Pneumocystis carinii pneumonia after renal transplantation

Being immuno-suppressed, renal allograft recipients are at increased risk of contracting various infectious complications. Pneumocystis carinii pneumonia (PCP) is one of the important opportunistic infection causing high morbidity and mortality in these patients. Majority of studies has reported the occurrence of PCP during 6 months to one year after renal transplantation. This communication describes occurrence of PCP in five renal allograft recipients 10 weeks to 72 months after transplantation. In view of elusive presentation, strong clinical and radiological suspicion followed by direct demonstration of the organisms is essential for early diagnosis and prompt treatment. These observations also indicate that PCP is an emerging opportunistic infection in immuno-compromised patients in tropical countries.     

A Pneumocystis jirovecii pneumonia outbreak in a single kidney-transplant center: role of cytomegalovirus co-infection

Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) infection represent possible complications of medical immunosuppression. Between 2005 and 2010, non-human immunodeficiency virus (HIV) PCP patients admitted to a nephrology unit were analyzed for outcome, CMV comorbidity, and patient-to-patient contacts prior to PCP. In contrast to 2002-2004 (no cases) and 2008-2010 (10 cases), a PCP outbreak of 29 kidney-transplant recipients and one patient with anti-glomerular basement membrane disease occurred between 2005 and 2007. None of the patients were on PCP chemoprophylaxis. In four PCP patients, the genotyping data of bronchoalveolar lavage specimen showed an identical Pneumocystis strain. PCP cases had a higher incidence of CMV infection (12 of 30 PCP patients) and CMV disease (four patients) when compared to matched PCP-free controls (p?相似文献   

High risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapy

Cytomegalovirus infection (CMV) in solid organ transplant recipients is a major clinical problem. The aim of this study was to evaluate the incidence of CMV infection and its association with mortality during the first year after transplantation in a large solid organ transplant cohort at the Royal Infirmary of Edinburgh between January 2006 and April 2009. Data including the use of CMV prophylaxis, nature of CMV disease, treatment and deceased date (when appropriate) was collected retrospectively using hospital databases and patient notes for all transplanted patients with detectable CMV viraemia. The outcomes between recipients of kidney and liver transplants in the four CMV donor/recipient serostatus categories (D+R+, D?R?, D+R?, D?R+) were compared. A total of 428 individuals were included. Despite the administration of valganciclovir prophylaxis, CMV disease (syndrome or end‐organ involvement) was diagnosed within the year of transplantation in the D+R?‐group in 31.3% of liver and 19.2% of kidney recipients. All D+R? transplant recipients that received CMV‐prophylaxis presented with late‐onset CMV disease. Furthermore, the rate of CMV disease in the D+R+‐group was markedly higher in renal graft recipients compared to liver recipients (22% vs. 5%). The highest mortality was observed among the D+R+ liver and kidney graft recipients with CMV infection. The high incidence of late‐onset CMV disease in D+R? transplant recipients receiving CMV prophylaxis demonstrates that CMV disease remains an important problem after organ transplantation. Furthermore, the surprisingly high mortality in the D+R+‐transplant patients with CMV viraemia highlights the need for proactive monitoring of this group. J. Med. Virol. 85:893–898, 2013. © 2013 Wiley Periodicals, Inc.     

Clinical Applications of Cytomegalovirus IgG Avidity Testing

Cytomegalovirus (CMV) IgG avidity, defined as the strength with which IgG binds to an antigen, matures gradually following primary infection. Low avidity indicates recent infection (within the prior 3 months), whereas high avidity indicates infection >6 months earlier. In adults, IgG avidity testing is better than CMV IgM testing for identifying primary infection, since IgM persists for many months in some individuals. The key clinical application of CMV IgG avidity testing is to identify primary CMV infection during pregnancy, which is associated with increased risk for intrauterine transmission. A related application is diagnosis of primary CMV infection in children less than 1 year old. In transplantation, avidity testing helps identify the cellular source of CMV IgG in seroconverting solid organ recipients; in seropositive bone marrow recipients, avidity results serve as an indicator of successful engraftment. An unrealized application is assessment of CMV IgM⁺ IgG⁺ organ or blood donors; many are IgM⁺ due to IgM persistence and may thus still qualify as donors. This article provides a review of CMV IgG avidity methodology, as well as clinical applications.     

Going beyond serology for stratifying the risk of CMV infection in transplant recipients

Knowledge of donor and recipient (D/R) cytomegalovirus (CMV) serostatus is critical for risk stratification of CMV infection and disease in transplant recipients, particularly in the solid organ transplantation (SOT) setting. Despite its broad availability and the success of it use, the risk stratification based on the D/R serostatus is not free of limitations since there are a nondepreciable number of patients that are not accurately categorized by this approach. In fact, up to 20% of seropositive SOT recipients, classically considered at intermediate risk, develop episodes of CMV infection and disease after transplantation. Here, we provide an overview of additional donor and recipient factors that may have utility in identifying patients at risk for post‐transplant CMV infection. Specifically, we summarize our current understanding regarding the potential use of use CMV‐specific T‐cell‐mediated immunity, neutralizing antibodies and host genetics that may influence the risk of CMV infection and disease. We provide an overview of the benefits and limitations associated with using these immunological factors in risk stratification and propose specific variables that could be analyzed at the pretransplant evaluation to improve the identification of patients with increased individual susceptibility.     

Simultaneous Monitoring of Cytomegalovirus-Specific Antibody and T-cell levels in Seropositive Heart Transplant Recipients

Purpose

Human cytomegalovirus (CMV) active infection (CMV infection) poses serious risks to CMV-seropositive heart transplant recipients. We evaluated the usefulness of simultaneous assessment of CMV-specific values for parameters of the humoral (antibodies) and cellular (CD4+ and CD8+ T-cells) immune responses in the identification of heart recipients at risk of developing CMV infection after transplantation.

Methods

We prospectively studied 38 CMV-seropositive heart recipients. Anti-CMV antibody titers were assessed using enzyme-linked immunosorbent assays. CD4+ and CD8+ T-cell responses to overlapping peptide pools of the CMV proteins pp65 and immediate early protein-1 (IE1) were evaluated by flow cytometry. Immunological studies were performed before transplantation and at 30?days after transplantation. Patients with CMV infection were compared with heart recipients without CMV infection.

Results

During the 6-month follow-up period, 13 (34.2%) patients developed CMV infection. At baseline, the mean anti-CMV-IgG antibody titer was lower in patients who developed CMV infection. This difference remained at 30?days after transplantation. One month after transplantation, the mean percentage of IE1-specific CD8+ T cells that are IFNg-positive (CD8/IFNg?+?IE1) was lower in CMV-infected patients. The predictive value of these variables at 30?days was increased when they were combined. Cox regression analysis revealed an association between the risk of developing CMV infection and the combination marker (low anti-CMV titer [<16,100] and low CD8/IFNg?+?IE1 percentages [<0.40%], relative hazard, 6.07; p?=?0.019). The combination marker remained significant after adjustment for clinical variables.

Conclusions

This novel approach of a simultaneous assessment of specific anti-CMV antibody titers and CD8/IFNg?+?IE1 percentages might help identify heart transplant recipients with an increased risk of developing CMV infection.     

复方磺胺甲恶唑对肾移植后卡氏肺孢子虫肺炎的预防作用

背景：卡氏肺孢子虫肺炎是由卡氏肺孢子虫寄生于肺部引起的一种严重的致命性肺炎。复方磺胺甲恶唑是目前用于治疗卡氏肺孢子虫肺炎的一线药物,治疗量往往有明显的不良反应,小剂量预防用药临床疗效及毒副作用尚不清楚。 目的：观察复方磺胺甲恶唑对肾移植后卡氏肺孢子虫肺炎的预防效果。 方法：选择肾移植后1个月且无复方磺胺甲恶唑过敏者。肾移植后1个月至半年或1年常规服用复方磺胺甲恶唑(0.48 g/d)。观察移植肝肾功能,感染情况,药物不良反应。 结果与结论：2006年起,随访125例肾移植术后早期患者,73例术后1个月起常规服用复方磺胺甲恶唑(0.48 g/d)至术后半年者,1例停药4个月后感染卡氏肺孢子虫肺炎死亡,47例服用复方磺胺甲恶唑(0.48 g/d)至术后1年者,无感染卡氏肺孢子虫肺炎者,5例因复方磺胺甲恶唑过敏或医从性差未服用复方磺胺甲恶唑者,2例分别在术后4,5个月感染卡氏肺孢子虫肺炎,1例死亡。结果提示,肾移植术后1个月至1年常规服用复方磺胺甲恶唑(0.48 g/d),可有效预防卡氏肺孢子虫肺炎,临床无明显不良反应。     

Virological significance of low-level hepatitis B virus infection in patients with hepatitis C virus associated liver disease

Cytomegalovirus (CMV) infection is an important cause of morbidity in solid organ recipients. Early markers to identify the progress of the infection and patients at high risk are required in order to apply a strategy of pre-emptive therapy. The efficacy of pre-emptive therapy relies on accurate laboratory tests to monitor CMV infection. The evaluation of CMV DNA kinetics by the polymerase chain reaction (PCR) is widely used for the management of CMV infection but markers predicting the progression of the infection and standardization of the technique are essential for the clinical interpretation of PCR results. A commercially available PCR system, the COBAS AMPLICOR Monitor (Roche Diagnostics, Brachburg, NJ), was used for the quantitation of CMV DNA in weekly blood samples (n = 504) from 47 solid organ recipients in the first 6 months after transplantation. PCR results were evaluated according to the development of clinical disease in order to find a DNA threshold and time points predicting the progression of CMV infection. Week 4 from transplantation was the earliest time point to note a significant difference between those patients who eventually developed CMV disease (n = 30) and those who remained asymptomatically infected (n = 17). At week 4, viral loads were significantly higher in patients who developed CMV disease than in asymptomatic infections (median value: 4 log(10)/10(6) leukocytes vs. 2.8, P < 0.0001). At week 4, a DNA level >/=4 log(10)/10(6) leukocytes was associated with a 45.37 odds ratio for CMV disease. Any increase >/=1 log from the first DNA detection to week 4 correlated with the clinical progression of CMV infection (odds ratio 1.74). In those patients who were treated with anti-CMV therapy, a >97% reduction of the baseline viral load was associated with a complete therapeutic success. In conclusion, CMV infection is a highly dynamic process and the quantitation of CMV DNA by PCR is a powerful marker to control successfully the infection, but a strict follow-up of the recipient and standardized PCR tests are mandatory for the best management of the infection.     

Factors influencing the occurrence of active cytomegalovirus (CMV) infections after organ transplantation.

In this study, several factors influencing the occurrence of active CMV infection after organ transplantation (Tx) are analysed. For this purpose, 105 heart, kidney and lung transplant recipients who were CMV-positive or had a CMV-positive donor, were closely monitored for active CMV infection by antigenaemia, cultures, CMV serology and lymphocyte proliferation (LP) to CMV. Univariate and multivariate regression analysis were performed. As pretransplant risk factors the HLA-type and numbers of HLA mismatches between recipients and their donors, and the CMV serology of the recipient and donor were analysed. A new finding was that recipients of donors positive for HLA-B7 were especially at risk for developing active CMV infection (P = 0.03) and CMV disease (P = 0.03). This was not due to increased rejection treatment in these patients. Post-transplant risk factors for development of active CMV infection were absence of detectable cellular immunity to CMV (lymphocyte proliferation) after Tx (P < 0.01) and rejection treatment with OKT3 or ATG (P = 0.05). High levels of IgG anti-CMV did not prevent occurrence of active CMV infection or CMV disease in the CMV+ recipients.     

Cytomegalovirus infection after bone marrow transplantation in children

Cytomegalovirus (CMV) is a well-known cause of disease occurring after bone marrow transplantation (BMT). The manifestations of CMV range from asymptomatic infection, defined as active CMV replication in the blood in the absence of clinical manifestations or organ failure abnormalities, to CMV disease, characterized by CMV infection with clinical symptoms or organ function abnormalities. Diagnostic procedures to assess the viral load have improved greatly with the increased use of antigenemia, CMV DNA, and immediate early-messenger RNA. Many conditions concur in determining the risk of developing CMV reactivation or disease after bone marrow transplant with serologic status of donor and recipient, type of bone marrow transplant, presence of graft-versus-host disease being the most studied. However, time and quality of immune reconstitution seems to be the pivotal factors. Pneumonia and gastrointestinal involvement are the most frequently documented clinical pictures with late-onset CMV reactivation or disease representing a new challenge. CMV prophylaxis or pre-emptive therapy adopted during the last few years in allogeneic BMT recipients has changed the natural history of the disease, reducing the risk of CMV disease, CMV-associated death, transplant-related mortality, and has prolonged the period at risk. Specific studies on children are lacking, however, the clinical pictures and features seems to be similar both in children and adults.     

Comparative clinical manifestations and immune effects of cytomegalovirus infections following distinct types of immunosuppression

BackgroundCytomegalovirus (CMV) infection is a well-recognised complication of solid organ and hematopoietic cell transplantation. However, CMV infection also occurs in patients with human immunodeficiency virus infection, previously immunocompetent intensive care unit patients, and individuals on immunosuppressive medications for various underlying diseases.ObjectivesThis review describes the comparative effects of CMV infection in distinct types of acquired immunosuppression.SourcesSelected peer-reviewed publications on CMV infections published until December 2021.ContentCMV infection affects various organ systems through direct cytolytic mechanisms but may also exert indirect effects by promoting pro-inflammatory and immunosuppressive responses. This has been well studied in transplant recipients, for whom antiviral prophylaxis and pre-emptive therapy have now become standard practice. These strategies not only prevent direct CMV disease manifestations but also mitigate various immunopathological processes to reduce graft-vs.-host disease, graft rejection, and the occurrence of secondary bacterial and fungal infections. The efficacy of neither prophylactic nor pre-emptive treatment of CMV infection has been demonstrated for patients with critical illness- or medication-induced immunosuppression. Many observational studies have shown an independent association between CMV reactivation and a prolonged duration of mechanical ventilation or increased mortality in the intensive care unit. Furthermore, data suggest that CMV reactivation may increase pulmonary inflammation and prolong the duration of mechanical ventilation.ImplicationsA large number of observational and experimental studies suggest attributable morbidity and mortality related to CMV infection, not only in transplant recipients and patients with human immunodeficiency virus infection but also in patients with critically illness- or medication-induced immunosuppression. Adequately powered randomised controlled trials investigating the efficacy of prophylaxis or pre-emptive treatment of CMV infection in these patients are lacking, with a notable exception for transplant recipients.     

Update on post-liver transplantation infections, malignancies, and surgical complications

Complications of liver transplantation are not limited to acute and chronic rejection, and recurrence of original disease, but include surgical complications, most commonly hepatic artery occlusion, infections, and development of de novo malignancies. In the early posttransplantation period, procurement/preservation injury, non-immunologic injury to the graft during harvesting and implantation, is manifested by centrilobular hepatocyte pallor and cholestasis but rarely leads to significant graft dysfunction. Ischemic complications, such as hepatic artery thrombosis, are more serious complications and may lead to early graft loss or biliary stricture. Infectious complications generally occur in the mid-to-late period after transplantation; cytomegalovirus (CMV) remains a common pathogen. Human herpes 6 virus infection has been implicated in allograft dysfunction, but is usually seen in the setting of co-infection with CMV. De novo malignancies are emerging as a significant cause of mortality after liver transplantation; risk is cumulative, and increases with time posttransplantation. Development of such malignancies in the setting of solid organ transplantation is multifactorial, and is related to individual and regional predispositions to malignancy, pre-transplantation disease states, recipient viral status, and use and intensity of immunosuppression regimens.     

Multicenter, prospective clinical evaluation of respiratory samples from subjects at risk for Pneumocystis jirovecii infection by use of a commercial real-time PCR assay

Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection. Microscopic diagnosis, including diagnosis using the Merifluor-Pneumocystis direct fluorescent antigen (MP-DFA) test, has limitations. Real-time PCR may assist in diagnosis, but no commercially validated real-time PCR assay has been available to date. MycAssay Pneumocystis is a commercial assay that targets the P. jirovecii mitochondrial large subunit (analytical detection limit, ≤ 3.5 copies/μl of sample). A multicenter trial recruited 110 subjects: 54 with transplants (40 with lung transplants), 32 with nonmalignant conditions, 13 with leukemia, and 11 with solid tumors; 9 were HIV positive. A total of 110 respiratory samples (92% of which were bronchoalveolar lavage [BAL] specimens) were analyzed by PCR. Performance was characterized relative to investigator-determined clinical diagnosis of PCP (including local diagnostic tests), and PCR results were compared with MP-DFA test results for 83 subjects. Thirteen of 14 subjects with PCP and 9/96 without PCP (including 5 undergoing BAL surveillance after lung transplantation) had positive PCR results; sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were 93%, 91%, 59%, and 99%, respectively. Fourteen of 83 subjects for whom PCR and MP-DFA test results were available had PCP; PCR sensitivity, specificity, PPV, and NPV were 93%, 90%, 65%, and 98%, respectively, and MP-DFA test sensitivity, specificity, PPV, and NPV were 93%, 100%, 100%, and 98%. Of the 9 PCR-positive subjects without PCP, 1 later developed PCP. The PCR diagnostic assay compares well with clinical diagnosis using nonmolecular methods. Additional positive results compared with the MP-DFA test may reflect low-level infection or colonization.     

A case of Pneumocystis jiroveci pneumonia in X-linked agammaglobulinaemia treated with immunosuppressive therapy: a lesson for immunologists

The case of a 20-year-old patient, affected by X-linked agammaglobulinaemia (XLA), who developed severe pneumonia from Pneumocystis jiroveci (formerly Pneumocystis carinii) (PCP), is reported. This infection usually affects patients with AIDS, children affected by severe combined immunodeficiency or hypogammaglobulinaemia with hyperimmunoglobulin M, or patients undergoing severe immunosuppression. The XLA patient developed PCP during therapy with steroids and cyclosporine A, carried out for several months, due to an extended skin vasculitis, accompanied by general symptoms. The pneumonia had a severe clinical course, requiring a long hospitalization. At the diagnosis of PCP, immunosuppressive therapy was suspended and the patient recovered after a long-term trimethoprim/sulfamethoxazole therapy. Immunological studies revealed an unexpected normal number of CD4+ and CD8+ T cells. The two subsets had an exclusive na?ve phenotype (95% CD4+CD45RA+CD62L+ and 89% CD8+CD45RA+CD62L+ cells), with an absence of primed cells. Lymphoproliferative responses to P. carinii and recall antigens as well as to mitogens were extremely deficient. During the follow-up, memory cells appeared with recovery of the lymphoproliferative response to mitogens and maintained defective responses to antigens. This is one of the few reported XLA cases experiencing severe PCP. In this patient, the infection became clinically evident during immunosuppressive therapy. We believe that the absence of functional activities, despite a normal level of T lymphocyte counts, sustained this long-lasting infection. Thus, the CD4+ and CD8+ T cell count evaluation, without functional studies, may not be per se sufficient for predicting the risk of a severe clinical course of PCP in patients undergoing immunosuppression.     

Impact of pretransplant CMV-specific T-cell immune response in the control of CMV infection after solid organ transplantation: a prospective cohort study

IntroductionAlthough solid organ transplant (SOT) recipients with pretransplant serology for cytomegalovirus (CMV-R+) are considered at intermediate risk for CMV infection post transplantation, CMV infection remains a major cause of morbidity in this population. We prospectively characterized whether having pretransplant CMV-specific cellular immunity is independently associated with controlling infection after transplantation in R + SOT recipients.MethodsA prospective cohort of consecutive R + SOT recipients that received pre-emptive treatment for CMV infection was monitored after transplantation and variables were recorded during the follow-up. The cytomegalovirus-specific T-cell immune response was characterized by intracellular cytokine staining and viral loads determined using real-time PCR.ResultsOne hundred and thirty-five R + SOT recipients were included (67 kidney, 64 liver, four liver–kidney). Only one-third of the patients (42; 31.85%) had CMV-specific T-cell immunity (CD8⁺CD69⁺INF-γ⁺ T cells >0.25%) before transplantation. Patients with negative pretransplant immunity had more CMV infection (49, 52.7% vs. 15, 35.7%; p 0.07) and received more antiviral therapy than those with immunity (32, 34.4% vs. 6, 14.3%, p 0.016). Having CMV specific immunity was an independent factor for protection from developing viraemia ≥2000 IU/mL (OR 0.276, 95% CI 0.105–0.725, p < 0.01) and lower administration of treatment (OR 0.398, 95% CI 0.175–0.905, p 0.028). Only patients with no pretransplant CMV-specific T-cell response were diagnosed with CMV-disease (8, 8.6% vs. 0, 0%, p 0.05).Discussion.Our results show that having a pretransplant CMV specific T-cell response may be associated with a lower rate of CMV viraemia and less antiviral treatment after transplantation; however, more prospective studies are needed to confirm these findings.     

CMV Infection in Bone Marrow and Solid Organ Transplant Patients in the Era of Antiviral Prophylaxis

Recent developments in the diagnosis and therapy of cytomegalovirus (CMV) infection have helped to reduce CMV-associated morbidity and mortality following allogeneic bone marrow and solid organ transplantation. The clinical symptoms of active CMV infection and the prevalence of life-threatening CMV disease vary widely between different patient populations according to the type of transplant and the intensity of immunosuppression employed. Antiviral prophylaxis with aciclovir, valaciclovir and ganciclovir has been shown to reduce CMV infection and disease following organ transplantation. Antiviral drugs, in particular ganciclovir and foscarnet, have varying sideeffects, however, and antiviral resistance due to prolonged administration of ganciclovir and foscarnet has been reported recently. Short courses of pre-emptive antiviral therapy for documented CMV infection help to reduce the duration and sideeffects of therapy, offering an alternative strategy to antiviral prophylaxis. Studies are required to compare the efficacy and costs of antiviral prophylaxis with pre-emptive therapy.     

Cytomegalovirus infections in heart and heart and lung transplant recipients.

Of the first 166 heart and 15 heart and lung transplant recipients at Papworth Hospital, Cambridge, who survived for more than one month after transplantation, 162 were investigated for cytomegalovirus (CMV) infection by serological methods. Altogether, 73 (45%) developed CMV infection after transplantation: 30 (18.5%) had acquired primary infection and 43 (26.5%) reactivation or reinfection. Six patients died of primary infection, probably acquired from the donor organ. Recipients negative for CMV antibody who received an organ from an antibody positive donor had the most severe disease. Heart and lung transplant recipients experienced more severe primary CMV infection than those in whom the heart alone was transplanted. The most sensitive and rapid serological method was a mu-capture enzyme linked immunosorbent assay (ELISA) for detecting CMV specific IgM, the amount of which was often of prognostic value and influenced the management of patients.     

抗CD3单克隆抗体在预防肾移植术后急性排斥反应中的作用

目的 :观察抗CD3单克隆抗体在预防肾移植术后急性排斥反应的作用。方法 :16 4例肾移植患者分为两组 ,4 2例移植术后应用抗CD3单克隆抗体 (5mg d)为治疗组 ;其它 12 2例为对照组。观察移植术后人 肾存活率、急性排斥反应及CMV感染的发生率。结果 :治疗组 1年、2年及 3年人存活率与对照组无显著差异 ,而治疗组移植肾存活率明显高于对照组(P <0 0 5 )。治疗组急性排斥反应发生率 (18 6 % )比对照组 (2 8 7% )低 ,P <0 0 5 ,且首次急性排斥反应发生时间明显延长 ,对MP冲击治疗效果好。治疗组CMV感染的发生率 (33 3% )高于对照组 ,P <0 0 5。结论 :肾移植术后预防性使用抗CD3单克隆抗体对提高移植肾存活率 ,降低急性排斥反应发生率有较好的作用 ;用药期间应注意预防及治疗CMV感染。     

Immune-based monitoring for cytomegalovirus infection in solid organ transplantation: is it ready for clinical primetime?

The impact of CMV infection and disease in solid organ transplant (SOT) recipients continues despite remarkable improvements in its prevention and management with antiviral drugs. Studies that have investigated the host immune response to CMV have paved way for the development of novel immune-based assays that are anticipated to complement the current antiviral-based strategies for CMV management after transplantation. In this article, we review the emerging data on the clinical application of innovative CMV-specific T-cell assays, including their role in risk-stratification, prognostication, prevention and treatment of CMV infection and disease in SOT recipients.