The role of therapeutic drug monitoring in the treatment of cytomegalovirus disease in kidney transplantation

Cytomegalovirus (CMV) infection is a common complication following solid organ transplantation that may severely affect the outcome of transplantation. Ganciclovir (GCV) and its prodrug valganciclovir are successfully used to prevent and treat CMV infection; however, in a small percentage of patients, CMV gene mutations may lead to drug resistance. GCV resistance is defined as increasing CMV viremia or progressive clinical disease during prolonged antiviral therapy, due to CMV gene mutation. This has emerged as a new challenge, especially because alternative drugs such as cidofovir and foscarnet have a number of important side effects. Here we report the case of a kidney transplanted patient who experienced life-threatening CMV disease, which initially appeared to be GCV-resistant, but was instead found to be associated with inadequate antiviral drug levels. The patient was then successfully treated by monitoring plasma GCV levels. We suggest using plasma GCV monitoring in the management of all cases of critical CMV disease, in which GCV resistance is suspected.     

Cytomegalovirus Replication Kinetics in Solid Organ Transplant Recipients Managed by Preemptive Therapy

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.     

Cytomegalovirus (CMV) DNA quantification in bronchoalveolar lavage fluid of immunocompromised patients with CMV pneumonia

Cytomegalovirus (CMV) pneumonia causes major morbidity and mortality. Its diagnosis requires demonstration of viral cytopathic changes in tissue, entailing risks of lung biopsy. This study aimed to determine CMV viral load (VL) thresholds in bronchoalveolar lavage fluid (BALF) for diagnosis of CMV pneumonia in immunocompromised patients. CMV VL in BALF was studied in 17 patients (83% transplant recipients) and 21 control subjects with and without CMV pneumonia, respectively, using an FDA‐approved PCR assay (Cobas^® AmpliPrep/Cobas TaqMan^® CMV Test, Roche Molecular Systems, Inc.) calibrated to the WHO International Standard for CMV DNA (NIBSC: 09/162). Receiver operating characteristic curve analysis produced a BALF CMV VL threshold of 34 800, IU/mL with 91.7% sensitivity and 100.0% specificity for diagnosis of possible, probable, and proven CMV pneumonia in transplant patients, while a threshold of 656 000 IU/mL yielded 100% sensitivity and specificity among biopsy‐proven cases. For all immunocompromised patients, a VL threshold of 274 IU/mL was selected. VL thresholds also were normalized to BALF cell count yielding a threshold of 0.32 IU/10⁶ cells with 91.7% sensitivity and 90.5% specificity for possible, probable, and proven CMV pneumonia in transplant recipients. Monitoring CMV VL in BALF may be a less invasive method for diagnosing CMV pneumonia in immunocompromised patients.     

Histologically atypical Pneumocystis carinii pneumonia.

BACKGROUND--Infection with Pneumocystis carinii typically results in a pneumonia which histologically is seen to consist of an eosinophilic foamy alveolar exudate associated with a mild plasma cell interstitial infiltrate. Special stains show that cysts of P carinii lie within the alveolar exudate. Atypical histological appearances may occasionally be seen, including a granulomatous pneumonia and diffuse alveolar damage. In these patients the clinical presentation may be atypical and results of investigations negative unless lung biopsies are performed and tissue obtained for histological examination. METHODS--The incidence and mode of presentation of histologically atypical pneumocystis pneumonia was studied in a cohort of HIV-I antibody positive patients. RESULTS--Over a 30 month period 138 patients had pneumocystis pneumonia, of whom eight (6%) had atypical histological appearances which were diagnosed (after negative bronchoalveolar lavage) by open lung biopsy in five, percutaneous biopsy in one, and at post mortem examination in two. Atypical appearances included granulomatous inflammation in four patients, "pneumocystoma" in two (one also had extrapulmonary pneumocystosis), bronchiolitis obliterans organising pneumonia in one patient, diffuse alveolar damage and subpleural cysts in one (who also had intrapulmonary cytomegalovirus infection), and extrapulmonary pneumocystosis in two patients. CONCLUSIONS--Various atypical histological appearances may be seen in pneumocystis pneumonia. Lung biopsy (either percutaneous or open) should be considered when bronchoalveolar lavage is repeatedly negative and evidence of P carinii should be sought, by use of special stains, in all lung biopsy material from HIV-I antibody positive patients.     

The impact of cytomegalovirus infections and acute rejection episodes on the development of vascular changes in 6-month protocol biopsy specimens of cadaveric kidney allograft recipients

BACKGROUND: The role of cytomegalovirus (CMV) in chronic kidney allograft rejection remains controversial. The purpose of this study was to examine the impact of CMV infection on histopathologic changes in 6-month protocol biopsy specimens of kidney allografts. METHODS: Altogether, 52 renal allograft recipients were studied. CMV infection was diagnosed by CMV antigenemia test, viral cultures from blood and urine, or both. CMV was demonstrated in the biopsy specimens by antigen detection and hybridization in situ. Acute rejections were diagnosed by biopsy histology, and biopsy specimens were graded according to the Banff '97 classification. RESULTS: CMV infection was diagnosed in 41 patients. The 11 patients in whom CMV infection was not detected were used as controls. Acute rejection was diagnosed in 22 of 41 CMV patients and in 6 of 11 control patients. CMV was demonstrated in the biopsy specimens of 19 of 41 CMV patients. CMV was not associated with increased glomerular, tubular, or interstitial changes. However, the arteriosclerotic changes in small arterioles were significantly increased in the subgroup of patients where CMV was demonstrated in the graft as compared with controls (P<0.01). Analysis of the impact of acute rejection on arteriolar thickening showed that only a positive history of both acute rejection and CMV found in the graft was associated with significantly increased vascular changes compared with CMV-free recipients (P<0.05). CONCLUSIONS: Neither CMV nor acute rejection alone was associated with increased vascular or other histopathologic changes in 6-month protocol biopsy specimens of kidney allografts, but a previous history of both acute rejection and the presence of CMV in the graft was associated with increased vascular changes.     

肝移植术后巨细胞病毒肺炎的诊断和治疗

目的探讨肝移植术后巨细胞病毒（CMV）肺炎的诊断和治疗方法。方法回顾分析5例肝移植术后CMV肺炎病例。CMV肺炎的诊断主要根据临床表现、肺部x线检查和病原学检查。5例患者均接受以抗病毒和免疫调节为主的综合治疗。结果CMV肺炎的临床表现呈非特异性。其症状主要包括发热、咳嗽、呼吸困难、心率增快、疲乏、低氧血症和白细胞减少等。肺部x线检查显示问质性肺炎。患者血清中可检测到CMV抗原或抗体。4例治愈,1例死亡。治愈率为80％,死亡率为20％。结论肝移植术后CMV肺炎的临床表现呈非特异性,其诊断主要根据临床表现、肺部X线检查及病原学检查,采取以抗病毒和免疫调节为主的综合治疗有较好疗效。     

肝移植术后巨细胞病毒性肺炎的治疗策略

探讨肝移植术后巨细胞病毒（cytomegalovirus，CMV）性肺炎的治疗方法。方法回顾分析我科2003年10月至2005年6月所行的451例肝移植病人的临床资料。发生CMV肺炎的共7例。采用更昔洛韦联合磷甲酸钠联合抗CMV，结合停用免疫抑制剂、加用大剂量丙种球蛋白和适量的胸腺肽等免疫增强剂的个体化免疫调节方案，同时采用广谱抗生素预防感染和其他对症支持等综合治疗方法。结果发生CMV感染共86例，感染率为19．1％。其中CMV肺炎7例，发生率为1．66％。治愈6例，治愈率为85．7％。结论采取联合抗病毒和个体化免疫调节等综合治疗措施效果确切。     

肾移植术后巨细胞病毒肺炎的诊治

目的：探讨肾移植术后巨细胞病毒（CMV）肺炎的发病特点及诊治方案。方法：回顾分析9例肾移植术后并发CMV肺炎患者的临床资料。结果：治愈6例,2例有效好转,但后因经济困难放弃治疗,1例无效而死亡．结论：肾移植术后3～6个月为CMV感染易感期,术前,术后加强CMVPP65抗原及CMVIgM监测对CMV肺炎的预防及早期诊断有帮助。尽早诊断、减少或停用免疫抑制剂、早期足量长疗程抗病毒治疗、加强营养、适时机械辅助砰吸的综合治疗可提高治愈率。     

Combined Prophylaxis Decreases Incidence of CMV-Associated Pneumonia After Lung Transplantation

Among solid-organ recipients, those with lung transplants are at highest risk of cytomegalovirus (CMV) infection or to die of CMV-associated disease. We evaluated the effect of combined CMV antiviral prophylaxis and CMV-immunoglobulin prophylaxis on CMV-associated pneumonia diagnosed in 303 follow-up transbronchial biopsy (TBB) specimens from lung transplant recipients. At our center, 24 recipients (control group; 1999-2002) received acyclovir for 24 months and 33 recipients (study group; 2003-2008) received combined CMV prophylaxis consisting of CMV immunoglobulin on days 1, 4, 8, 15, and 30 and monthly for 12 months plus gancyclovir or valgancyclovir from postoperative day 21 for 3 weeks followed by acyclovir for up to 24 months. The percentage of pneumonia-positive TBB specimens at 1-month follow-up was similar in the study and control groups: 9.1% (3 of 33 specimens) vs 8.3% (2 of 24) (P = .90). However, after the first month, the percentage of pneumonia-positive TBB specimens was significantly lower in the study group in the first year (months 3, 6, 9, and 12) of follow-up, at 1% (1 of 99) vs 6.4% (5 of 78) (P = .048), and in the first 2 years (months 3, 6, 9, 12, 18, and 24), at 0.8% (1 of 122) vs 6.5% (8 of 124) (P = .02). These data suggest the efficacy of combined prophylaxis to decrease the incidence of CMV-associated pneumonia after the first month in lung transplant recipients. The effect of combined prophylaxis after transplantation seems useful to prevent CMV-associated pneumonia not only in the first year after lung transplantation but also in the second year, which suggests a long-lasting immunologic role of prophylaxis.     

Immunomodulation by hyperimmunoglobulins after solid organ transplantation: Beyond prevention of viral infection

Hyperimmunoglobulins are pharmaceutical formulations of human IgG which contain high titers of antibodies against specific viruses. They have been successfully used in solid organ transplantation (SOT) to prevent Cytomegalovirus (CMV) and Hepatitis B Virus (HBV) infection. The introduction of effective and cheaper antiviral drugs has resulted in decreasing usage of hyperimmunoglobulins in SOT. However, it may still be attractive to combine antiviral drug therapy with hyperimmunoglobulins after SOT, as there is some evidence that hyperimmunoglobulins, similar to high doses of intravenous immunoglobulins (IVIgs), might exert anti-inflammatory activity and thereby prevent immunological graft damage and improve graft and patient survival. In this review we discuss the existing clinical evidence for beneficial anti-inflammatory effects of hyperimmunoglobulins after cardiac, lung, kidney, and liver transplantation. Only a limited number of studies have addressed this issue, and these studies often included small patient cohorts and showed considerable variations in the type, intensity and duration of treatment regimens. Due to these limitations, it is difficult to draw firm conclusions. Retrospective studies consistently demonstrated that addition of CMV hyperimmunoglobulin (CMV-Ig) to antiviral drug prophylaxis after lung transplantation is associated with reduced rates of CMV disease and bronchiolitis obliterans syndrome (BOS), and improved patient survival. The doses of CMV-Ig administered after SOT are much lower than the minimal effective dose of IVIg used for anti-inflammatory therapy in auto-immune diseases. Therefore, it is questionable whether the reduced incidence of BOS is the result of ‘direct’ anti-inflammatory effects of CMV-Ig or is caused by a reduction of CMV infection, which is a risk factor for BOS. No or very limited evidence for better prevention of immunological graft damage by anti-CMV combination therapy is available for heart, kidney and liver transplant patients. In liver transplantation published evidence suggests that the high-doses of Hepatitis B virus hyperimmunoglobulin (HBIg) administered to prevent HBV-infection may reduce the risk of acute rejection, while combination therapy of HBIg and antiviral drugs in HBV-infected patients is consistently associated with better graft and patient survival compared to antiviral monotherapy. Well-designed prospective randomized studies with larger patient cohorts are needed to substantiate the current limited evidence for anti-inflammatory benefits of hyperimmunoglobulins besides prevention of CMV and HBV infection after SOT.     

Exogenous lipoid pneumonia

Although a rare form of nonresolving pulmonary infiltrate, exogenous lipoid pneumonia is a great mimicker. It often is mistaken for bacterial pneumonia or cancer. Many cases have been diagnosed only by open lung biopsy or other invasive procedures. Depending on the type of lipid ingested and the degree of inflammation that occurs, damage to the lung can be little to none or can fulminate to necrosis and hemorrhage. Symptoms may range from none to respiratory failure. In the case presented, the patient was ingesting Vaseline Intensive Care Lotion and baby oil as laxatives. This information was elicited only after diagnosis was made by open lung biopsy.     

Cytomegalovirus in transplantation - challenging the status quo

BACKGROUND: Cytomegalovirus (CMV) infection of solid organ transplant (SOT) recipients causes both 'direct' and 'indirect' effects including allograft rejection, decreased graft and patient survival, and predisposition to opportunistic infections and malignancies. Options for CMV prevention include pre-emptive therapy, whereby anti-CMV agents are administered based on sensitive viral assays, or universal prophylaxis of all at-risk patients. Each approach has advantages and disadvantages in terms of efficacy, costs, and side effects. Standards of care for prophylaxis have not been established. METHODS: A committee of international experts was convened to review the available data regarding CMV prophylaxis and to compare preventative strategies for CMV after transplantation from seropositive donors or in seropositive recipients. RESULTS: Pre-emptive therapy requires frequent monitoring with subsequent treatment of disease and associated costs, while universal prophylaxis results in greater exposure to potential toxicities and costs of drugs. The advantages of prophylaxis include suppressing asymptomatic viremia and prevention of both direct and indirect effects of CMV infection. Meta analyses reveal decreased in mortality for patients receiving CMV prophylaxis. Costs associated with prophylaxis are less than for routine monitoring and pre-emptive therapy. The optimal duration of antiviral prophylaxis remains undefined. Extended prophylaxis may improve clinical outcomes in the highest-risk patient populations including donor-seropositive/recipient-seronegative renal transplants and in CMV-infected lung and heart transplantation. CONCLUSIONS: Prophylaxis is beneficial in preventing direct and indirect effects of CMV infection in transplant recipients, affecting both allograft and patient survival. More studies are necessary to define optimal prophylaxis regimens.     

多源化巨细胞病毒DNA定量检测在异基因造血干细胞移植后巨细胞病毒肺炎诊断中的应用

目的 研究不同来源[血浆、痰液、支气管肺泡灌洗液(BALF)]标本的巨细胞病毒(CMV)DNA定量检测对异基因造血干细胞移植后CMV肺炎的诊断价值.方法 回顾性分析接受异基因造血干细胞移植的405例受者的临床资料,其中诊断为CMV肺炎的19例受者设为CMV肺炎组,选择同期仅发生CMV血症的229例受者、接受纤维支气管镜...     

Polyoma virus-associated nephropathy and concurrent cytomegalovirus infection in the kidney transplant recipients

INTRODUCTION: Cytomegalovirus (CMV) and polyoma virus BK (BKV) may both establish latency following primary infection. Frequent reactivation of these viruses can occur in the kidney transplant recipients. BKV may induce CMV gene expression by stimulating cellular regulator proteins or by its own gene regulator proteins. A high rate of concurrent CMV infections has been noted in kidney transplant recipients with polyoma virus-associated nephropathy (PVAN). METHODS: PVAN was identified in 10 of 191 patients who received kidney transplants between October 1998 and September 2003. PVAN was confirmed by allograft kidney biopsy. Four of the 10 patients were complicated by concurrent CMV infection. RESULTS: Two patients had only serological evidence of CMV infection and one patient had CMV gastritis. These three patients were treated with intravenous ganciclovir with good results. Disseminated ganciclovir-resistant CMV disease was demonstrated in the remaining patient. This 34-year-old kidney transplant recipient with PVAN died of multiorgan failure despite antiviral therapy with both ganciclovir and foscarnet. CONCLUSION: PVAN with concurrent CMV infection in kidney transplant recipients showed variable clinical courses including mortality. Further studies are needed to elucidate the influence of PVAN on the pathogenesis of CMV infection.     

Fibreoptic bronchoscopy in diagnosis of bronchopulmonary Kaposi''s sarcoma.

Kaposi's sarcoma of the lung patients with the acquired immune deficiency syndrome is often indistinguishable by clinical and radiographic criteria from opportunistic pneumonia. Pulmonary Kaposi's sarcoma and pneumonia may frequently be present in the same patient. Previous observers have commented on the repeated failure to establish a diagnosis of Kaposi's sarcoma of the lung by fibreoptic bronchoscopy. Thirteen fibreoptic bronchoscopies were performed in a series of 11 patients with thoracic manifestations of AIDS and Kaposi's sarcoma was identified in transbronchial or bronchial biopsy specimens in four patients. This diagnostic yield is comparable to that obtained only by open lung biopsy procedures in previous reports. Fibreoptic bronchoscopy may contribute to the correct management of the patient and facilitate an accurate prognosis by differentiating between opportunistic pneumonia and pulmonary Kaposi's sarcoma.     

Ganciclovir Dosing Strategies and Development of Cytomegalovirus Resistance in a Kidney Transplant Recipient: A Case Report

In renal transplant recipients, delayed graft function and accompanying renal impairment may lead to therapeutic underexposure of valganciclovir. We describe a case of a cytomegalovirus (CMV)-seronegative kidney transplant recipient from a CMV-seropositive donor, whose course was complicated during valganciclovir prophylaxis by CMV disease, ultimately progressing to ganciclovir, foscarnet, and cidofovir resistance. Assessments and adjustments for renal dysfunction, according to both Cockgroft-Gault and Modification of Diet in Renal Disease study equations, are described. Therapy was complicated by outpatient parenteral therapy with pump-administered antiviral therapy, which may have led to drug underexposure and the fostering of antiviral resistance. Suppression was ultimately achieved in conjunction with reduction in immunosuppressive therapy, CMV immunoglobulin, and initiation of leflunomide. At-risk recipients may benefit from 24 hour creatinine clearance assessments, direct creatinine clearance measurement, or therapeutic drug monitoring. Optimal dosing strategies in recipients with impaired kidney function remain undefined, with limited pharmacokinetic data to date.     

Rapid detection of cytomegalovirus DNA and RNA in blood of renal transplant patients by in vitro enzymatic amplification.

Cytomegalovirus infection causes significant morbidity and mortality in renal transplant patients. The only marker of CMV infection that appears to correlate with the development of symptomatic illness is viremia. However, CMV grows slowly in tissue culture, requiring 2-6 weeks of incubation for detection of characteristic cytopathic effect. The efficacy of antiviral therapy for CMV may be improved by earlier detection of viremia and institution of antiviral therapy. We performed amplification of CMV DNA and RNA from peripheral blood of renal transplant patients using the polymerase chain reaction (PCR) technique. We consistently detected CMV DNA by PCR earlier than CMV was detected by culture. Detection of CMV RNA in one patient confirmed the presence of actively replicating virus in peripheral blood. Amplification of peripheral blood from healthy CMV-seropositive and seronegative individuals, and from seropositive renal transplant patients without evidence of active CMV disease, was consistently negative. These preliminary data indicate that PCR may provide a means for earlier diagnosis of CMV viremia. Future prospective studies should determine if early detection of CMV DNA by PCR in peripheral blood does predict viremia and symptomatic illness, and if earlier institution of antiviral therapy based on PCR results improves outcome for the CMV-infected transplanted patient.     

Treatment of cytomegalovirus infection and disease pre‐ and post‐quantitative nucleic acid test standardization: does use of a more sensitive assay lead to longer treatment duration?

Quantitative cytomegalovirus (CMV) nucleic acid testing (NAT) has been standardized using the World Health Organization (WHO) international calibration standard. A new FDA‐approved WHO‐calibrated assay (CA) was found to be more sensitive than a laboratory‐developed test (LDT). We hypothesized that monitoring therapeutic response using a more sensitive assay may lead to longer antiviral therapy in solid organ and hematopoietic stem cell transplant patients with CMV infection. We reviewed transplant patients with CMV disease retrospectively, and divided them into two groups: those diagnosed and managed based on LDT and those managed using WHO‐CA. Compared to patients monitored by LDT, the time to reach an undetectable viral load was significantly longer in the group monitored by the WHO‐CA. However, a trend toward shorter duration of antiviral treatment was observed (median, 34 vs. 41 d; p = 0.058), with earlier discontinuation of induction antiviral therapy upon reaching undetectable viral load using WHO‐CA (11 vs. 18 d; p = 002). We concluded that despite using a more sensitive CMV NAT, the total duration of antiviral treatment was not significantly prolonged in transplant patients with CMV infection and disease. Relapse rates did not differ between the two groups.     

肾移植术后巨细胞病毒性肺炎56例临床分析

目的：回顾分析肾移植术后巨细胞病毒性肺炎（CMV）的临床特点,探讨预防和诊治巨细胞病毒肺炎的方法,提高人肾存活率。方法：对2000年1月-2007年12月肾移植术后发生的56例CMV肺炎患者的临床特点及诊疗措施进行回顾性分析。结果：56例患者,肺炎发生在术后6个月以内37例,28例患者表现为急性呼吸窘迫综合征．经抗病毒等综合治疗后39例患者治愈,人肾存活,17例死亡,其中12例死于呼吸功能衰竭,5例死于严重混合感染。平均住院时间32天。结论：由于CMV肺炎病情凶险,强调早期预防、早期诊断及早期应用抗CMV药物等综合治疗方法,针对不同的患者采取不同的诊疗策略,适当调整免疫抑制方案、改善肺功能及加强支持治疗均能有效的促进病情的恢复,     

A Case Report of Successful Use of Twice-Daily Letermovir in the Treatment of Resistant Cytomegalovirus in a Small Bowel Transplant Recipient

Cytomegalovirus (CMV) is considered one of the most notable pathogens that affect patients after solid organ transplantation (SOT), especially small bowel transplant patients with a risk of high mortality rate. Its management relies historically on the use of CMV DNA polymerase inhibitors (namely, ganciclovir and valganciclovir). Second-line options include foscarnet and cidofovir, which are highly nephrotoxic and thus less preferred and only used in ganciclovir intolerance or resistance cases. Letermovir is a novel antiviral agent approved for CMV prophylaxis in hematopoietic stem cell transplant, but not for SOT (neither for prophylaxis nor for treatment).We report the first case on the successful use of letermovir in treating CMV disease in a small bowel transplant patient who failed to achieve viral clearance due to ganciclovir resistance and severe intolerance to foscarnet.