 64 (64.06%) patients with hematological malignancies were colonized with GI pathogens, and 19 of 23 (82.60%) patients who developed a diarrheal infection were colonized by pathogens (Fig. 4). On the other hand, patients with aplastic anemia and inherited metabolic disorders were much less frequently colonized with GI pathogens (35.14% and 50.00%, respectively, P < 0.001), and the risk of developing infectious diarrhea was also comparatively lower (28.57% and 37.50%, respectively, P = 0.005) (Fig. 4).
Comparison of FilmArray GI-detected pathogens with clinic-confirmed pathogens detected during diarrhea episodes
In 57 patients who developed infectious diarrhea posttransplantation, 92 pathogens were detected by various methods and confirmed by clinicians. Norovirus and C. difficile were the most frequently detected diarrheal pathogens, present in 26 and 25 patients, respectively. EBV, adenovirus, and Enterococcus faecium were present in 7, 5, and 4 patients, respectively. Other pathogenic microbes, such as Salmonella spp., CMV, and HHV6, were less frequently detected (Table 2, left part).
Discussion
In the present study, we evaluated whether the use of the FilmArray GI panel for the management of pediatric HSCT patients can (1) predict post-transplantation infectious diarrhea caused by pre-transplantation colonization and (2) increase the diagnostic yield for patients with diarrhea episodes. It is notable that 60.13% (95/158) of the HSCT patients were colonized with at least one GI pathogen before conditioning therapy, which is higher than the data reported in adult patients [14].
While most of the previous studies focused on C. difficile colonization [11, 13, 14], we found in our study that patients colonized by norovirus are at the highest risk of developing diarrhea after transplantation, higher than those colonized by C. difficile. Previous studies have shown that hospital transmission of norovirus frequently occurs and causes excess patient morbidity, especially in vulnerable populations [17, 18]. Furthermore, noroviruses are stable in the environment and may be viable for days or longer on various surfaces [19, 20]. Therefore, although norovirus decolonization may be difficult, screening of norovirus before transplantation may have positive implications for infection prevention and control. For patients colonized with norovirus, single room assignment or bedside isolation is recommended to reduce the risk of in-hospital outbreaks [21].
Another dominant colonizing pathogen before transplantation is EPEC, similar to other GI panel studies in immunocompromised patients, which have also reported a surprisingly large percentage of diarrheagenic E. coli pathotypes, including EPEC. Such a high detection rate also raised the concern of false positives and possible cross-reactivity because EPEC detection could be due to low-level colonization or false-positive results, possibly owing to the detection of the eae gene in other microbes, such as Aeromonas spp. [22,23,24]. Whether there is false-positive EPEC detection in our study awaits further investigation. Nonetheless, the risk of diarrhea caused by EPEC as well as EAEC and ETEC colonization was relatively lower in our study than in Kubiak’s report [14]. We speculated that the conditioning therapy as well as other medications used during the transplantation period may eliminate most bacterial pathogens, including diarrheagenic E. coli, thereby reducing the risk of colonization and diarrhea after transplantation.
Studies focusing on post-transplantation diarrhea in adult patients have suggested that non-infectious causes predominated, and fewer patients had an infectious cause for their diarrhea (13%–40%) [1, 25]. Interestingly, recent studies have reported that the cause of GI disease remains undefined in 60%–83% of solid organ transplant recipients [26, 27]. The low detection rate of traditional diagnostic methods, which rely on culture, microscopy or antigen detection techniques, may be one of the reasons for these contradictory conclusions. With the rapid development of new diagnostic technologies (including RT‒qPCR, multiplexed PCR, and mNGS), our understanding of the etiologies of diarrhea has improved [9, 28]. In this study, we comprehensively analyzed the etiologies of post-transplantation diarrhea in pediatric HSCT patients and found that only 50.00% of patients developed diarrhea due to a single factor. For the other 50.00% of patients, diarrheal symptoms were multifactorial, and positive results from microbiological tests did not rule out other clinically important causes (GVHD, medication-induced diarrhea, etc.). This observation is in accordance with recent data showing that the use of multiplexed PCR panels improves the diagnostic accuracy of infectious diarrhea, thus facilitating accurate and effective clinical therapeutic decision-making [4]. However, outcome studies demonstrating the overall clinical benefit of using the GI panel for transplant patients are still lacking and much needed.
Although FilmArray GI panel testing improves the diagnostic yield by almost twofold in our study (55/92, 59.78% vs. 30/92, 32.61%), the current version of the FilmArray GI panel cannot fully meet the pathogen detection needs and may decrease its utility in HSCT patients. For example, CMV and EBV are common causes of infectious diarrhea in HSCT patients, but most U.S. Food and Drug Administration-cleared GI panels (including the FilmArray GI panel) do not target those pathogens. In our study, nine patients developed infectious diarrhea due to CMV or EBV infection, and all of these pathogens were detected by either RT‒qPCR or mNGS. In addition, although adenovirus is included in the FilmArray GI panel menu, detection is limited to two specific serotypes, F40/F41, which represent a minority of clinically relevant adenovirus (ADV) species in HSCT patients [29, 30]. McMillen et al. reported that in cancer patients with ADV infections, ADV species C accounted for 54% of the species compared to only 14% for ADV species F in stool samples [30]. The limited ability to detect ADV in pediatric HSCT patients was also evident in our study, where 4 (80.00%) cases of proven ADV infections were missed by the FilmArray GI panel. For patients at high risk of ADV infections, it is necessary to use other tests, such as antigen detection or RT‒qPCR, to be able to detect all clinically relevant ADV species.
The underlying disease type of HSCT patients can also affect the cause of post-transplantation diarrhea [31, 32]. Compared to patients with aplastic anemia and inherited metabolic disorders, patients with primary immunodeficiency and hematological malignancies have a much higher risk of pre-transplantation pathogen colonization, leading to a higher proportion of post-transplantation infectious diarrhea. As both primary immunodeficiency and hematological malignancy patients were immunocompromised and may have a complex hospitalization history, screening of colonized pathogens in these patients may lead to increased clinical benefits and optimized healthcare resource utilization.
In summary, our data show that more than half of pediatric patients who were admitted for HSCT were colonized with various gastrointestinal pathogens, and more than one-third of these pathogens were associated with posttransplantation diarrhea. In addition, the FilmArray GI panel can increase the detection rate of diarrheal pathogens in pediatric HSCT patients, but the panel needs to be optimized for pathogen species, and further studies assessing its clinical impact and cost-effectiveness in this specific patient population are also needed.
Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Shanghai Children’s Medical Center.
References
Cox GJ, Matsui SM, Lo RS, Hinds M, Bowden RA, Hackman RC, et al. Etiology and outcome of diarrhea after marrow transplantation: a prospective study. Gastroenterology. 1994;107:1398–407.
Arango JI, Restrepo A, Schneider DL, Callander NS, Ochoa-Bayona JL, Restrepo MI, et al. Incidence of clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma. Bone Marrow Transplant. 2006;37:517–21.
Tuncer HH, Rana N, Milani C, Darko A, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012;18:1851–60.
Saullo JL, Polage CR. Tackling infectious diarrhea in hematopoietic cell transplantation. Clin Infect Dis. 2020;71:1701–3.
van Kraaij MG, Dekker AW, Verdonck LF, van Loon AM, Vinje J, Koopmans MP, et al. Infectious gastro-enteritis: an uncommon cause of diarrhoea in adult allogeneic and autologous stem cell transplant recipients. Bone Marrow Transplant. 2000;26:299–303.
Liesman RM, Binnicker MJ. The role of multiplex molecular panels for the diagnosis of gastrointestinal infections in immunocompromised patients. Curr Opin Infect Dis. 2016;29:359–65.
Spina A, Kerr KG, Cormican M, Barbut F, Eigentler A, Zerva L, et al. Spectrum of enteropathogens detected by the FilmArray GI Panel in a multicentre study of community-acquired gastroenteritis. Clin Microbiol Infect. 2015;21:719–28.
Cybulski RJ Jr, Bateman AC, Bourassa L, Bryan A, Beail B, Matsumoto J, et al. Clinical impact of a multiplex gastrointestinal polymerase chain reaction panel in patients with acute gastroenteritis. Clin Infect Dis. 2018;67:1688–96.
Yoo IH, Kang HM, Suh W, Cho H, Yoo IY, Jo SJ, et al. Quality improvements in management of children with acute diarrhea using a multiplex-PCR-based gastrointestinal pathogen panel. Diagnostics (Basel). 2021;11:1175.
Rogers WS, Westblade LF, Soave R, Jenkins SG, van Besien K, Singh HK, et al. Impact of a multiplexed polymerase chain reaction panel on identifying diarrheal pathogens in hematopoietic cell transplant recipients. Clin Infect Dis. 2020;71:1693–700.
Cohen MB, Hawkins JA, Weckbach LS, Staneck JL, Levine MM, Heck JE. Colonization by enteroaggregative Escherichia coli in travelers with and without diarrhea. J Clin Microbiol. 1993;31:351–3.
Crobach MJT, Vernon JJ, Loo VG, Kong LY, Pechine S, Wilcox MH, et al. Understanding Clostridium difficile colonization. Clin Microbiol Rev. 2018;31:e00021–117.
Silva ALO, Marra AR, Martino MDV, Mafra A, Edmond MB, Dos Santos OFP. Identification of Clostridium difficile asymptomatic carriers in a tertiary care hospital. Biomed Res Int. 2017;2017:5450829.
Kubiak J, Davidson E, Soave R, Kodiyanplakkal RP, Robertson A, Besien KV, et al. Colonization with gastrointestinal pathogens prior to hematopoietic cell transplantation and associated clinical implications. Transplant Cell Ther. 2021;27:e1–6.
World Health Organization. The treatment of diarrhoea: a manual for physicians and other senior health workers, 4th rev. Geneva: World Health Organization; 2020.
Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, et al. Bone-marrow transplantation (second of two parts). N Engl J Med. 1975;292:895–902.
Harris JP, Adams NL, Lopman BA, Allen DJ, Adak GK. The development of Web-based surveillance provides new insights into the burden of norovirus outbreaks in hospitals in England. Epidemiol Infect. 2014;142:1590–8.
Wikswo ME, Kambhampati A, Shioda K, Walsh KA, Bowen A, Hall AJ, et al. Outbreaks of acute gastroenteritis transmitted by person-to-person contact, environmental contamination, and unknown modes of transmission—United States, 2009–2013. MMWR Surveill Summ. 2015;64:1–16.
Evans MR, Meldrum R, Lane W, Gardner D, Ribeiro CD, Gallimore CI, et al. An outbreak of viral gastroenteritis following environmental contamination at a concert hall. Epidemiol Infect. 2002;129:355–60.
Nims R, Plavsic M. Inactivation of caliciviruses. Pharmaceuticals (Basel). 2013;6:358–92.
Munier-Marion E, Benet T, Regis C, Lina B, Morfin F, Vanhems P. Hospitalization in double-occupancy rooms and the risk of hospital-acquired influenza: a prospective cohort study. Clin Microbiol Infect. 2016;22:e7–9.
Coste JF, Vuiblet V, Moustapha B, Bouin A, Lavaud S, Toupance O, et al. Microbiological diagnosis of severe diarrhea in kidney transplant recipients by use of multiplex PCR assays. J Clin Microbiol. 2013;51:1841–9.
Alejo-Cancho I, Fernandez Aviles F, Capon A, Rodriguez C, Barrachina J, Salvador P, et al. Evaluation of a multiplex panel for the diagnosis of acute infectious diarrhea in immunocompromised hematologic patients. PLoS One. 2017;12:e0187458.
Chao AW, Bhatti M, DuPont HL, Nataro JP, Carlin LG, Okhuysen PC. Clinical features and molecular epidemiology of diarrheagenic Escherichia coli pathotypes identified by fecal gastrointestinal multiplex nucleic acid amplification in patients with cancer and diarrhea. Diagn Microbiol Infect Dis. 2017;89:235–40.
Yolken RH, Bishop CA, Townsend TR, Bolyard EA, Bartlett J, Santos GW, et al. Infectious gastroenteritis in bone-marrow-transplant recipients. N Engl J Med. 1982;306:1010–2.
Bunnapradist S, Neri L, Wong W, Lentine KL, Burroughs TE, Pinsky BW, et al. Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality. Am J Kidney Dis. 2008;51:478–86.
Echenique IA, Penugonda S, Stosor V, Ison MG, Angarone MP. Diagnostic yields in solid organ transplant recipients admitted with diarrhea. Clin Infect Dis. 2015;60:729–37.
Ramakrishnan B, Gopalakrishnan R, Senthur Nambi P, Durairajan SK, Madhumitha R, Tarigopula A, et al. Utility of multiplex polymerase chain reaction (PCR) in diarrhea—an Indian perspective. Indian J Gastroenterol. 2018;37:402–9.
Feghoul L, Chevret S, Cuinet A, Dalle JH, Ouachee M, Yacouben K, et al. Adenovirus infection and disease in paediatric haematopoietic stem cell transplant patients: clues for antiviral preemptive treatment. Clin Microbiol Infect. 2015;21:701–9.
McMillen T, Lee YJ, Kamboj M, Babady NE. Limited diagnostic value of a multiplexed gastrointestinal pathogen panel for the detection of adenovirus infection in an oncology patient population. J Clin Virol. 2017;94:37–41.
Wang M, Yuan Q, Deng PF, Fei Y, Zhang H, Zhou F, et al. Measles, mumps, and rubella revaccination in children after completion of chemotherapy and hematopoietic stem cell transplantation: a single-center prospective efficacy and safety analysis. World J Pediatr. 2023;19:1062–70.
Luo YH, Yang J, Wei A, Zhu GH, Wang B, Zhang R, et al. Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein–Barr virus infection: a retrospective analysis of a single center. World J Pediatr. 2021;17:626–36.
Acknowledgements
Thanks to all the participants for their involvement in the study.
Funding
This study was supported by Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics (20dz2260900), Shanghai Key Laboratory of Emergency Prevention Diagnosis and Treatment of Respiratory Infectious Diseases (20dz2261100), Natural Science Foundation of Shanghai (22ZR1440300 to TY), National Natural Science Foundation of China (81971890 to MX), Science and Technology Development Fund of Shanghai Pudong New Area (PKJ2020-Y01 to TY, PKJ2020-Y04), Scientific and Technology Commission of Shanghai Municipality (20Y11903600 to MX), Shanghai Municipal Health Commission (2022XD054 to MX), and Shanghai Municipal Education Commission (22SG13 to MX).
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TY, LCJ and ZBH contributed equally to this study. TY contributed to conceptualization of the study, data curation, formal analysis, funding acquisition, investigation, validation, and visualization. LCJ contributed to data curation, formal analysis, investigation, resources, and validation. ZBH contributed to data curation and investigation. SXY contributed to investigation. ZRK contributed to investigation and validation. MBY contributed to data curation and validation. SN and LCY contributed to resources. WJM contributed to investigation and resources. XYJ contributed to methodology and software. XL contributed to formal analysis, methodology and software. CJ contributed to conceptualization of the study, project administration, and supervision. MX contributed to conceptualization of the study, formal analysis, funding acquisition, project administration, supervision, and visualization. The first draft of the manuscript was written by TY and MX, and all authors commented on previous versions of the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Ethical approval
The study was approved by the Institutional Review Board and the Ethics Committee of Shanghai Children’s Medical Center (SCMCIRB-K2018109), and written informed consent was obtained from each patient and/or their parents.
Conflict of interest
No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Nan Shen is a member of the Editorial Board for World Journal of Pediatrics. The paper was handled by the other Editor and has undergone rigorous peer review process. Nan Shen was not involved in the journal's review of, or decisions related to, this manuscript. Yi-Jun Xia is an employee of BioMérieux. He was involved in the technical support and data analysis. BioMérieux (Shanghai) Company has no conflict of interest with this study.
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Tao, Y., Luo, CJ., Zhang, BH. et al. Diagnostic performance of a multiplexed gastrointestinal PCR panel for identifying diarrheal pathogens in children undergoing hematopoietic stem cell transplant. World J Pediatr (2024). https://doi.org/10.1007/s12519-023-00776-w
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DOI: https://doi.org/10.1007/s12519-023-00776-w