Diarrhea is a frequently encounter encountered symptom in LTx recipients, occurring in 51.2% of our cohort. Diarrhea is of particular clinical significance, as it may lead to other serious adverse effects such as graft rejection (possibly from inadequate absorption of antirejection medications), dehydration, malabsorption, and medication non-adherence. In our study, we found that the most frequent cause of diarrhea in LTx recipients was medication-induced diarrhea (97 patients [33.6%]) followed by diarrhea due to CDI (45 patients [15.6%]). These findings correlate with previous studies and our anecdotal experience with LTx recipients: medication-associated side effects and infection are common causes for diarrhea [3, 9]. It can be postulated that the use of immunosuppressive agents and broad-spectrum antibiotics in the immediate post-operative period account for these findings.
Studies among kidney transplant recipients demonstrate that post-transplant diarrhea varies by immunosuppressive regimen, ranging from 9–33% [10]. LTx recipients at our institution are most commonly started on MMF, tacrolimus, and low dose prednisone. MMF has been frequently implicated in post-transplant diarrhea. In a meta-analysis by Knight et. al, a significant increase in the risk of diarrhea was observed with MMF (RR 1.57, CI 1.33–1.86, p < 0.0001) [9]. Our results are consistent with this finding, as MMF use was shown to be the most common cause of medication-induced diarrhea in our cohort. It is proposed that MMF can cause direct drug toxicity and damage by inhibiting replication and repair of intestinal epithelial cells, thus leading to diarrhea [11].
Tacrolimus is also associated with an increased risk of diarrhea. Studies have shown that the incidence of post-transplant diarrhea due to tacrolimus is increased in liver and kidney transplant recipients. Ginsbrug et. al reviewed diarrhea in liver transplant recipients and described the LIS2T trial (Levy et. al), which compared the microemulsion form of cyclosporine with tacrolimus. Notably, the incidence of diarrhea was significantly higher in the tacrolimus group (29% vs. 14%, p < 0.001) compared to cyclosporine. This association was further described in the Symphony study by Ekberg et, al, in which several immunosuppressant agents in renal transplant recipients were evaluated for adverse events. The tacrolimus group was noted to have the highest incidence of diarrhea (27.4 %) [10, 12]. The mechanism of diarrhea in patients receiving calcineurin inhibitors is unknown. However, when evaluating kidney transplant patients, the tacrolimus trough levels were significantly elevated before the onset of diarrheal symptoms [12]. This suggests that tacrolimus itself is toxic to the GI epithelium, thereby leading to diarrhea. Furthermore, tacrolimus may have an effect on intestinal motilin receptors to some degree given its’ macrolide structure [13].
CDI was noted to be the second most common cause of diarrhea in our cohort. The incidence and clinical course are influenced by a variety of factors: patient co-morbidities, concurrent illnesses, and the degree and duration of broad-spectrum antimicrobial exposure [12].
CDI is associated with increased mortality in solid organ transplants, although data is scarce in LTx recipients. Lee et. al performed a retrospective record review of 388 patients which showed that LTx recipients who developed CDI (89 patients [22.9%]) had a higher risk of death, especially when CDI developed within the first 6 months of LTx [14]. Notably, our large cohort study did not show that the development of CDI (45 patients [15.6%]) was associated with an increased risk of mortality in either early or late CDI. Since 2011, our institution has implemented a CDI treatment protocol in all patients with a history of CDI. These patients preemptively received oral vancomycin 125 mg, 4 times daily while on antibiotics and for 7 days thereafter. While this was not the focus of the study nor directly evaluated, this could account for the lower incidence of CDI and therefore, no significant association with mortality observed in our cohort.
Importantly, CDI development was significantly associated with presence of rejection (OR = 2.65, p = 0.003). It is plausible this observation is due to broad-spectrum antibiotics, especially in the setting of a decompensated patient presentation (e.g. a hypoxic LTx patient presenting with infiltrates on chest imaging and ultimately found to be in rejection). LTx recipients receive aggressive antimicrobial and immunosuppressive therapy postoperatively, thereby making them susceptible to infection. The initial broad-spectrum antibiotic use along with immune suppression could lead to heightened risk of CDI development in LTx recipients.
It is interesting to note that among LTx recipients who developed late onset CDI, the mean onset was 400.5 days post-LTx, suggesting that providers must remain vigilant of diarrhea that develops > 1 year after LTx and continue to screen for CDI when deemed clinically appropriate. CDI constitutes a significant proportion of post-LTx diarrhea and therefore requires efforts to control transmission of disease and prompt recognition to facilitate management.
Our study demonstrates that diarrhea is associated with an increased risk of LTx rejection. This can be due to a number of factors. Diarrhea may reduce absorption of anti-rejection medications, either by leading to rapid transit of medications through the GI tract or by direct injury to the small bowel, thereby leading to increased rejection. If frequent dose adjustments are required to alleviate diarrheal symptoms, this may lead to sub-therapeutic immunosuppression levels. Lastly, discontinuation of immunosuppressive medications with trials of other immunosuppressive medications by either patients or clinicians can result in graft dysfunction and rejection. Of note, younger LTx recipients were at increased risk for LTx rejection when compared with their older counterparts. This finding is in keeping with current literature that suggests that increased age is associated with decreased rejection rates. Vadnerkar et. al performed a retrospective review of LTx recipients at their institution. The authors noted that LTx rejection was more common among patients 60–65 years old as compared to those > 65 years old, hypothesizing that age-associated immunosenescence may be responsible for lower rejection rates among older LTx recipients [15]. Diarrhea is not associated with an increased risk of mortality in LTx recipients (Table 2) in our study. We retrospectively analyzed 564 patients who underwent either single or double LTx between January 2011 and February 2019. Due to this, by the time our data was collected, a significant number of patients in this cohort had a shorter follow-up time compared to patients who received LTx in earlier years. At least 40 patients were followed for less than one year. The lack of uniform and longer follow-up time could explain the incongruence in mortality and rejection in our cohort.
Lastly, recipient factors (i.e. age, gender, and indication for transplant) did not influence the development of post-LTx diarrhea in our study, suggesting that post-LTx diarrhea is an independent complication that can be seen in any patient, making post-operative vigilance and preemptive measures important for all post-LTx patients.
This is a large, single-center study evaluating LTx recipients and a common, yet poorly described post-operative complication: diarrhea. Temple University Hospital is a major lung transplant center, allowing for significant data collection and observation. Limitations of our study include bias inherent to retrospective studies. Given the retrospective nature of this study, the onset of diarrhea episodes is estimated, which precludes a Cox analysis of our available data. Variations in diagnostic workups and interventions during the study period may lend to variable patterns and duration of symptoms. Many of our patients travel from far distances for LTx evaluation and thus may have completed GI evaluations outside our institution, leading to additional variation, as some data may not have been captured. Our study could be further strengthened by the addition of information on mean maintenance levels of immunosuppressants before and after diarrhea, longer observation period, all stool and endoscopic testing done outside our institution, antibiotic duration, diarrheal complications leading to surgical intervention, and the hospitalization rate due to diarrheal symptoms. In addition, not all providers documented the proposed etiology of diarrhea, which further limits analysis.
Our study was performed prior to the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. While patients with SARS-CoV-2 often present with respiratory symptoms and fever, GI symptoms have been reported, including diarrhea in up to 50% of patients [16]. In a multi-center study conducted in China, Pan et. al investigated patients presenting with digestive symptoms (103 patients) and found that anorexia (81 patients [78.8%]) and diarrhea (35 patients [34%]) were most commonly reported. At present, little is known about the relationship between SARS-CoV-2 and post-LTx diarrhea but should be explored in future analyses [17].
As seen in other solid organ transplant populations, post-LTx diarrhea is a frequently encountered phenomenon. Our large retrospective review identifies diarrhea occurring in more than half of all LTx recipients, with medication-induced diarrhea representing the most substantial etiology, followed by CDI. Importantly, diarrhea is significantly associated with increased LTx rejection. Perhaps diarrhea interferes with the antirejection therapies, limiting contact time for absorption. It is also reasonable to speculate that these medications are being discontinued due to the diarrheal side effects, leading to rejection. While treatment protocol of diarrhea in in this patient population may not change, recognizing the etiologies of diarrhea in LTx recipients and their prevalence allows for early diagnosis and expedited delivery of appropriate medical management, which is of the uptmost importance for improving quality of life and preventing graft rejection. Additional studies, prospective and multi-center, would be useful to further delineate the implications of diarrhea in LTx recipients.