Progressive multifocal leukoencephalopathy after liver transplantation can have favorable or unfavorable outcome

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204 months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3 years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26 months after diagnosis.     

Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study.

STUDY OBJECTIVES: The efficacy of antithymocyte induction therapy in lung transplantation is controversial, and its use varies from center to center. We hypothesized that rabbit antithymocyte globulin (RATG) induction therapy would decrease acute rejection after lung transplantation, and we designed a single-center, randomized, prospective study to test this hypothesis. DESIGN: A total of 44 single or bilateral adult lung transplant recipients were randomly assigned to receive either RATG induction therapy (dosage, 1.5 mg/kg/d for 3 days) at the time of transplantation, along with conventional immunosuppression (cyclosporine, azathioprine, and prednisone), or conventional immunosuppression alone with no induction therapy. RESULTS: Although a similar number of biopsies were performed in each group, the number of patients experiencing biopsy-proven grade II or greater acute rejection was significantly reduced in the group receiving RATG induction therapy (23% incidence), as compared to the patients treated with conventional immunosuppression alone (55% incidence; p = 0.03). In addition, there was a nonsignificant reduction in the incidence of bronchiolitis obliterans syndrome at the conclusion of the study in patients who received RATG induction (20%), as compared to patients in the control group (38%). The incidence of posttransplant infections and malignancies were similar between the two groups. CONCLUSION: Induction therapy with RATG significantly reduces the incidence of acute allograft rejection after lung transplantation.     

Subclinical central nervous system infection with JC virus in patients with AIDS.

Immunocompromised patients, particularly those with AIDS, develop progressive multifocal leukoencephalopathy (PML) due to central nervous system infection with JC virus (JCV). It is unknown whether JCV infection in the central nervous system can occur in the absence of PML symptoms. To address this question, autopsy specimens from patients with AIDS were examined. The brains of a group of patients without AIDS or central nervous system disease were also examined. JCV DNA was detected by the polymerase chain reaction in brain tissue from 4 (31%) of 13 human immunodeficiency virus (HIV)-positive patients. JCV was also detected in 1 elderly HIV-negative patient but not in the 11 other control brains. JCV was not detected in 22 myocardial specimens obtained at autopsy from HIV-negative patients nor 10 peripheral blood specimens from HIV-positive patients. The presence of JCV in brains of patients without clinically evident PML suggests that JCV may be present in the central nervous system without clinical disease.     

A longitudinal molecular surveillance study of human polyomavirus viremia in heart, kidney, liver, and pancreas transplant patients

In this study of 263 heart, kidney, liver, and pancreas transplant patients, BK virus (BKV) and JC virus (JCV) DNAemia were observed most commonly in kidney and/or pancreas transplant patients (26%), although they were also observed, to a lesser extent, in heart (7%) and liver (4%) transplant patients. The majority of episodes of polyomavirus DNAemia were subclinical, although, in some cases, BKV DNAemia was associated with kidney rejection, and JCV DNAemia was accompanied by nonspecific symptoms. Hence, BKV and JCV DNAemia are not uncommon during the first year after kidney, heart, liver, and pancreas transplantation, and they could be associated with certain clinical syndromes in transplant patients.     

A case of immune reconstitution syndrome complicating progressive multifocal leukoencephalopathy after kidney transplant: Clinical,pathological, and radiographic features

Progressive multifocal leukoencephalopathy (PML) is a life‐threatening central nervous system (CNS) disorder, most commonly described in patients infected with the human immunodeficiency virus (HIV). Limited data exist on its natural history and treatment in solid organ transplant (SOT) recipients. A complication of PML is the immune reconstitution inflammatory syndrome (IRIS), which develops after T cell reconstitution and can have severe consequences when it occurs in the CNS. While well described in HIV‐infected individuals, its clinical features, diagnosis, and treatment after SOT are largely unknown. We report a case of a kidney transplant recipient who was diagnosed with PML and developed significant worsening of her symptoms upon reduction of immunosuppression. Thallium SPECT showed avid uptake suggestive of lymphoma, but the diagnosis of PML‐IRIS was ultimately established by brain biopsy. She survived with nearly complete restoration of her functional status after a prolonged steroid taper.     

Concurrent cytomegalovirus glomerulitis and BK polyomavirus‐associated nephropathy in a kidney allograft biopsy

A 58‐year‐old renal transplant recipient underwent biopsy 11 weeks post transplantation for increasing creatinine. The biopsy showed cytomegalovirus (CMV) glomerulitis together with BK polyomavirus (BKPyV)‐associated nephropathy (PVAN). Treatment with intravenous ganciclovir and overall reduction in maintenance immunosuppression resulted in prompt resolution of the CMV glomerulitis, but with persistence of PVAN in a follow‐up biopsy 4 weeks later. Stable creatinine and BKPyV viral clearance were observed at the last clinical visit 15 months post transplantation. This case exemplifies infectious glomerulitis, which requires differentiation from the more common glomerulitis caused by antibody‐mediated allograft rejection. The morphological similarities and differences between BKPyV and CMV infections are discussed.     

Extracorporeal Photochemotherapy: A Treatment for Organ Graft Rejection

Abstract: Extracorporeal photochemotherapy (ECPC) has been investigated experimentally and in clinical conditions in transplant rejection treatment and prevention. Repeated injections of photochemically modified syngeneic alloreactive T cells prior to transplant significantly delay rejection in a mouse skin graft model as well as in a heterotopic heart transplant model in rats. In the latter, we found this effect to be dependent on 3 main parameters, i.e., treatment intensity (number of injections), schedule (injections before and after transplant), and associated immunosuppression (because there is no detectable effect in animals without immunosuppression). In human beings, ECPC was first used for the treatment of acute rejection episode after heart transplantation. At least 2 studies provided evidence that ECPC is as effective as high dose corticosteroids in controlling moderate acute rejections, and several case reports showed that ECPC could be effective in recurrent and/or steroid resistant rejections. ECPC has also been investigated in an open trial to prevent rejection episodes after heart transplantation in patients at high risk of acute rejection because of human leukocyte antigen (HLA) immunization and/or a second or third transplant and found to be successful. In heart transplant recipients at standard risk of rejection episodes, a small scale randomized trial showed a reduction in both rejection episodes and infections in the ECPC treated vs. the standard group. Beyond these studies and other isolated case reports, several large scale randomized trials in heart, lung, and even kidney transplantations (some of them already ongoing), will enable us to define the role of ECPC in the management of transplant recipients.—     

JC virus genotypes in France: molecular epidemiology and potential significance for progressive multifocal leukoencephalopathy

JC virus (JCV) induces progressive multifocal leukoencephalopathy (PML), especially in human immunodeficiency virus (HIV)-infected patients. Although JCV genotypes have primarily been associated with geographic patterns, a distinctive neuropathogenicity was recently attributed to genotype 2. A multicenter study was conducted to describe the distribution of JCV genotypes in France and to investigate correlations between genotypes and PML. Genotypes were determined by sequencing 494 bp in the VP1 capsid gene. Peripheral JCV was studied in 65 urine samples from 43 HIV-infected patients and from 22 control subjects. Genotypes 1, 4, 2, and 3 were detected in 52.3%, 30.8%, 12.3%, and 4.6% of the samples, respectively. In 56 brain or cerebrospinal fluid samples, PML-associated JCV of genotypes 1, 2, 4, and 3 was found in 66%, 19.7%, 8.9%, and 5.4%, respectively. Infection with JCV genotypes 1 or 2 was correlated with PML (odds ratio, 3.29). On the other hand, infection with JCV genotype 4 could represent a lower risk for PML.     

Penicillium marneffei infection in a lung transplant recipient

Penicillium marneffei is a thermally dimorphic fungus that can cause severe opportunistic infections in endemic regions of Southeast Asia, particularly in individuals infected with human immunodeficiency virus‐1, but has rarely been reported in solid organ transplant recipients. Herein, we report the first case, to our knowledge, of P. marneffei infection in a lung transplant recipient, occurring in a 41‐year‐old woman 28 months post lung transplantation, after recent travel to Vietnam. We have reviewed the literature to derive some management principles for this rare infection in this clinical context. The number of P. marneffei infections in transplant recipients may increase, as a result of increasing rates of transplantation and travel to endemic areas.     

JC病毒研究进展

JC病毒为小双链DNA病毒,在人群中广泛感染,只有一种血清型,可分为30多个基因型。JC病毒可垂直传播,也可通过呼吸道、消化道传播。严重免疫抑制患者感染JC病毒后可引起进行性多灶性脑白质病(progressive multifocal leukoen-cephalopathy,PML),而CD4+、CD8+T淋巴细胞对感染后是否发病起关键作用。JC病毒对培养细胞和实验动物有很强的致癌潜能,与人类肿瘤存在一定关联性。对感染者的尿液、脑脊液、血液及病变组织进行JC病毒DNA检测和对活组织进行原位杂交及免疫组化检测等为确定JC病毒感染的主要手段,而抗体检测并非确证存在活动性PML的可靠方法。目前没有针对JC病毒有效的抗病毒药物,应用高效抗反转录病毒治疗来获得免疫重建是治疗HIV/AIDS患者感染JC病毒引起PML最好的方法。     

The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy

A multicenter analysis of 57 consecutive human immunodeficiency virus-positive patients with progressive multifocal leukoencephalopathy (PML) was performed, to identify correlates of longer survival. JC virus (JCV) DNA was quantified in the cerebrospinal fluid (CSF) by polymerase chain reaction. Two months after therapy, 4% of the patients without highly active antiretroviral therapy (HAART) and 26% with HAART showed neurologic improvement or stability (P=.03), and 8% and 57%, respectively, reached undetectable JCV DNA levels in the CSF (P=.04). One-year probability of survival was.04 without HAART and.46 with HAART. HAART and lack of neurologic progression 2 months after diagnosis were independently associated with longer survival. Among HAART-treated patients, a baseline JCV DNA <4.7 log, and reaching undetectable levels after therapy predicted longer survival. Survival of AIDS-related PML is improved by HAART when JCV replication is controlled.     

Detection of human herpesvirus 6 and JC virus in progressive multifocal leukoencephalopathy complicating follicular lymphoma

Progressive multifocal leukoencephalopathy (PML), a demyelinating infectious disease caused by JC virus (JCV), occurs almost exclusively in immunocompromised patients usually with malignant diseases. We report here a Japanese female with follicular lymphoma who subsequently developed PML. In addition to JCV, human herpesvirus 6 (HHV-6) was detected in the affected brain lesions of the patient by polymerase chain reaction and by in situ hybridization. HHV-6, recognized as a neurotropic virus, is known to be reactivated during immunosuppression and can cause fatal complications such as encephalitis/encephalopathy. It is likely that impaired immunity associated with lymphoma and the additional immunosuppression following cytopenia-inducing chemotherapies predisposed the patient to reactivated HHV-6 infection. Although it remains to be clarified whether HHV-6 plays an important role as a co-agent with JCV in causing demyelination of the brain, our observation alerts physicians to the possible association of HHV-6 with the pathogenesis of PML.     

Successful lung transplantation for chronic Mycobacterium abscessus infection in advanced cystic fibrosis,a case series

Pulmonary Mycobacterium abscessus infection in cystic fibrosis (CF) patients is difficult to treat and considered a contra‐indication for lung transplantation in most centers. We present four CF patients with chronic pulmonary M abscessus infection, in whom lung transplantation was performed. Through intensive treatment before transplantation, we achieved control of the infection in all but one patient. After a mean of 16 months of follow up, 3 patients are doing well, without evidence of local or disseminated recurrence. One patient died early post‐transplant due to an unrelated cause. These findings support the possibility of lung transplantation with favorable outcome in CF patients with M abscessus infection.     

Multifocal progressive leukoencephalopathy occurring after refractory anemia and multiple infectious disorders consecutive to severe lymphopenia

Progressive multifocal leukoencephalopathy (PML) is related to central nervous system infection with JC virus (JCV). This leukoencephalopathy occurs in immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS) or lymphoid malignancies. We describe here a patient with myelodysplastic syndrome who developed several life-threatening infections including listeriosis, tuberculosis, and PML. Listeriosis and recurrence of tuberculosis preceded the occurrence of PML. Neurologic features associated with major ataxia, speech disorders, and PML were documented by cranial magnetic resonance imaging showing typical features in the cerebellum and proven by polymerase chain reaction (PCR) detection of JCV DNA in the cerebrospinal fluid. No specific treatment was decided because of progression toward acute myeloid leukemia. In this case, PML occurred with no susceptibility and without immunosuppressive treatment. Our case adds further support to the association between the impairment of T-cell immune responses and myelodysplastic disorders.     

肺移植术后的免疫抑制剂应用进展

肺移植是肺脏疾病终末期的治疗选择,闭塞性细支气管炎、巨细胞病毒感染都是移植后第1年常见的慢性排斥反应。所有的肺移植患者终生服用3种免疫抑制药物,包括钙调神经磷酸酶抑制剂、抗代谢药物及小剂量激素。不同的医疗机构使用的免疫抑制剂的方案存在差异,肺移植使用免疫抑制剂的共识尚未形成。本综述主要探讨肺移植术后诱导和维持免疫抑制治疗药物与方案,为规范治疗提供参考。     

Double lung transplantation in an HIV‐positive patient with Mycobacterium kansasii infection

Good outcomes with kidney and liver transplantation in HIV‐positive patients have led clinicians to recommend lung transplantation in HIV‐positive patients based on extrapolated data. Pre‐transplant mycobacterial infection is associated with an increased risk of developing new infection or aggravating existing infection, though it does not contraindicate transplantation in non‐HIV–infected patients. However, no data exists regarding the outcome of HIV‐positive patients with pre‐transplant mycobacterial infection. We report a case of double lung transplantation in a 50‐year‐old HIV‐positive patient with alpha‐1 antitrypsin deficiency. Prior to transplantation, Mycobacterium kansasii was isolated in one sputum culture and the patient was considered merely colonized as no clinical evidence of pulmonary or disseminated disease was present. The patient successfully underwent a double lung transplantation. Nontuberculous mycobacterial infection was diagnosed histologically on examination of native lungs. Surveillance and watchful waiting were chosen over treatment of the infection. HIV remained under control post‐transplantation with no AIDS‐defining illnesses throughout the follow‐up. A minimal acute rejection that responded to increased corticosteroids was reported. At 12 months post‐transplant, a bronchiolitis obliterans syndrome was diagnosed after a drop in FEV1. No evidence of isolation nor recurrence of nontuberculous mycobacteria was reported post‐transplantation. At 15 months post‐transplant, the patient remained stable with an FEV1 of 30%. The presence of pre‐transplant nontuberculous mycobacterial infection did not translate into recurrence of nontuberculous mycobacterial infection post‐transplant. Whether it contributed to bronchiolitis obliterans syndrome remains unknown.     

Exhaled nitric oxide after lung transplantation: impact of the native lung.

It has already been demonstrated that exhaled nitric oxide (eNO) is increased in lung transplant patients with chronic rejection, although it is not known whether the diseased native lung after single lung transplantation (SLTx) contributes to the increased eNO values. This study aimed to compare the eNO values in stable lung transplant patients (SLTx versus sequential (S)SLTx and heart (H)LTx) and in patients with established chronic rejection. Altogether, 42 LTx patients (25 females, 13 SLTx, 18 SSLTx, 11 HLTx), with a mean follow-up of 1149 days and a mean age of 44.6 yrs at transplantation, were included. Twenty-six patients had no signs of chronic rejection (five SLTx and 21 SSLTx/HLTx). There was no difference in their eNO values (10.2 in SLTx versus 12.2 (parts per billion) ppb in SSLTx/HLTx). Sixteen patients (eight SLTx and eight SSLTx/HLTx) had a chronic rejection (eight bronchiolitis obliterans syndrome (BOS) potential stage, four BOS stage 1, three BOS stage 2 and one BOS stage 3). Their eNOs were 18.1 (SLTx) and 17.0 (SSLTx/HLTx) ppb, respectively, which were significantly different to the stable LTx patients and showed a trend towards significance for SSLTx/HLTx. There was no significant difference in eNO between the patients with chronic rejection who underwent SLTx and those who underwent SSLTx/HLTx. The diseased native lung after single lung transplantation probably does not contribute much to the exhaled nitric oxide values, either in stable lung transplant patients or in lung transplant patients with chronic rejection.     

A messenger at the door: cytomegalovirus retinitis in myeloma patients with progressive disease

Cytomegalovirus (CMV) retinitis is an uncommon manifestation of CMV disease and is a marker of severe and profound immunosuppression in human immunodeficiency virus‐positive patients. Here, we describe 2 cases of CMV retinitis in myeloma patients with progressive disease, following autologous stem cell transplantation and immunomodulatory therapy for myeloma. To our knowledge, this is the first report of CMV retinitis in this patient population. This report illustrates the need for close monitoring of relapsed and refractory myeloma patients for new presentations of opportunistic infections secondary to severe immunosuppression.     

Differential expression of mRNAs for JC virus large and small tumor antigens in brain tissues from progressive multifocal leukoencephalopathy patients with and without AIDS.

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML), the fatal demyelinating infection of oligodendrocytes, in up to 5% of AIDS patients. An intron-differential RNA PCR was developed to study the expression of alternately spliced JCV early mRNAs in brain tissues from PML patients with and without AIDS and in JCV-induced hamster brain tumors. The method utilizes primers that span the large tumor (T) and small tumor (t) antigen introns allowing amplification of specific cDNAs in the presence of contaminating viral genomic DNA. Hybridization with specific junctional probes and DNA sequence analysis confirmed the identity of the PCR products. Sequencing showed that JCV early mRNA is alternatively spliced as previously predicted by analogy to simian virus 40. Large T antigen mRNA was detected in all the brain tissues from PML patients with and without AIDS. The expression of small t antigen mRNA varied depending upon the association of PML with AIDS and upon other unknown factors. Of the 12 PML/AIDS brain tissue samples, 11 (92%) expressed small t antigen mRNA, whereas only 8 of 13 (62%) brain samples from patients with PML alone showed detectable levels of small t antigen mRNA. Human immunodeficiency virus 1 proviral DNA was detected in 10 of 12 PML/AIDS brain samples. The results indicate that alternative splicing of JCV early mRNA is regulated in the human brain and that the production of small t antigen may not be essential for the pathogenesis of PML.     

A rare case of disseminated Mycobacterium avium complex with colitis in a renal transplant recipient

Mycobacterium avium complex (MAC) colitis is a rare complication of immunosuppression in solid organ transplant (SOT) recipients. Here, we describe a case of disseminated MAC infection with colitis following renal transplantation. Despite common pathways of immunosuppression, SOT recipients and human immunodeficiency virus (HIV)‐infected patients differ in their typical presentations of MAC infection. Intestinal infections have been more commonly reported in HIV‐infected patients than in SOT recipients. The explanation for this difference may be related to HIV's targeted effects on the CD4⁺ T‐cell reservoir in gut‐associated lymphoid tissue.