In Brief Objective: To examine the outcome of technical variant liver transplant techniques relative to whole organ liver transplantation in pediatric liver transplant recipients. Background: Technical variant liver transplant techniques comprising split, reduced, and live-donor liver transplantation evolved to address the need for timely and size appropriate grafts for pediatric recipients. Methods: Analysis of data from the Studies of Pediatric Liver Transplantation (SPLIT) registry, a multicenter database of 44 North American pediatric liver transplant programs. The outcome (morbidity and mortality) of each of the technical variants were compared with that of whole organ recipients. Results: Data were available on 2192 transplant recipients (1183 whole, 261 split, 388 reduced, and 360 live donor). Recipients of all technical variant graft type were significantly younger than whole organ recipients, but on average spent 2.3 months less on the waiting list. Thirty-day post-transplant morbidity was increased for each type of technical variant relative to whole organ (45.1% whole, 66.7% split, 65.5% reduced, 51.9% live-donor). Biliary complications (30 day: 7.5% whole, 18.8% split, 16% reduced, 17.5% live-donor) and portal vein thrombosis (30 day: 3.6% whole, 8% split, 8% reduced, 7.5% live-donor) were more common in all technical variant types. Graft type was an independent predictor of graft loss (death or retransplantation) in a multivariate analysis. Split and reduced (relative risk = 1.74 and 1.77, respectively) grafts had a worse outcome when compared with whole organ recipients. Conclusions: Technical variant techniques expand the pediatric donor pool and reduce time from listing to transplant, but they are associated with increased morbidity and mortality. Technical variant liver transplantation comprising reduced, split, and live-donor grafts evolved to address the need for size appropriate organs for pediatric liver recipients. This study will examine the outcome and morbidity of the technical variant techniques relative to whole organ transplants in the Studies of Pediatric Liver Transplantation (SPLIT) database.
The aim of the study was to describe long-term growth postpediatric liver transplantation and to conduct bivariate and multivariate analysis of factors that may predict post-transplantation growth in children who received a liver transplant from January 1999 to December 2008 at the Hospital for Sick Children.A retrospective cohort study was conducted with follow-up of up-to 10 years post-transplantation. Mean height and weight z scores and annual differences in mean z scores were plotted against time after transplantation. A 1-way analysis of variance was conducted. Multivariate and univariate Cox proportional hazards analyses were conducted to determine factors associated with reaching the 50th and 25th percentiles for height.A total of 127 children met eligibility criteria. The mean height z score at time of transplantation was -2.21 which by the second year post-transplantation increased significantly to -0.66 (mean increase of 1.55 standard deviation units). There were no further significant increases in mean height z score from 2 years post-transplantation until the end of follow-up at year 10. In multivariate analysis, height at transplant was the most important predictor of linear growth post-transplantation.Children who underwent liver transplantation had significant catch-up growth in the first 2 years post-transplantation followed by a plateau phase. Increased height z-score at transplantation is the most important predictor of long-term growth.
Abstract: We hypothesized that aspects of the virus–host interaction could be measured to help predict progression to EBV–PTLD. We examined the spectrum of host genes differentially expressed and any relevant clustering in children at risk of EBV lymphoproliferation after organ transplantation. We compared the genes expressed among patients with different levels of viral loads. Gene expression was measured by microarray analysis of RNA from CD19+ B lymphocytes using the Human Genome U133 Plus 2.0 GeneChip. Among 27 samples from 26 transplant recipients, the viral load categories were: low or undetectable loads (LU), n = 14; high or intermediate loads (HI), n = 13. There were seven healthy EBV‐seropositive (P) and ‐seronegative controls (N). Median time of post‐transplantation was 0.5 yr (range 0.1–3.8). We identified 24–54 differentially expressed genes in each of four comparisons of HI vs. P, LU vs. P, HI vs. LU, and P vs. N. We identified patterns of 563 gene expressions, creating five clusters aligned with levels of viral load. PTLD occurred in four of five clusters. In summary, we demonstrated varying degrees of alignment between levels of VL and gene clusters. Analyses for differential expression of genes showed genes that could be implicated in the pathogenesis of EBV–PTLD.
Sirolimus (SRL, rapamycin, Rapamune, Wyeth-Ayerst, Philadelphia, PA) is a recent addition to the immune-suppression protocols for pediatric solid organ transplantation (1–4). SRL blocks signal 3 of T-cell activation and prevents T-cell proliferation by inhibiting the mammalian target of rapamycin (mTOR) (5,6). Common adverse effects of SRL include hyperlipidemia and myelosuppression (7–9), both of which are dose dependent and generally responsive to dose reduction. We describe a pediatric orthotopic liver transplant (OLTx) recipient in whom interstitial granulomatous pneumonitis developed while on SRL. Interstitial pneumonitis associated with SRL treatment has been reported in adults after solid organ transplantation (10–13). However, this is the first report of interstitial granulomatous pneumonitis secondary to SRL in the pediatric OLTx population. CASE REPORT An 8-year-old female who underwent an orthotopic liver transplantation for extrahepatic biliary atresia at one year of age, developed fatigue and decreased appetite. There was no history of fever, gastrointestinal, or respiratory symptoms. Medical history included recurrent Epstein-Barr virus (EBV) hepatitis, and early infectious mononucleosis-like post-transplant lymphoproliferative disease (PTLD) of the tonsils with no other organ involvement. Treatment of PTLD including tonsillectomy, led to its resolution. Because of chronically elevated EBV viral load after treatment (from 100-1000 to >1000 viral genome copies per 106 peripheral blood mononuclear cells (PBMC) by semiquantitative PCR), she remained on PTLD prophylaxis using acyclovir and a low dose of cyclosporine (target trough level 50-100 μg/L). Therapy with SRL (0.12-0.18 mg/kg/day) in conjunction with tapering and then discontinuation of cyclosporine, was started 9 months before admission. Indications for SRL treatment were previous PTLD, calcineurin inhibitor mediated nephrotoxicity (creatinine 65 μmol/L, urea 8.5 mmol/L, and glomerular filtration rate of 44 mls/min/1.73sq.m), and biopsy-proven recurrent acute rejection episodes while on low dose cyclosporine therapy. SRL trough levels were maintained at 8 to 12 ng/ml for the first 5 months and later decreased to 4 to 6 ng/ml due to the development of SRL-induced leukopenia and mouth ulcers. On admission, physical examination and vital signs were normal. Laboratory testing included normal complete blood count, serum electrolytes, liver enzymes, and renal function tests. The trough level of SRL was 5 ng/ml. Despite the lack of respiratory symptoms at the time of presentation, a chest radiograph demonstrated increased bilateral interstitial marking. Computed tomography of the chest showed multiple parenchymal nodular opacities in the lung (Fig. 1). Pulmonary function tests (PFTs) revealed a forced expiratory volume in 1-second (FEV-1) of 91% of predicted normal values. Blood cultures, nasopharyngeal cultures, serologic tests for human herpes virus-6/7, herpes simplex virus-1/2, and varicella-zoster virus were negative. Evaluation for Mycobacterium tuberculosis, including Mantoux testing and repeated gastric aspirates, were negative. Semiquantitative EBV PCR was positive at 100 to 1000 viral genome copies per 106 peripheral blood mononuclear cells, but this value was unchanged compared with previous values. An infectious pneumonia was the initial working diagnosis and empiric treatment was initiated with cefu roxime and azithromycin. Despite antibiotic treatment, the patient developed dyspnea and tachypnea. Repeated radiographic imaging of the chest showed no improvement. An open lung biopsy was performed. Histologic examination of lung tissue revealed two pathologic processes. The first was diffuse pneumonitis with alveolar proteinosis and two well-formed granulomas with multinucleated giant cells (Fig. 2). The second was mucosal lymphoid hyperplasia along the bronchiolo-vascular bundles with positive EBV encoded RNA (EBER) stain and positive anti-CD-20 stain consistent with EBV positive PTLD of the benign lymphoid hyperplasia subtype. EBER stain of the granulomas was negative. Cultures and immunohistologic assessment of lung tissue for bacteria, fungi, Pneumocystis carinii, Mycobacterium tuberculosis, cytomegalovirus, adeno-virus, human herpes virus-6/7, herpes simplex virus-1/2, and varicella-zoster virus were negative.FIG. 1.: Computed tomography scan of the chest revealing diffuse parenchymal abnormalities with multiple bilateral lung parenchymal micronodular opacities. Areas of consolidation or collapse were not detected.FIG. 2.: Histopathologic sections showing a well-formed non-necrotic granuloma containing multi-nucleated giant cells, with no infective agents identifiable (stain, hematoxylin-eosin; original magnification, ×200).The patient was thought to have two concurrent pathologic processes—a drug reaction causing interstitial granulomatous pneumonitis and PTLD. Therefore, SRL was stopped and low-dose tacrolimus (trough level- 3.5-4.5 μg/L) was initiated. In addition, treatment for PTLD, including ganciclovir (10 mg/kg/d) and CytoGam (150 mg/kg/dose every other day) was instituted. Because of increasing dyspnea, hypoxia (blood oxygen saturation of 90% in room air), and deterioration of the FEV-1 to 48% of predicted normal values, additional therapy for PTLD with anti CD-20 monoclonal antibody (Rituximab) and prednisone (3 mg/kg/d) was started. There was a gradual improvement in respiratory distress after these changes in therapy. Four months later, EBV viral load had dropped to 10 to 100 viral genome copies per 106, the FEV-1 was 74% of predicted normal values and a CT scan of the chest showed an improvement in the micronodular pattern. DISCUSSION This is the first reported case of interstitial granulomatous pneumonitis caused by SRL in a child following liver transplantation. The clinical, radiographic, and pathologic findings were consistent with the combination of SRL associated granulomatous pneumonitis and PTLD of the lungs. Currently, SRL is not widely used following liver transplantation. However, small case series report its use for indications including primary immunosuppressive therapy in conjunction with low doses of calcineurin inhibitor (9,14,15); PTLD (1); hepatocellular carcinoma before transplantation (9); calcineurin inhibitor mediated toxicity or treatment failure (1,16,17); renal failure documented before liver transplantation (16); and rescue therapy for chronic rejection (4). The use of SRL in children after liver transplantation is less common than in adults. It is used mainly to treat calcineurin inhibitor toxicity and PTLD (1–4). Therapy with SRL was initiated in our patient because of her history of PTLD, recurrent acute rejection episodes while on cyclosporine treatment, and calcineurin inhibitor mediated nephrotoxicity. Following the introduction of SRL, GFR improved from 44 to 63 mls/min/1.73sq.m in the 4 months after discontinuation of cyclosporine. The patient experienced only one acute rejection episode in 4 months compared with 3 episodes during the same period of time before SRL initiation. On the other hand, despite the potential inhibitory effect of SRL on proliferation of EBV positive B-cells (18), the patient had a recurrence of PTLD. This case emphasizes that the occurrence of new or rare adverse effects following introduction of a new medication is not merely a theoretical risk. In the field of transplantation, such events may occur even more frequently due to ongoing development of new drugs and immunosuppressive protocols. In many cases, unknown adverse events mimic common symptoms and signs, and physicians must consider a drug reaction in the differential diagnosis when confronted with common symptoms and signs amidst an unusual clinical course. A diagnosis of SRL toxicity in our patient with the non-specific symptoms of dyspnea and fatigue was based on the four criteria for confirming the diagnosis of methotrexateinduced pneumonitis described by Henry et al. (19). These criteria include exposure to the drug before the onset of pulmonary symptoms, exclusion of infection or alternative pulmonary disease, histopathology consistent with drug-induced lung pathology, and new or evolving pulmonary infiltrates on chest radiographs. While we are not aware of reports describing PTLD-induced granulomas with diffuse pneumonitis, interstitial pneumonitis with granulomas has been reported in adult patients treated with SRL after solid organ transplantation (10–13). Morelon et al. (10) reported interstitial lymphocytic infiltrates, bronchiolitis obliterans with organizing pneumonia (BOOP), and non-necrotizing granulomas in lung biopsies obtained from two adults with kidney transplantation receiving SRL. The striking similarities between these biopsies and the biopsy in our patient led us to conclude that our patient's condition was at least in part related to SRL toxicity. The mechanism of SRL induced interstitial granulomatous pneumonitis is unknown. Some investigators have suggested that a dose dependent toxicity induces an autoimmune response resulting in interstitial pneumonitis (10). However, in our case the patient trough levels of SRL (4-6 ng/ml) were relatively low, suggesting that the effect may not be dose dependent. Treatment for drug-induced toxicity includes immediate discontinuation of the drug and, in severe or life-threatening cases, consideration of high-dose steroid therapy. In three small case series, SRL withdrawal led to improvement of pneumonitis in some of the patients (10,12,13). However, our patient did not improve after withdrawal of SRL and her respiratory status improved only after the initiation of steroid treatment (3 mg/kg/d) and anti-CD-20 antibody. Although this treatment was intended to target the PTLD, the steroids may have had an adjunctive effect on the SRL-induced pneumonitis. Monitoring of respiratory status by repeated pulmonary function tests is an important tool in the evaluation and follow-up of patients with interstitial pneumonitis (20). The most sensitive indicator of our patient's respiratory status was her PFTs while changes in blood oxygen saturation, physical examination, and radiographic studies were subtle or delayed. PFTs, measured before and during SRL treatment may be a sensitive marker for the development of SRL-induced pneumonitis in the asymptomatic patient. Acknowledgments: The authors thank Dr. Philip Sherman for his critical review of this manuscript.
Liver transplant (LT) decisions in pediatric acute liver failure (PALF) are complex. Three phases of the PALF registry, containing data on 1,144 participants over 15 years, were interrogated to characterize clinical features associated with listing status. A decrease in the cumulative incidence of listing (P < 0.005) and receiving (P < 0.05) LT occurred without an increase in the cumulative incidence of death (P = 0.67). Time to listing was constant and early (1 day; quartiles 1-3 = 0-2; P = 0.88). The most frequent reasons for not listing were "not sick enough" and "medically unsuitable." Participants listed for LT were more likely male, with coma grade scores >0; had higher international normalized ratio, bilirubin, lactate, and venous ammonia; and had lower peripheral lymphocytes and transaminase levels compared to those deemed "not sick enough." Participants listed versus those deemed "medically unsuitable" were older; had higher serum aminotransferase levels, bilirubin, platelets, and albumin; and had lower lactate, venous ammonia, and lymphocyte count. An indeterminate diagnosis was more prevalent in listed participants. Ventilator (23.8%) and vasopressor (9.2%) support occurred in a significant portion of listed participants but less frequently than in those who were not "medically suitable." Removal from the LT list was a rare event. Conclusion: The cumulative incidence of listing for and receiving LT decreased throughout the PALF study without an increase in the cumulative incidence of death. While all participants fulfilled entry criteria for PALF, significant differences were noted between participants listed for LT and those deemed "not sick enough" as well as those who were "medically unsuitable." Having an indeterminate diagnosis and a requirement for cardiopulmonary support appeared to influence decisions toward listing; optimizing listing decisions in PALF may reduce the frequency of LT without increasing the frequency of death.
The aim of the study was to examine the association of corticosteroid exposure and other skeletal risk factors with bone mineral density (BMD) and fractures following pediatric liver transplantation (LT) at a large single center.Lumbar spine BMD, measured using dual-energy x-ray absorptiometry (DXA), was corrected for bone age in 52 ambulatory children ages 4 to 18 years, at least 1 year post-LT. Potential risk factors for skeletal health such as corticosteroid exposure, dietary and lifestyle factors, and growth and fracture occurrence, were related to BMD using univariate and multivariate regression analyses.The prevalence of low BMD (z score <-2) and post-LT fractures was 3 of 52 (5.8%) and 11 of 52 (21%), respectively. Univariate analysis revealed age >10 years at LT and body mass index (BMI) < 85th percentile at time of DXA were significantly associated with BMD (both P = 0.02). BMD did not correlate with corticosteroid dosage in the first year post-LT, the year before DXA or cumulative lifetime exposure. A cholestatic primary LT indication, acute rejection episodes, and fractures post-LT were not associated with BMD. Extracurricular physical activity, vitamin D, and calcium intake were not associated with BMD or fractures. Multivariate linear regression revealed increased time post-LT (P = 0.04) and higher BMI z score at time of DXA (P = 0.02) as the strongest independent variables associated with greater BMD.Neither corticosteroid exposure nor a cholestatic primary indication for LT influenced BMD, which was largely normal in this ambulatory group. Children and adolescents undergoing LT after the age of 10 years and those with low BMI post-LT may be at greatest risk of poor skeletal health later in life, and thus a potential target patient population to benefit from preventive interventions.
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