Key words : Children, Hospitalization, Intensive care unit, Mortality, Posttransplant complications

Introduction

Pediatric patients constitute 7% to 8% of all liver transplant recipients, with many being under 2 years old.¹ The success rate of liver transplant has been progressively increasing, particularly among young patients; overall survival rates for pediatric liver transplant recipients have been reported as 94% after 1 year and 89% after 5 years.^1-4

Nearly half of transplant recipients visit the emergency department within 2 years after transplant and one-fifth within 1 month.^1,5 Many of these visits do not necessitate hospitalization; however, challenges remain regarding distinguishing between minor illnesses and life-threatening complications or rare diseases in liver transplant recipients due to their diverse therapeutic regimens affecting multiple organ systems and causing immunosuppression.^1,5 Most visits to the pediatric emergency department (PED) that result in hospital admission during the early posttransplant period are either because of infection or rejection, compromising about one-third of liver transplant patients.¹ Vascular or biliary complications are also commonly observed during the early posttransplant period but can occur at any phase after transplant.¹ Later complications lead to symptoms such as fever, jaundice, abdominal pain, or vomiting, which result in presentation to emergency departments. Long-term complications are usually related to graft problems (late rejection, recurrence of primary disease), infections, and malignancies (especially posttransplant lymphoproliferative disease).^1,6 Gastrointestinal, renal, cardiovascular, and bone-related problems may also arise in the long term because of transplant or immunosuppressive medications.^1,6

Here, our main objective was to describe the clinical features of liver transplant patients admitted to a PED and to identify risk factors that may necessitate admission to a pediatric intensive care unit (PICU).

Materials and Methods

This study was designed as a retrospective cohort study. For the study group, we included pediatric liver transplant patients who visited the PED of Baskent University Hospital between January 1, 2023, and December 31, 2023. Patients with missing or incomplete information in hospital records and those who underwent transplant at another center were excluded. Pretransplant visits were also excluded. The study protocol was approved by the Baskent University Ethics Committee and carried out in accordance with the Declaration of Helsinki.

Epidemiological data of the patients, the main diagnosis leading to transplant, date of transplant, posttransplant day of presentation to PED, main presenting complaint to PED, results of laboratory and imaging studies in PED, hospitalization status, and final diagnosis of patients were recorded. To identify risk factors for severe presentation, we compared clinical and laboratory features of patients admitted to the PICU with those who were not admitted.

Statistical analyses
We used SPSS version 25 for statistical analyses. Descriptive statistics are presented as percentages and frequencies for categorical variables, mean and standard deviation for normally distributed continuous variables, and median with minimum and maximum for nonnormally distributed continuous variables. We assessed the normality of distribution with the Kolmogorov-Smirnov test. We assessed equality of variances with the Levene test. The chi-square test was used to compare categorical variables, and independent sample t test was used to compare continuous variables. P<.05 was considered statistically significant for all tests.

Results

In 2023, we identified 33 liver transplant patients who were admitted to the PED 108 times. Among these, 46.3% were girls and median age was 8 years (range, 1-17 years). The most common underlying diseases leading to transplant were progressive familial intrahepatic cholestasis (5 patients, 15%), Alagille syndrome (4 patients, 12%), and biliary atresia (4 patients, 12%). Six patients (18%) underwent liver transplant because of metabolic diseases (propionic acidemia, tyrosinemia, citrullinemia, urea cycle disorder). Only 2 patients underwent transplant due to acute liver failure, with 1 due to fulminant hepatitis A infection and 1 due to toxic hepatitis (Figure 1).

The median posttransplant day at the time of PED visit was 622 days (range, 10-6189 days). Thirteen of the total visits (12%) occurred in the early posttransplant period (days 0-90) (Figure 2). The most common presenting symptoms were vomiting (48%), fever (46%), rhinorrhea, and cough (34%). The median white blood cell count of patients was 9.52 ×103/µL (680-55.90 × 103/µL), and the median C-reactive protein level was 33.5 mg/L (2-371.2 mg/L). The median alanine aminotransferase level was 34 U/L (11-585 U/L), the median aspartate aminotransferase level was 50 U/L (18-332 U/L), the median gamma-glutamyl transferase was 67 U/L (7-1049 U/L), and median total bilirubin was 1.1 mg/dL (0.2-39.5 mg/dL) (Table 1). The most prevalent electrolyte disturbance was hyponatremia, with a median sodium level of 136 mEq/L (117-142 mEq/L). Of 109 samples, 20 showed sodium levels in the mild hyponatremic range (18.3%), and 7 were moderately hyponatremic (6.4%).

Seventy-three patients (67%) underwent radiological tests, with anterolateral chest radiography being the most common (48%). Blood culture was taken from 5 patients (4.6%) in PED.

Among total visits, 54 (50%) were discharges. Forty-nine visits (45.4%) resulted in hospitalization in the transplant ward of our hospital, and 5 visits (4.6%) resulted in PICU admission; 2 of these patients (1.8%) died.

The most common final diagnoses were acute gastroenteritis in 23 patients (21.2%), upper respiratory tract infections in 23 patients (21.2%), and lower respiratory tract infections in 13 patients (12%). Cholangitis was diagnosed in 7 patients (6.5%), intra-abdominal infection in 6 patients (5.6%), and sepsis in 5 patients (4.6%). Six patients (5.6%) were hospitalized because of surgical problems (biliary leak, obstruction in the biliary system or anastomosis, or ileus) (Table 2).

One patient who had chronic graft rejection visited the PED 3 times during the study period with symptoms of encephalopathy. This patient eventually underwent a successful second transplant.

Another patient who presented to PED with fever and elevated transaminases was diagnosed with the acute graft rejection and was successfully treated with immunosuppressive treatment without graft loss. Two other patients who visited PED with complaints of chronic diarrhea and inguinal lymphadenopathy were diagnosed with posttransplant lymphoproliferative disease. Four patients had posttransplant portal hypertension.

Three patients visited the PED for gastrointestinal bleeding:1 for variceal bleeding, 1 for bleeding from a Dieulafoy lesion, and 1 for severe colitis, which led to severe sepsis and death at day 151 posttransplant. The other patient developed severe lower respiratory tract infection and sepsis due to neutropenia, which led to death at day 136 posttransplant. Seizures (2 patients, 1.8%) and sepsis (5 patients, 4.6%) were significantly correlated with PICU admission (P < .001).

The day posttransplant until presentation to PED occurred earlier in patients admitted to PICU compared with those not admitted to PICU (518 ± 324 days for PICU patients and 1498 ± 1658 days for non-PICU patients; P<.001).

Discussion

Our study contributed to the limited body of literature describing the general characteristics of pediatric patients who visit the PED after liver transplant. Among the visits in our patient sample, we found that, although nearly half of these visits were not associated with serious conditions and could be managed on an outpatient basis, a few resulted in PICU admission and mortality, particularly when related to infectious and neurological complications. One of the main findings of our study was the importance of the length of the posttransplant period on the risk of PICU admission. Admission to the PED after a short period posttransplant was significantly associated with increased risk of hospitalization in the PICU.

Several factors may have contributed to our finding. First, postoperative complications, especially those related to vascular or biliary tracts, are more common in the early postoperative period, as shown previously.^1,7 However, the incidence of these complications was low in our study group (5.6%), and none of the patients with these complications were admitted to the PICU. More importantly, sepsis and graft rejection are the 2 most significant risks, especially in the early transplant period.^1,8 One of our patients was diagnosed with acute rejection during this time period but did not require PICU admission and was successfully treated with immunosuppressives.

The most critical clinical situations resulting in PICU admission among our patient sample were sepsis and status epilepticus due to posterior reversible encephalopathy, which were early complications in our study cohort. Two mortalities in our study resulted from serious infections that led to multiorgan failure. Therefore, acute complications after transplant, especially those related to infections, can likely result in the most serious clinical presentations in liver transplant patients. This finding is consistent with the literature; according to data from the SPLIT registry, the death rate of liver transplant patients is nearly 12%, with half of these deaths attributed to infections, whereas only 5% are from malignancies and 4% from rejection, with similar ratios for medium-term outcomes.^3,9,10 Infections are commonly seen in transplant recipients. More than half of patients have some kind of infection, especially within the first year posttransplant, and the risk increases after immunosuppressive switch; these infections are directly related to mortality, disease severity, and other morbidities.^11-13 Cholangitis has been shown to be a frequent cause of bacterial infection after liver transplant, in the literature and in our study group.¹¹

Another important aspect of posttransplant visits to the PED among liver transplant recipients is the presence of neurological complications. Neurological complications are frequently observed (8%-46%) among liver transplant patients, resulting in high morbidity and mortality, especially in children, with seizures being the most prevalent of these complications.^14-17 The underlying cause may not always be obvious, but the effects of immunosuppressive medications, metabolic and electrolyte disturbances, infections, and strokes seem to play a role.^15,16 Several studies in the literature have shown that rate of survival is decreased in patients with neurological complications, and our results are consistent with this finding.^15,16 Seizures were one of the main risk factors for critical presentations of transplant patients resulting in PICU admission in our study. One patient in our cohort visited the PED for seizures and was found to have posterior reversible leukoencephalopathy, which is a common etiology of seizures for transplant patients, usually related to immunosuppressive regimens.^15,18 The other patient had seizures due to hypoglycemia and sepsis.

Regarding infections and neurological complications, the balance of immune suppression is crucial in controlling acute and serious transplant complications. Inadequate immune suppression can lead to graft rejection, especially in the early phases, whereas intense immunosuppressive regimens could lead to serious infections and complications, including seizures. Therefore, strict control of immunosuppressive regimens is crucial.^6,8

Age seems to be an important risk factor for early and late transplant complications⁶; however, in our study, age did not affect PICU admission status.

Optimization of laboratory studies in transplant patients is challenging; however, we believe that laboratory tests provide valuable information, especially in the early transplant period.¹⁹ Hyponatremia is related to increased mortality, increased aminotransferase and bilirubin levels can guide determination of graft-related problems (graft rejection, cholangitis), and increased acute phase reactants can be beneficial to diagnose infections quickly and promptly in patients with critical complications.^11,20 Although the difference did not reach clinical significance as the groups were not homogeneously distributed, levels of aminotransferases and acute phase reactants were higher and sodium levels were lower in patients admitted to the PICU in our study group. Nevertheless, we still believe that laboratory values are important clinical parameters for diagnosis of patients with critical complications. Blood cultures are also valuable laboratory parameters, although the yield has been low in the literature.²¹

More than half of the PED visits in our study group (60.5%) occurred in the long term after transplant (>1 year). Infections pose a significant clinical risk even in this period in transplant patients; however, the incidence of serious infections decreases as the intensity of immunosuppressive treatment is lessened.¹ Most visits to the PED among our patients were because of infectious etiologies; however, most infections did not pose a serious risk and could be treated on an outpatient basis. Only 1 patient was admitted with a diagnosis of sepsis in this period.

Posttransplant lymphoproliferative disorder was the most common serious long-term complication in our study group. This disorder is responsible for most posttransplant de novo cancers in transplant patients with uncontrolled proliferation of lymphocytes, especially in patients with positive tests for Epstein-Barr virus, which was the case in both of our patients.^1,8,22-24 Immunosuppressive regimens, especially calcineurin inhibitors, are thought to play a role in development of posttransplant lymphoproliferative disorder; the disorder can be treated by reducing the immunosuppressive regimen or adding rituximab, which was also done in our patients.^8,23,24 Other long-term complications include cardiovascular and gastrointestinal complications.¹ Three patients visited the PED because of gastrointestinal bleeding, and 1 patient visited the PED because of abdominal pain, which was eventually diagnosed as gastritis. None of the patients had cardiovascular or diabetic complications of liver transplant.

The main limitation of our study was its retrospective nature. We could not obtain detailed information related to the general appearance and pediatric assessment of patients from hospital records, which would have provided valuable information about the severity of the clinical situation of patients at the time of PED visit. Second, the heterogeneous nature of the study group created difficulties in the interpretation of results. Similarly, the small number of patients admitted to the PICU and the even smaller mortality rate also created difficulties in interpretation. Larger prospective studies would provide more detailed data on this subject.

Conclusions

The most common diagnoses among our pediatric liver transplant patients who presented to the PED were upper respiratory and gastrointestinal infections. Serious complications after transplant were also observed, especially in the early transplant period, mainly as sepsis and seizures, but not frequently. Nevertheless, physicians caring for liver transplant patients in PEDs should be aware of serious complications that may occur in these patients and should closely monitor them, especially during the early transplant period when intensive immunosuppressive treatment regimens are used.

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