tacrolimus and Neutropenia

We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after > or = 3 days of empirical antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized to receive therapy with ABCD (4 mg/[kg.d]) or amphotericin B (0.8 mg/[kg.d]) for < or = 14 days. A total of 213 patients were enrolled, of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B-treated patients had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients (P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD treatment than with amphotericin B treatment.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Colloids; Cyclosporine; Double-Blind Method; Female; Fever; Humans; Immunosuppressive Agents; Infant; Infusions, Intravenous; Kidney Function Tests; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Pilot Projects; Prospective Studies; Tacrolimus; Treatment Outcome

Topics: Adult; Granulocyte Colony-Stimulating Factor; Humans; Immunoglobulins, Intravenous; Liver Transplantation; Living Donors; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Tacrolimus

We describe the successful pediatric liver transplant for unresectable hepatoblastoma in a 4-year-old male with COVID-19 prior to transplant. The first negative NP swab was documented 1 month after initial diagnosis, when SARS-CoV-2 antibodies were also detected. The patient was actively listed for liver transplant after completing four blocks of a SIOPEL-4 based regimen due to his PRETEXT IV disease which remained unresectable. Following three additional negative NP swabs and resolution of symptoms for 4 weeks, he underwent a whole-organ pediatric liver transplant. COVID-19 positivity determined via NP swab SARS-CoV-2 real-time RT-PCR (Hologic Aptima SARS-CoV-2 RT-PCR assay). IgG and IgM total SARS- CoV-2 antibodies detected by Ortho Clinical Diagnostics VITROS® Immunodiagnostics Products Anti-SARS-CoV-2 Test. Patient received standard prednisone and tacrolimus-based immunosuppression without induction therapy following transplant. Post-transplant course was remarkable for neutropenia and thrombocytopenia, with discharge home on post-transplant day #11. Surveillance tests have remained negative with persistent SARS-CoV-2 IgG antibodies at 6 weeks after transplant. We describe one of the earliest, if not the first case of liver transplant following recent recovery from COVID-19 in a pediatric patient with a lethal malignant liver tumor. A better understanding of how to balance the risk profile of transplant in the setting of COVID-19 with disease progression if transplant is not performed is needed. We followed existing ASTS guidelines to document clearance of the viral infection and resolution of symptoms before transplant. This case highlights that pediatric liver transplantation can be safely performed upon clearance of COVID-19.

Topics: Child, Preschool; COVID-19; COVID-19 Testing; Disease Progression; Hepatoblastoma; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Neutropenia; Prednisone; Tacrolimus; Thrombocytopenia; Treatment Outcome

We sought to determine the occurrence, risk factors, effect of antifungal prophylaxis, and outcomes of invasive fungal infections (IFIs) in patients with acute myeloid leukemia (AML).. We performed a retrospective analysis of all adult patients admitted to the University of Michigan Health System for AML over a 3-year period from 2010 to 2013. We determined comorbidities, hematopoietic cell transplant (HCT) status, antifungal prophylaxis, proven and probable IFI, and outcomes at 12 weeks after initiation of appropriate antifungal therapy.. Of 333 patients in our cohort, 116 of whom had received a HCT, 98 (29%) developed an IFI. Of the 30 (9%) patients who had a proven or probable IFI, 18 had breakthrough infection while on micafungin (n = 5), voriconazole (n = 4), posaconazole (n = 5), or fluconazole (n = 4). Breakthrough IFIs were due to Aspergillus species (n = 11), other molds (n = 4), and Candida species (n = 3). Factors associated with breakthrough IFI were prolonged severe neutropenia (p = .05) and having received tacrolimus (p = .04). Antifungal therapy was successful in 7 of the 18 (39%) patients with breakthrough IFI and 8 of the 12 (67%) patients with non-breakthrough IFI, p = .13. Mortality at 12 weeks was 27%, 5 with breakthrough IFI and 3 with non-breakthrough IFI and was associated with prolonged severe neutropenia, p = .04.. Patients with AML remain at risk for IFI despite the use of several different antifungal agents for prophylaxis. Mortality remains high in patients with AML who develop IFI.

Topics: Adult; Aged; Antifungal Agents; Aspergillus; Candida; Cohort Studies; Female; Humans; Immunosuppressive Agents; Invasive Fungal Infections; Leukemia, Myeloid, Acute; Male; Middle Aged; Mortality; Neutropenia; Retrospective Studies; Risk Factors; Tacrolimus; Tertiary Care Centers

BACKGROUND Renal Transplant recipients are at risk for developing neutropenia from a multitude of causes. The cause is often multifactorial, and reversal of the most common causes/insults is sometimes insufficient. CASE REPORT We present the case of a renal transplant recipient who developed a prolonged course of post-transplant (PTx) neutropenia that resolved after switching from tacrolimus (tac) to cyclosporine (CsA). CONCLUSIONS Transplant recipients with persistent neutropenia, sometimes despite discontinuation of potential myelosuppressive agents like mycophenolic acid (MPA), valganciclovir, and sulfamethoxazole-trimethoprim (SMZ-TMP), and with introduction of granulocyte colony-stimulating factor (G-SF), and ruling out alternative diagnoses, may benefit from changing from tac to CsA.

Topics: Calcineurin Inhibitors; Cyclosporine; Female; Humans; Kidney Transplantation; Middle Aged; Neutropenia; Tacrolimus; Transplant Recipients

Progress in immunosuppression has reduced acute rejection, graft loss and mortality after renal transplantation. Adverse drug reactions are well described in adults but few data are available in children. Our objectives were to analyse the adverse events reported in the first 3 years post-transplantation in children receiving tacrolimus or cyclosporine-based immunosuppression and compare them with the information of the Summary of Product Characteristics.. This retrospective study included all children who underwent a renal transplant at Hospital Robert Debré between 2002 and 2015. Initial immunosuppression was based on induction, calcineurin inhibitor, mycophenolate mofetil and corticosteroids. Adverse events were collected from medical records and coded using the Medical Dictionary for Regulatory Activities and the implications of tacrolimus and cyclosporine analysed. Statistical analyses were performed using SAS 9.4.. One hundred and twenty-five children were included. During the observation period [2.7 years (0.6-4.3)], 105 patients received tacrolimus and 39 received cyclosporine. The incidence rate for gastrointestinal disorders was 0.128 and 0.056 by patient-years of exposure (p < 0.05), under tacrolimus and cyclosporine schedules. For neutropenia, it was 0.064 and 0.014 (p < 0.05). The frequencies of toxic nephropathy and gastrointestinal pain were higher than those in the Summary of Product Characteristics of tacrolimus (> 20%) and cyclosporine (> 10%). Cosmetic events for cyclosporine and neutropenia for tacrolimus were frequently observed (18 and 14.3%, respectively), although uncommon in the Summary of Product Characteristics.. The exposure-adjusted incidence rate of gastrointestinal disorders and neutropenia was higher in children under the tacrolimus schedule. Our findings contribute to the evaluation of the benefit-risk balance of immunosuppressive therapy following paediatric renal transplantation.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Neutropenia; Retrospective Studies; Tacrolimus; Time Factors; Young Adult

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Neutropenia; Prognosis; Tacrolimus

Immune cytopenias are a recognized life-threatening complication following pediatric solid organ transplants (SOT), but treatment responses and overall outcome are not well described. The aim of this study was to evaluate the demographic characteristics, response to treatments, and outcomes of a cohort of patients who developed immune cytopenias following SOT.. In this single center retrospective review, patients with immune cytopenias after SOT were identified by electronic medical record (EMR) search and transplant databases from 1995-2012.. Of 764 SOT patients, 19 (2.4%) developed immune cytopenias. Incidence varied widely by transplant type from 1.2% (renal) to 23.5% (multivisceral). Autoimmune hemolytic anemia (AIHA) was the most common immune cytopenia. Overall median time from transplant to immune cytopenia was 8 m and varied by transplant type from 3 m (liver) to 74 m (heart). Standard therapies for immune cytopenias were often used and ineffective. The most effective therapy for the immune cytopenia was changing immunosuppression from tacrolimus to another agent. Three of 19 patients died; none directly attributed to the immune cytopenia.. Immune cytopenias are not rare after SOT, and patients usually do not respond well to traditional first line therapies. Provided that the risk of organ rejection is otherwise manageable, temporary cessation of tacrolimus could be more widely explored in this challenging clinical context. Pediatr Blood Cancer 2015;62:214-218. © 2014 Wiley Periodicals, Inc.

Topics: Anemia, Hemolytic, Autoimmune; Child; Child, Preschool; Female; Humans; Immunologic Factors; Immunosuppressive Agents; Infant; Male; Neutropenia; Organ Transplantation; Retrospective Studies; Rituximab; Tacrolimus; Thrombocytopenia; Treatment Outcome

Topics: Cardiomyopathy, Dilated; Child, Preschool; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Neutropenia; Neutrophils; Tacrolimus; Treatment Outcome

We report a 4-year-old boy with severe congenital neutropenia (SCN), who was successfully treated with hematopoietic stem cell transplantation (HSCT). The patient had frequently developed bacterial infections since 6 months of age, and showed severe neutropenia below 100/μl at 1 year and 4 months of age. The patient harbored a heterozygous missense mutation in ELANE exon 3 (p.Q73P, g.2253 A>C). This was a novel de novo mutation, and he was thus diagnosed as having SCN. Because of failure to respond to granulocyte colony-stimulating factor treatment and repeated admissions due to bacterial infections, allogeneic HSCT was performed from a serologically matched unrelated donor following the conditioning regimen: fludarabine/melphalan/anti-thymocyte globulin and a low dose of total body irradiation. Tacrolimus and a short course of methotrexate were used for graft-versus-host disease prophylaxis. Engraftment was achieved at day 12, and the patient maintained normal hematopoiesis for over 15 months after HSCT. We concluded that HSCT is a useful treatment for SCN patients, especially those who are at high risk for leukemic transformation. However, a larger number of SCN patients and longer follow-up are necessary to identify appropriate conditioning regimens and long-term prognosis.

Topics: Allografts; Congenital Bone Marrow Failure Syndromes; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Leukocyte Elastase; Male; Methotrexate; Mutation, Missense; Neutropenia; Tacrolimus; Transplantation Conditioning; Treatment Outcome

Tacrolimus has become an important cornerstone in the prevention of rejection after kidney transplantation. However, its use has been complicated by several side effects, including chronic allograft nephropathy, diabetes mellitus, arterial hypertension, and neurotoxicity. Tacrolimus-induced neutropenia is a less recognized, but potentially harmful complication. Three patients with severe neutropenia developing within 3 months after kidney transplantation are described. After having excluded other well known causes, tacrolimus was considered the most probable culprit. Definitive proof of this hypothesis was obtained by discontinuation of tacrolimus and switching to cyclosporine, which led to recovery of white blood cell count in all three patients.

Topics: Cyclosporine; Drug Substitution; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Neutropenia; Severity of Illness Index; Tacrolimus

Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimus-mycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02-1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/microL achieved in a mean of 1.5+/-0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G-CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients.

Topics: Adult; Aged; Bacterial Infections; Drug Therapy, Combination; Female; Graft Rejection; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neutropenia; Retrospective Studies; Risk Factors; Tacrolimus

Hematological complications have been occasionally described after cardiac transplantation. We are reporting a 5-yr-old child who developed sequential severe neutropenia and thrombocytopenia following cardiac transplantation while on tacrolimus-based immune suppression therapy. There was no improvement in blood counts following a change in immune suppression to cyclosporine A. The neutropenia was associated with a maturation arrest in the bone marrow. The occurrence of thrombocytopenia coincided with rising anti-herpes virus 6 IgG titers suggesting a possible contributory role. Neutropenia resolved following treatment with rituximab, and the thrombocytopenia responded to Dapsone therapy eventually. This case points out the potential multifactorial pathogenesis of cytopenias following cardiac transplantation with differing response to various immune suppressive therapies.

Topics: Antibodies, Viral; Child, Preschool; Heart Transplantation; Herpesvirus 6, Human; Humans; Immunosuppressive Agents; Male; Neutropenia; Tacrolimus; Thrombocytopenia

Tacrolimus is a common component of multi-drug immunosuppressive regimens that are used for the prevention of rejection in transplant recipients. Tacrolimus therapy has been associated with anemia after transplantation, and recent clinical evidence in children suggests its association with the development of neutropenia for which an alternative etiology is not apparent. Mechanisms of suspected tacrolimus-related neutropenia have not been previously elucidated. We hypothesized that this variety of neutropenia might be due to a negative effect of tacrolimus on neutrophil production and/or survival.. We designed in vitro studies to determine the dose-dependent effect of tacrolimus on myeloid cell production and/or apoptosis. CD34+ cells and neutrophils isolated from umbilical cord blood of term gestations were cultured with tacrolimus (0-1,000 ng/ml). To evaluate apoptosis, cells cultured for 24 hours were stained with annexin V-fluorescein isothiocyanate (V-FITC) and 7-amino-actinomycin D (7-AAD) and analyzed by flow cytometry. For clonal analysis, CD34+ cells cultured in cytokine-enhanced semi-solid media were scored for their myeloid/erythroid mix colony forming units (CFU-Mix) and myeloid (CFU-GM) progenitor cell contents.. Tacrolimus induced a dose-dependent enhancement of clonogenesis and survival of CD34+ cells at clinically relevant doses. Conversely, tacrolimus had no effect on the survival of mature neutrophils or on the upregulation of CD11b in response to chemotactic stimulation.. In contrast to our initial hypothesis, we observed that tacrolimus at clinically relevant concentrations enhanced clonogenesis of neutrophil progenitors and promoted their survival. Our in vitro studies suggest that tacrolimus alone is unlikely to be a significant factor in the neutropenia observed during immunosuppressive therapy.

Topics: Apoptosis; CD11b Antigen; Dose-Response Relationship, Drug; Fetal Blood; Graft Rejection; Humans; Immunosuppressive Agents; Myelopoiesis; Neutropenia; Neutrophils; Tacrolimus

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated.

Topics: Adolescent; Adult; Child; Child, Preschool; Creatinine; Drug Therapy, Combination; Female; Hepatitis; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Neutropenia; Oral Ulcer; Postoperative Care; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

To define the incidence, course, and etiology of hematologic abnormalities in children on tacrolimus-based immunosuppression, we reviewed records of 106 transplant patients (70 heart, 16 heart and lung, 20 double lung), 0-21 yr of age, who were transplanted at the Children's Hospital of Pittsburgh from 1989 to 1997. Fifty-four of the 106 patients (51%) developed 65 abnormal hematologic episodes (32 anemia, nine neutropenia, nine thrombocytopenia, 15 simultaneous anemia and neutropenia with or without thrombocytopenia). Common etiologies included: infections, post-transplant lymphoproliferative disease, and medications. Eleven episodes (seven anemia, one neutropenia, and three simultaneous anemia and neutropenia) had unclear etiologies and process of elimination suggested an association with tacrolimus. Interventions included filgrastim (effective in 15 of 15 patients, with resolution of neutropenia in a median of 5 days) and epoetin alfa (effective in five of 16 patients, including four of four patients with anemia possibly related to tacrolimus). Five patients (two with neutropenia and three with simultaneous neutropenia and anemia) were switched to cyclosporin A (CsA); rapid resolution occurred in four of the five patients, suggesting a possible association of the hematologic abnormalities with tacrolimus. In summary, hematologic abnormalities are common in children on tacrolimus-based immunosuppression. Most of these hematologic abnormalities are caused by common etiologies; however, a sub-population exists where tacrolimus may be the etiologic agent. Anemia and neutropenia respond to treatment with epoetin alfa and filgrastim. After thorough investigation, a trial switch to CsA may be warranted.

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Heart Transplantation; Heart-Lung Transplantation; Hematologic Diseases; Humans; Immunosuppressive Agents; Infant; Lung Transplantation; Male; Neutropenia; Recombinant Proteins; Retrospective Studies; Tacrolimus; Thrombocytopenia

Bacterial infections complicate the course of up to 80% of pediatric liver transplant recipients, and in some cases, neutropenia, surgical complications and/or antibiotic resistance prevent successful control of sepsis. The aim of the present study was to evaluate the safety and efficacy of granulocyte macrophage colony stimulating factors (GM-CSF) in treating neutropenia following pediatric orthotopic liver transplantation.. Among a cohort of 430 pediatric orthotopic liver transplantation recipients, 13 children (12 months to 15 years, median 2 years, 10 males) received 15 courses of GM-CSF, 5 microg x kg(-1) x d(-1) subcutaneously, during their post-transplant course. In nine cases, the initial neutrophil count was below 1000/mm3. Ten patients were infected. Three received GM-CSF for severe sepsis without neutropenia. The mean duration of treatment was 16.3 days (range 4-49).. In all but one neutropenic patient the neutrophil count increased above 1500/mm3 and the mean neutrophil count increased from 1392+/-1912/mm3 (range 130-7170, median 640) to 4508+/-2459/mm3 (range 350-9630, median 4390) (p<0.01). Only one neutropenic patient (FK506 related) failed to respond to treatment. No rejection episode was induced by treatment, no side effects were noted, and patients with sepsis were cured.. In these patients, GM-CSF was safe, it achieved a significant increase in neutrophilic count, and was beneficial in patients with severe bacterial infections. This compound may prevent infectious complications in neutropenic patients and may benefit patients with severe sepsis with or without neutropenia.

Topics: Adolescent; Child; Child, Preschool; Graft Rejection; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Incidence; Infant; Leukocyte Count; Liver Transplantation; Neutropenia; Postoperative Complications; Sepsis; Survival Rate; Tacrolimus