Immune Suppressive Medications Research Articles

Kidney Transplantation and Gastric Bypass: A Better Control of Comorbidities

The database of patients who underwent laparoscopic gastric bypass at our institution from 2002 to 2008 was reviewed. Five patients with kidney transplants were found. The impact of the laparoscopic gastric bypass on their comorbidities and the grafts and patients' survival were studied. The five patients of the group are between 36 and 66 years old, three men and two women. Preoperative body mass index ranged between 35 and 42 kg/m(2). The first patient was operated on 4 years ago and presented an anastomotic leak at the gastrojejunal anastomosis that healed with medical treatment. The remaining four patients did not present postoperative complications. At the moment of analysis, the five patients were healthy and enjoying a good quality of life. All the patients had dyslipidemia which reached normal levels after surgery. Three of the patients had diabetes and achieved good control after the surgery. Most importantly, the absorption of immune suppressors was not altered; while some of the patients were even able to reduce their doses. Patients with renal terminal renal diseases and those with renal transplants with severe or morbid obesity are a group that can particularly benefit from a gastric bypass. The laparoscopic gastric bypass is feasible in severely or morbidly obese patients with kidney transplantation. The absorption of the immune-suppressive medication is not altered after a gastric bypass.

Spectral Analysis of Platelet Oscillations in Cyclic Thrombocytopenia.

Abstract 4459 IntroductionCyclic thrombocytopenia (CT) is a rare autoimmune condition characterized by predictable oscillations in platelet count levels. Periodic platelet cycles in CT have not been well characterized. MethodsWe studied three patients with wide platelet count fluctuations to identify patterns consistent with CT. Medical charts were reviewed and platelet levels and treatments were abstracted. Platelet counts were plotted over time for each patient. Spectral analyses were completed using the method of Lomb and Scargle to determine if platelet count fluctuations were random or had a stable period of oscillation. Where stable periods were identified (fixed time from peak to peak) the likelihood of those periods being random was calculated using the false-alarm probability.Table 1:Spectral Analysis (LS Periodogram) ResultsPatientAssessment periodPlatelet counts measurements (N)Primary Period (days)Spectral Power at Primary PeriodFalse-Alarm Probability*I10 years18441.916.7p= 0.00001II11 years14239.313.3p= 0.0003III6 years14023.014.2p= .00012** Platelet count fluctuations in Patient III subsequently became random.*the probability that the identified period is random (P<0.01 is significant). ResultsRegular periods of platelet oscillation were identified for each patient (Table 1). Periods varied between 23 and 42 days and were not random. Patient I had a 2-year remission induced by immune suppressive medications during which time the platelet count was normal and stable. Platelet count oscillation amplitudes were 350 ×109/L both at presentation of CT and at relapse. Gradual building and decaying of oscillations were noted at the onset of relapse, and remission, respectively. Patient IIMatching a sine curve to the platelet data demonstrated that platelet nadirs of <20 ×109/L could be predicted to within 4 days for every cycle up to one year in advance. Patient III had typical CT oscillations for 6 years, but thereafter platelet fluctuations became random and no regular period was observed. Treatment with eltrombopag, a thrombopoietin (TPO) mimetic agent for 5 days resulted in a peak platelet count peak in excess of 1200 ×109/L in this patient. ConclusionIn three patients with CT, we identified regular periodic oscillations in platelet counts that were non-random. Some patients have predictable cycles that may allow timed delivery of treatments such as TPO-mimetic agents. These findings may provide insight into the nature of the autoantibody in CT. Disclosures:Arnold:Hoffman-LaRoche: Research Funding; Amgen: Consultancy, Honoraria.

Mindfulness meditation training to reduce symptom distress in transplant patients: rationale, design, and experience with a recycled waitlist.

Solid organ transplant recipients must take immune suppressive medications that have side effects, cause complications, and lead to distressing symptoms that reduce health-related quality of life (QOL). Mindfulness meditation has been shown to reduce these symptoms in other patient populations, and it is unlikely to interfere with the immune suppressive medication regimen. This article describes the design and rationale of a clinical trial to determine whether training in mindfulness meditation can reduce depression, anxiety and insomnia after transplantation, and summarizes baseline characteristics of the participants. Transplant recipients were randomized in equal numbers to one of three arms: a Mindfulness-based Stress Reduction (MBSR) program consisting of 8 weeks of group instruction, home practice and telephone monitoring; a time and attention control Health Education program; or a waitlist arm. After serving 6 months as waitlist controls, these participants were re-randomized to MBSR or Health Education. Evaluations were obtained at baseline (prior to the active interventions), 8 weeks, 6 months, and 1 year (after randomization to MBSR or Health Education only). The primary analysis will compare composite symptom scores between MBSR and Health Education, initially or after serving in the waitlist. Subsequent analyses will compare these two groups on depression, anxiety, and insomnia symptom scales and secondary outcomes of health-related QOL, actigraphy, and health care utilization. A separate analysis, using only data collected before re-randomization, will compare short-term outcomes between the waitlist and active treatment arms. One hundred fifty recipients were randomized and 72% of waitlist participants (31/43) were recycled to an active intervention after 6 months. Patient characteristics were balanced across trial arms after initial and secondary randomizations. Transplant recipients are a very select population. Their adherence to the intervention and willingness to serve as waitlist controls prior to re-randomization may be atypical. Participants were not blinded to treatment and primary outcomes are self-reports. The innovative design used in the trial enabled the waitlist group to directly contribute to the number in the primary analysis of active arms, and to also serve as an internal validation test. The trial may be a useful model for trials involving very small target populations.

Ocular Complications in 2 Cases With Porphyria

We aimed to report our observation regarding the long-term follow-up results of 2 cases with similar ophthalmic manifestations of 2 different porphyrias, congenital erythropoietic porphyria (CEP), and porphyria cutanea tarda (PCT). Both patients presented with ocular pain and photophobia in both eyes. The patient with CEP had a scleral necrosis of 3 mm in diameter at the lateral limbus of the right eye and medial limbus of the left eye, accompanied with cicatricial ectropion and lid swelling OU. The patient with PCT had scleral necrosis in the interpalpebral area nasally, OU. Both patients were followed-up for 4 years. The patients received intensive topical lubrication and topical and oral immune-suppressive medication. They underwent amniotic membrane grafting, when required, and were advised to wear UV glasses. The case with PCT followed a more salient course and remained symptom free until the end of the follow-up period. In contrast, the patient with CEP developed further scleral necrosis, despite the treatment and evisceration surgery were inevitable owing to endophthalmitis unresponsive to the treatment. Ocular complications are rarely reported in porphyrias, and the studies on the long-term follow-up results are fewer. Despite careful follow-up and intensive treatment, scleral necrosis can be progressive and results in the loss of vision or even the loss of eye. Further studies regarding the care of patients with porphyrias are required to more effectively treat these rare ophthalmic conditions.

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update

Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon α2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier “Asian-Pacific consensus statement on the management of chronic hepatitis B” was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.

Current Options for the Treatment of Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelets and bleeding. Platelet autoantibodies result in accelerated platelet destruction by the reticuloendothelial cells in the spleen and liver, overwhelming the compensatory capability of the bone marrow to increase platelet production. The goal of treatment for patients with ITP is to raise the platelet count to high enough levels to prevent bleeding using the least toxic therapy, recognizing the generally benign nature of the illness. Corticosteroids, intravenous immune globulin, and splenectomy remain mainstays of treatment; however, newer therapies including rituximab and the thrombopoietin receptor agonists are remodeling conventional treatment algorithms. Immune suppressant medications and cytotoxic drugs continue to be used in patients with severe and chronic refractory ITP with some success; however, estimates of the effect of these and other treatments are limited by the lack of randomized trials using clinical end points. In this article, treatments for ITP are reviewed with a focus on their mechanism of action and the best available evidence from clinical studies. A move towards early aggressive therapy may alter the natural history of this self-perpetuating illness.

Management of Scalp Toxic Epidermal Necrolysis and Cranial Osteomyelitis With Serratus Anterior Myocutaneous Pedicle Flap: A Case Report

The aim of this report is to describe the management of scalp toxic epidermal necrolysis (TEN) and cranial osteomyelitis complicating malignant glioma therapy. A 21-year-old man developed TEN while being radiated and receiving antineoplastic and anticonvulsant therapies for a malignant intracranial glioma. The strategy used to manage the above situation included withdrawal of the medications causing TEN, meticulous dermatological wound care, resection of residual glioma, debridement of scalp and bone, and reconstruction of the scalp and calvarial defect with a myocutaneous vascularized free flap. The scalp wounds have healed completely in a cosmetically acceptable fashion and the patient remains free of tumor recurrence approximately 18 months after surgery, having completed a course of systemic chemotherapy. TEN may complicate the use of anticonvulsant and antineoplastic medications in malignant glioma patients. Withdrawal of the offending agent and immune suppressant medications, skin care and infection control, tumor resection to diminish steroid use, and reconstruction of scalp and calvarial defects with a vascularized myocutaneous flap facilitate wound healing and permit resumption of antineoplastic therapies.

Cutaneous Kaposiʼs Sarcoma in an HIV-Positive Patient

Cutaneous Kaposiʼs Sarcoma in an HIV-Positive Patient

Mycophenolate mofetil (CellCept) in patients with autoimmune hepatitis

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver of unknown cause. Typically, immune suppressive therapy is used initially for treatment, either in the form of steroids or Azathioprime. In a small proportion of patients, steroids resistance or steroid intolerance develops. When patients are unresponsive to steroids, or develop severe significant side effects to their use, alternative treatments must be used. Mycophenolate mofetil (Cellcept) is a potent immune suppressive medication that is used in a wide variety of autoimmune diseases as well as post solid organ transplantation. Data is emerging to suggest that this medication may be used in selected patients with steroid resistance or steroid intolerance. This data is summarized in this review.

Known and Plausible Modulators of Depressed Immune Functions Following Spinal Cord Injuries

Recent evidence suggests that depression of immune function occurs early after spinal cord injury (SCI) and is maintained thereafter. Deviations from immune function observed in healthy persons with intact neuraxes include natural killer cell number and cytotoxicity, T cell function and activation, macrophage phagocytosis, levels of interleukins (IL)-2 and -6, the soluble IL-2R receptor, and intracellular adhesion molecules. While a single etiology explaining these abnormalities has not been identified, decentralization of the autonomic nervous system is the most likely cause. Otherwise, many persons with SCI, who sustain episodic autonomic overstimulation, are among the most physically deconditioned of all humans, and often select a diet rich in fat and low in protein. All of these are associated with suppressed immune function in persons without SCI. Those with SCI may also be (over)exposed to drugs and medications that suppress immune function, including methylprednisolone administered immediately after traumatic injury. No evidence suggests that the immune profiles of persons with SCI favor disease and illness resistance. As opportunistic infections of the urinary tract, lungs, and skin represent major causes of morbidity for those aging with SCI, attention to, or intervention on, immune suppressive states, traits, behaviors, diets, and medications may represent a means through which host defenses of persons with SCI can be fortified and their illness proclivities reduced.

SIROLIMUS-BASED IMMUNE SUPPRESSION IN LUNG TRANSPLANT RECIPIENTS

385 Most lung transplant recipients are maintained on immune suppressive regimens based on the calcineurin inhibitors (CI), cyclosporine A (CSA) or tacrolimus (FK). In some cases, severe toxic reactions to these agents, including hemolytic-uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and renal insufficiency (RI), make their use problematic. We have treated 6 such pts (2M/4F, ages 17-60 yr) with sirolimus (SRL, rapamycin), a new non-nephrotoxic agent, to allow discontinuation or dose reduction of CI. Transplant types and underlying diseases: 3 HLT (1°PH=1, 2°PH=2) and 3 SLT (COPD=1, α-1 AT=2). Pts with life-threatening toxicity (n=3, Group A) had CI discontinued and were treated with SRL+MMF or AZA+pred. Subjects with chronic RI (n=3, Group B) had CI dose/level reduced by 50% and were treated with CI+SRL+pred. Two Group B subjects discontinued SRL due to side-effects; the remaining 4 subjects have taken SRL for 1-6 months, with current status as follows: (Table)TableLung function remained stable while on SRL. Thrombocytopenia in 2 pts resolved with dose reduction; hyperlipidemia in 2 pts was controlled with dose reduction + HMG-CoA reductase inhibitor. These results indicate that SRL can be used as the primary immune suppressive medication for pts with life-threatening side effects of CI, including HUS and TTP. In addition, SRL+reduced-dose CI can be used for pts with chronic RI, but more pts and longer follow-up will be needed to determine whether renal function will recover.

CD6-Depleted Allogeneic Bone Marrow Transplantation for Acute Leukemia in First Complete Remission

AbstractThe appropriate timing of bone marrow transplantation (BMT) for adults with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) is controversial. Although allogeneic transplantation results in a lower risk of disease recurrence than intensive chemotherapy alone, overall outcome following BMT may not be improved due to the higher incidence of therapy-related fatal complications, frequently as a result of the development of graft-versus-host disease (GVHD). Selective T-cell depletion of donor marrow can reduce the incidence of GVHD and thereby limit transplant-related toxicity. Herein we report the risk of GVHD, incidence of transplant related mortality (TRM), likelihood of disease relapse, and overall survival in adult patients undergoing BMT with CD6 depleted allogeneic marrow for acute leukemia in first remission. Forty-one consecutive allogeneic transplants were performed on patients with acute leukemia and high-risk features (28 AML, 13 ALL) using T12 monoclonal antibody and complement to remove CD6+ T cells from donor marrow. No pre- or posttransplant immune suppressive medications for GVHD prophylaxis were administered. The actuarial estimated risk of grade 2 to 4 acute GVHD was 15% in patients receiving HLA identical grafts. Chronic GVHD developed in five patients. The estimated risk of TRM for patients in first complete remission was 5% at Day +100 and 16% at 2 years. Fatalities attributable to infection with cytomegalovirus or Epstein-Barr virus occurred in only three patients. Estimated probabilities of relapse, overall survival, and event-free survival at 4 years were 25%, 71%, and 63%, respectively. No significant differences in GVHD, TRM, relapse rate, or survival was observed for patients with AML compared with those with ALL. Allogeneic transplantation with CD6 depleted bone marrow is effective in consolidating remissions of high-risk patients with acute leukemia in first remission without excessive toxicity.

Prediction of Graft-Versus-Host Disease by Phenotypic Analysis of Early Immune Reconstitution After CD6-Depleted Allogeneic Bone Marrow Transplantation

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). Because GVHD is frequently refractory to treatment, the early identification of high-risk patients could have significant clinical value. To identify such patients, we examined early immunologic recovery in 136 patients with hematologic malignancies who received anti-T12 (CD6)-purged allogeneic bone marrow over a 9-year period. The majority of patients received marrow from HLA-matched sibling donors after ablation with cyclophosphamide and total body irradiation. No patients received any immune suppressive medications for GVHD prophylaxis. The fraction and absolute numbers of peripheral blood lymphocytes (PBL) expressing the CD3, CD4, CD8, and CD56 surface antigens were determined weekly by immunofluorescence analysis in patients beginning 8 to 14 days (week 2) after marrow infusion. Results in patients who did or did not subsequently develop GVHD post-BMT were compared. Within 2 weeks of marrow infusion, patients who developed grades 2-4 GVHD had significantly higher percentages and absolute numbers of CD8+ T cells and a lower fraction of CD56+ natural killer (NK) cells than individuals who remained free of GVHD. Thirty-five percent of patients whose PBL were greater than 25% CD8+ in the second posttransplant week developed GVHD, compared with only 3% of patients who had < or = 25% CD8+ cells (odds ratio 37.8; 95% confidence interval [CI] 4.1 to 397). A subgroup of patients at very high risk for GVHD could be identified based on the combined frequency of CD8+ T cells and NK cells in blood. Seventy-five percent of patients with greater than 25% CD8+ cells and < or = 45% CD56+ cells during week 2 post-BMT developed GVHD, compared with only 11% of the remaining patients (odds ratio 24.9; 95% CI, 5.3 to 117.0). None of the 23 patients with both less than 25% CD8+ cells and greater than 45% CD56+ cells in the second posttransplant week developed grades 2-4 GVHD. Our findings indicate that CD8+ T cells play an important role in the pathogenesis of GVHD in humans. Analysis of immune reconstitution early after BMT is useful in predicting the onset of GVHD and can help direct the implementation of treatment strategies before the appearance of clinical manifestations. Such interventions may decrease the morbidity and mortality associated with allogeneic BMT and ultimately improve overall survival.

Prediction of graft-versus-host disease by phenotypic analysis of early immune reconstitution after CD6-depleted allogeneic bone marrow transplantation

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). Because GVHD is frequently refractory to treatment, the early identification of high-risk patients could have significant clinical value. To identify such patients, we examined early immunologic recovery in 136 patients with hematologic malignancies who received anti-T12 (CD6)-purged allogeneic bone marrow over a 9-year period. The majority of patients received marrow from HLA-matched sibling donors after ablation with cyclophosphamide and total body irradiation. No patients received any immune suppressive medications for GVHD prophylaxis. The fraction and absolute numbers of peripheral blood lymphocytes (PBL) expressing the CD3, CD4, CD8, and CD56 surface antigens were determined weekly by immunofluorescence analysis in patients beginning 8 to 14 days (week 2) after marrow infusion. Results in patients who did or did not subsequently develop GVHD post-BMT were compared. Within 2 weeks of marrow infusion, patients who developed grades 2–4 GVHD had significantly higher percentages and absolute numbers of CD8+ T cells and a lower fraction of CD56+ natural killer (NK) cells than individuals who remained free of GVHD. Thirty-five percent of patients whose PBL were greater than 25% CD8+ in the second posttransplant week developed GVHD, compared with only 3% of patients who had &lt; or = 25% CD8+ cells (odds ratio 37.8; 95% confidence interval [CI] 4.1 to 397). A subgroup of patients at very high risk for GVHD could be identified based on the combined frequency of CD8+ T cells and NK cells in blood. Seventy-five percent of patients with greater than 25% CD8+ cells and &lt; or = 45% CD56+ cells during week 2 post-BMT developed GVHD, compared with only 11% of the remaining patients (odds ratio 24.9; 95% CI, 5.3 to 117.0). None of the 23 patients with both less than 25% CD8+ cells and greater than 45% CD56+ cells in the second posttransplant week developed grades 2–4 GVHD. Our findings indicate that CD8+ T cells play an important role in the pathogenesis of GVHD in humans. Analysis of immune reconstitution early after BMT is useful in predicting the onset of GVHD and can help direct the implementation of treatment strategies before the appearance of clinical manifestations. Such interventions may decrease the morbidity and mortality associated with allogeneic BMT and ultimately improve overall survival.

Lipoprotein Metabolism in Normal and Uremic Patients

Abnormalities in circulating lipoprotein concentrations are a characteristic finding both in patients with uremia and in patients undergoing dialysis. These patients tend to have elevated triglyceride (TG) concentrations and low concentrations of high-density lipoprotein (HDL) cholesterol. Elevations of low-density lipoprotein (LDL) are not usually observed unless the patients have undergone renal transplantation and are receiving therapy with immune suppressive medications. Hypertriglyceridemia and low HDL may be the consequence of decreased actions of lipoprotein lipase (LPL), the endothelial cell-bound enzyme that degrades circulating lipoprotein triglyceride. A poorly characterized circulating inhibitor to this enzyme is found in uremic plasma. Preliminary data suggest that high-flux dialysis with polysulfone (PS) membranes improves the lipoprotein abnormalities and decreases circulating LPL inhibitors. Whether such therapy will alter the incidence of coronary morbidity and mortality in patients with end-stage renal failure remains to be tested.

Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.

Acute and chronic graft-versus-host disease (GVHD) continues to be the major causes of morbidity and mortality after allogeneic bone marrow transplantation (BMT). In this study, we have evaluated the clinical effects of selective in vitro T-cell depletion of donor allogeneic bone marrow by using a single monoclonal antibody ([MoAb] anti-T12, CD6) and rabbit complement. This antibody recognizes mature T cells, but not other cellular elements such as natural-killer (NK) cells, B cells, and myeloid precursors. From August 1983 to April 1991, 112 consecutive adult patients with hematologic malignancies underwent BMT with bone marrow from HLA-identical sibling donors. Marrow was harvested and depleted of mature T lymphocytes ex vivo by the use of three rounds of incubation with an anti-T12 antibody and rabbit complement. The preparative regimen consisted of cyclophosphamide and fractionated total body irradiation (TBI) in 108 patients. No patients received prophylactic immune suppression post-BMT. Purgation by anti-T12 was used as the only method for the prevention of GVHD. Twenty patients (18%) developed acute GVHD (grade 2 to 4); only eight patients developed chronic GVHD. The incidence of GVHD did not increase significantly with age. Only three of 112 patients (2.7%) exhibited acute graft failure. One patient developed late graft failure that was associated with cytomegalovirus (CMV) infection. Within the subset of 50 patients who had not previously undergone unsuccessful conventional therapy (acute leukemia in first remission or chronic myelogenous leukemia [CML] in stable phase), we estimated by the Kaplan-Meier method that the probability of disease-free survival was 50% at 3 years post-BMT, with a median follow-up of 44 months. The treatment-related mortality rate in this group was only 14% and was independent of patient age. We conclude that selective in vitro T-cell depletion with an anti-T12 monoclonal antibody effectively reduces the incidence of both acute and chronic GVHD after allogeneic BMT without compromising engraftment. Moreover, depletion of CD6-positive cells from donor marrow obviates the need to administer immune suppressive medications to the majority of patients. This approach reduces the morbidity and mortality of allogeneic BMT and permits the BMT of older patients.

Cutaneous lesions of listeriosis in a newborn

Although HIV-infected patients are commonly infected by organisms that require an intact T cell immune system for control or eradication, there are some exceptions. The intracellular pathogen Listeria monocytogenes is one such organism. Listeriosis occurs primarily in neonates, elderly patients, patients on immune suppressive medications, cancer patients, and during pregnancy. However, listeriosis is an uncommon opportunistic infection in HIV-infected patients. We report a case of listeriosis with cutaneous lesions in a neonate born to an HIV-infected woman.