Over half of the patients hospitalized for HCT at our institution developed diarrhea and submitted stool specimens for culture. Nevertheless, only 4 out of 947 bacterial stool cultures were positive. The total yield for entropathogenic stool cultures in our cohort was 0.42% (0.5% and 0.3% among autologous and allogeneic HCT patients, respectively) with the number of stools-needed-to-test to diagnose one case of bacterial (other than CD) infectious diarrhea of 237. Despite the fact that all isolates were Campylobacter spp., they do not represent a nosocomial outbreak since they were diagnosed in different years. The extremely low number of subjects with positive stool cultures in our cohort and lack of specific symptoms did not allow for a comparison analysis between patients with positive and negative stool cultures.
Our results support previous findings of high rates (40–50%) of diarrheal morbidity , yet with very low yield of bacterial (non-CD) stool cultures among patients undergoing HCT, as shown in Table 4 [8,9,10,11].
There are no explicit guidelines for the diagnostic evaluation of diarrhea in patients undergoing HCT outside the general guidelines for oncological patients. The 2017 guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) state that infection-related diarrhea due to enteric pathogens is a rare event (0–2.8%) among patients with cancer in general, advocating testing for these pathogens only in fecal samples taken within 72 h of hospital admission from symptomatic patients , by that adopting the “3-day rule” policy [5, 6]. On the basis of our local data, 77% of the patients would have been exempted from the “3-day rule” as they were neutropenic at the time of diarrhea, yet without improving the yield of stool culture sampling. We advocate not to repeat stool culture testing at the same diarrheal episode, since in our experience, all positive cultures were already identified in the initial stool culture performed. This is in line with a prior study demonstrating no excess yield with repetitive stool culture testing of the same patient with diarrheal episode during HCT admission .
Campylobacter is a leading cause of foodborne gastroenteritis worldwide . It was not surprising to find Campylobacter spp. as the main—and in our cohort the only—enteric pathogen isolated from stool specimens, since the majority of our patients (including the four patients with positive stool samples) were treated with ciprofloxacin prophylaxis during HCT  and campylobacter is notorious for its high rate of resistance to ciprofloxacin in Israel, as well as in other parts of the world .
Although hematological malignancies and immunosuppression are predisposing factors for campylobacter bacteremia [15, 16], none of our patients developed this complication. Of note, trials delineating campylobacter bacteremia in immunosuppressed patients found prognosis to be generally favorable regardless of appropriateness of antibiotic therapy [15, 16]. Boyle et al. reported 12 positive bacterial stool cultures out of 4069 collected among HCT recipients within 1 year of transplantation . None of the patients developed shock or was transferred to an intensive care unit and no attributable mortality was reported.
In contrast to infectious diarrhea due to enteropathogenic bacteria, Clostridioides difficile infection (CDI) is 10 times more commonly diagnosed among HCT patients with diarrheal illness [9, 18]. In two small prospective studies, diarrhea was very frequent, evident in over half of HCT recipients, with CDI identified in approximately 5% of patients [10, 19]. We chose not to assess its frequency in the present study, since data regarding CDI among HCT patients is more solid.
The current study has several limitations. Firstly, this is a retrospective, single-center study. Secondly, usage of quinolone prophylaxis in most of our patients may limit generalization of our results. Lastly, the low number of positive stool cultures in our cohort precluded us from comparing characteristics of patients with positive and negative stool cultures in order to illuminate characteristics that may increase the yield of stool culture testing. However, to the best of our knowledge, and as portrayed in Table 4, this is the largest study assessing the yield of bacterial stool cultures during patients’ admission for HCT.
In addition, as applies to all transplant centers in Israel, stool samples were not tested by PCR assays for GI pathogens. It has been suggested that the “3 day rule” does not apply when using PCR of stool samples; however, this stemmed mainly from the test’s ability to identify non-bacterial pathogens . Rogers et al. replaced conventional stool testing with a multiplexed PCR assay in HCT recipients. They identified infectious etiologies of diarrhea in a higher proportion of cases; however, they were unable to evaluate the impact of the GI PCR assay on overall antibiotic utilization or time to initiation of appropriate therapy for a diarrheal infection since many patients received antibiotics for reasons other than the treatment of infectious diarrhea. Most common pathogens identified were norovirus and Enteropathogenic Escherichia coli (EPEC) . Since EPEC may be part of an asymptomatic carriage state and its pathogenic role is unclear , it seems that identification of viral pathogens or EPEC is irrelevant.
Indeed, we had sporadic stool samples tested by PCR assay with no management impact on patients’ care. Thus we believe that although PCR stool testing is more sensitive than bacterial stool cultures in identifying GI pathogens, in most instances, stool PCR and stool cultures obtained from patients beyond 3 days of admission will be of low value and will not change patients’ treatment.