Clinical Utility of Cytomegalovirus Viral Load in Bronchoalveolar Lavage in Lung Transplant Recipients

The utility of cytomegalovirus (CMV) viral load (VL) by quantitative hybrid capture assay (Q-HCA) was investigated in bronchoalveolar lavage (BAL) from lung transplant recipients and compared with BAL cultures and blood VL. Forty-three consecutive BAL samples from 27 lung transplant recipients were analyzed. All samples had shell vial (SV) cultures in addition to Q-HCA. Histopathology was done on all lung tissues, and immunohistochemistry (IHC) in those with positive CMV cultures. Fifteen (56%) lung transplant recipients had both positive BAL SV cultures and BAL VL. Five of 15 had CMV pneumonitis with a VL in BAL >500 000 copies/mL (mean: 1638 450). Ten patients without CMV pneumonitis had VL in BAL <500 000 copies/mL (mean 81 820, p = 0.002). High VL in BAL and blood invariably meant CMV pneumonitis, but 2 patients with CMV pneumonitis had high BAL VL but relatively low blood VL. Initial CMV seronegativity was associated with pneumonitis (4/5 vs. 1/10; p = 0.004) and higher BAL CMV VL (p = 0.03). High CMV BAL or blood VL did not correlate with acute rejection or development of bronchiolitis obliterans syndrome (BOS). High CMV VL in BAL in lung transplant recipients is strongly associated with CMV pneumonitis, and may be more predictive than peripheral blood viral load.     

Infectious diseases in kidney transplant recipients treated with cyclosporin

Cyclosporin (CYA) is now recognized as an effective immunosuppressant to lead to a marked improvement in graft survival in organ transplant recipients. Although the incidence of infection in the CYA group has been decreased compared with that in the azathioprine group, infectious diseases in 400 kidney transplant recipients treated with CYA were noted in our single center. Treatment strategy for infectious diseases: Antibiotics and/or gamma-Globulin were administered to all recipients with bacterial infections. Aciclovir was added in recipients with herpes simplex virus (HSV) infection or varicella zoster virus (VZV) infection. Human interferon-beta (HuIFN-beta) was used in recipients who had life-threatening viral infection, especially cytomegalovirus (CMV) pneumonitis. Glycyrrhizin was used for acute hemorrhagic cystitis and nephropathy due to adenovirus (AV). Trimethoprim sulfamethoxazole and/or pentamidine were added in recipients complicated with Pneumocystis carinii (Pc) pneumonitis or in order to prevent Pc pneumonitis. Infectious diseases: One hundred and six recipients had infectious diseases 129 times in this series, seventy-six percent of all infections occurred during the first 4 months after the transplantation. Urinary tract infection (UTI), herpes zoster and pulmonary infection were the most common infectious diseases, occurring in 28.7%, 24.0% and 23.2%, respectively. Septicemia or bacteremia developed in 9 recipients, secondary to UTI in 8 and to surgical wound infection in one. Sixty-one symptomatic viral infections occurred in 57 recipients. A total of 5 recipients (1.3%) died of interstitial pneumonitis. Infectious organisms: Viral and bacterial infections were most common, occurring in 47.3% and 41.9%, respectively. Viral species detected in these recipients with the frequency were HSV 14 times, CMV 9 times, VZV 31 times and AV 7 times. 1) The incidence of viral infections in kidney transplant recipients treated with CYA is relatively high compared to bacterial infections. 2) HuIFN-beta therapy is effective in the treatment of serious opportunistic herpes virus infections, especially CMV pneumonitis. 3) Glycyrrhizin therapy is effective in the treatment of acute hemorrhagic cystitis and nephropathy due to AV and hepatic dysfunction. 4) Aerosolised pentamidine therapy is very useful for prophylaxis of Pc pneumonitis.     

Relationship of cytomegalovirus viral load in blood to pneumonitis in lung transplant recipients.

We developed a multiplex, quantitative, real-time, polymerase chain reaction assay for cytomegalovirus (CMV) and used it to measure the CMV viral load in weekly blood specimens from 43 lung transplant recipients. The median viral load in blood samples immediately preceding bronchoscopy was 1150 copies/microg human DNA for 12 subjects with pneumonitis compared to 91 copies for 31 subjects without (P=0.02, Mann-Whitney U test). Each log10 increase in CMV viral load resulted in an increase of 1.92 in the odds ratio for CMV pneumonitis (95% confidence interval 1.03-3.56). CMV viral load was elevated (>100 copies/microg human DNA) for a median of 21 days before bronchoscopy in those subjects with pneumonitis versus 0 days in those without (P=0.004). We conclude that the risk of CMV pneumonitis after lung transplantation is related to the level of CMV DNA in blood. Quantitative PCR should be evaluated prospectively for the preemptive management of CMV in lung transplant recipients.     

Treatment of cytomegalovirus pneumonitis with ganciclovir in renal transplantation

Ganciclovir, also called DHPG, was administered intravenously to eight renal transplant recipients with life-threatening cytomegalovirus (CMV) pneumonitis. One patient died of pulmonary failure; a favorable clinical response was observed in the seven others. In one patient, CMV pneumonitis recurred but responded well to a second course of the drug. At no time was the immunosuppressive regimen completely stopped in the seven surviving patients. Six of them maintained a good renal function 1–11 months after treatment with ganciclovir. No toxic effect was detected during therapy. We conclude that ganciclovir appears to be a promising and effective treatment for CMV pneumonitis after renal transplantation.     

Treatment of cytomegalovirus pneumonitis with ganciclovir in renal transplantation

Abstract. Ganciclovir, also called DHPG, was administered intravenously to eight renal transplant recipients with life-threatening cytomegalovirus (CMV) pneumonitis. One patient died of pulmonary failure; a favorable clinical response was observed in the seven others. In one patient, CMV pneumonitis recurred but responded well to a second course of the drug. At no time was the immunosuppressive regimen completely stopped in the seven surviving patients. Six of them maintained a good renal function 1–11 months after treatment with ganciclovir. No toxic effect was detected during therapy. We conclude that ganciclovir appears to be a promising and effective treatment for CMV pneumonitis after renal transplantation.     

Impact of prophylaxis with cytogam alone on the incidence of CMV viremia in CMV-seropositive lung transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection remains a serious problem after lung transplantation. The purpose of this study was to evaluate the efficacy of CytoGam, a CMV hyperimmune globulin (CMV-IGIV), as CMV prophylaxis after lung transplantation. METHODS: This prospective, randomized, open-label study compared prophylaxis with CMV-IGIV and no prophylaxis in 44 CMV-seropositive lung transplant recipients. The primary end-point was development of CMV viremia during the first year after transplantation. RESULTS: Cytomegalovirus viremia was detected in 13 of 22 recipients without prophylaxis and in 16 of 22 recipients with CMV-IGIV prophylaxis (p = 0.19). Cytomegalovirus pneumonitis developed in 8 controls vs in 11 CMV-IGIV recipients (p = 0.54). We found no significant difference between the groups in the incidence of positive shell vial assays (6.8% +/- 6.5% without vs 11.2% +/- 10.1% with prophylaxis, p = 0.09) or in the attack rate of CMV pneumonitis (0.41 +/- 0.59 episodes/patient without vs 0.86 +/- 0.99 episodes/patient with prophylaxis, p = 0.07). Similarly, no difference was apparent in the time to onset of CMV viremia, to detection of CMV DNA in peripheral blood leukocytes by polymerase chain reaction, or to development of CMV pneumonitis. The incidence of acute rejection and bronchiolitis obliterans syndrome and the survival rate during the first post-transplant year did not differ between the groups. CONCLUSIONS: Prophylaxis with CMV-IGIV alone did not decrease CMV viremia or pneumonitis, did not decrease the incidence of acute rejection or bronchiolitis obliterans syndrome, and did not affect 1-year survival of CMV-seropositive lung transplant recipients at our center.     

Incidence,Risk Factors,and Outcomes of Delayed-Onset Cytomegalovirus Disease in a Large,Retrospective Cohort of Heart Transplant Recipients

BackgroundDelayed-onset cytomegalovirus (CMV) disease can occur among heart transplant recipients after stopping anti-CMV prophylaxis. We evaluated a large, retrospective cohort of heart transplant recipients in the United States through the use of billing data from 3 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) to determine the epidemiology of delayed-onset CMV disease coded during hospital readmission.MethodsWe identified 2280 adult heart transplant recipients from 2004 to 2010 through the use of the California, Florida, and New York SID. Demographics, comorbidities, heart failure etiology, CMV disease, and inpatient death were identified. CMV disease was classified as early-onset (≤100 days) or delayed-onset (>100 days after transplant). Possible tissue invasion by CMV was determined through the use of codes for CMV pneumonitis, hepatitis, and gastrointestinal endoscopy. Multivariate analysis was performed with the use of Cox proportional hazards models.ResultsDelayed-onset CMV disease occurred in 7.5% (170/2280) and early-onset CMV disease occurred in 2.0% (45/2280) of heart transplant recipients. Risk factors for delayed-onset CMV disease included residence in a non-metropolitan locale (aHR. 1.8; 95% confidence interval [CI], 1.0–3.3) and ischemic cardiomyopathy as heart failure etiology (aHR, 1.8; 95% CI, 1.3–2.5). Inpatient death >100 days after transplant was associated with delayed-onset CMV disease with possible tissue invasion (aHR, 2.0; 95% CI, 1.1–3.8), transplant failure or rejection (aHR, 4.0; 95% CI, 2.7–5.8), and renal failure (aHR, 1.5; 95% CI, 1.1–2.0).ConclusionsDelayed-onset CMV disease is more common than early-onset CMV disease among heart transplant recipients. These results suggest that delayed-onset tissue-invasive CMV disease may be associated with an increased risk of death.     

The use of CMVIg rescue therapy in cardiothoracic transplantation: A single‐center experience over 6 years (2011‐2017)

Cytomegalovirus (CMV) is the most important infectious agent in solid organ transplant recipients and has a major impact on morbidity and mortality. Most cases are well managed with antiviral agents, but CMV hyperimmune globulin (CMVIg) can be used alongside antiviral therapy for prophylaxis in high‐risk thoracic organ recipients and to treat life‐threatening CMV infection or disease. CMVIg may also improve antiviral host defences when genetic resistance to antivirals or unwanted side effects occur. In this single‐center, retrospective study, we reviewed the CMVIg use to supplement antiviral therapy as a “rescue therapy” in cardiothoracic transplant recipients. These comprised 12 single lung, 11 double lung, and 12 heart transplant recipients. Patients received a median of 2 doses of CMVIg, most often in combination with ganciclovir or valganciclovir, and reduced immunosuppression. One week after rescue therapy was initiated, CMV DNA levels were significantly reduced, and after four weeks, CMV DNA was undetectable in 73% patients. Only one patient died as a result of CMV‐related disease. No significant adverse effects were observed. We conclude that CMVIg rescue therapy is safe, well tolerated, and effective at controlling viral replication in cardiothoracic transplant recipients.     

The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus (CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplant recipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associated with a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence of rejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplanted organ. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovascular disease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infection and increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number of pathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medication can reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly in kidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk of CMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMV infection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects.     

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）肺炎的诊断和治疗,方法,回顾性总结32例肾移植术后发生CMV肺炎的临床资料,通过检测外周血中CMV IgM和（或）CMV DNA,结合临床症状及胸片明确诊断,以更昔洛韦治疗,同时治疗混合感染,加强营养支持,并根据动脉血氧分压,尽早使用呼吸机,结果：27例（84．4％）治疗有效,其中26例治愈,2例好转,死亡5例,结论：对肾移植术后CMV肺炎应尽早诊断,及时应用以更昔洛为主的综合治疗。     

Treatment of cytomegalovirus infection or disease in solid organ transplant recipients with valganciclovir

Valganciclovir (VGC) has proved efficacious and safe for the prophylaxis against cytomegalovirus (CMV) in high-risk transplant recipients and for the treatment of CMV retinitis in AIDS patients. We used VGC for the treatment of CMV infection (viremia without symptoms) or disease (CMV syndrome or tissue-invasive disease) in kidney, heart, and lung transplant recipients. Fourteen transplant recipients were treated: five for asymptomatic CMV infection and nine for CMV disease. VGC was administered in doses adjusted to renal function for 4 to 12 weeks (induction and maintenance therapy). Clinically, all nine patients with CMV disease responded to treatment. Microbiologically, treatment with VGC turned blood culture negative for CMV within 2 weeks in all patients and was associated with a > or =2 log decrease in blood CMV DNA within 3 weeks in 8 of 8 tested patients. With a follow-up of 6 months (n = 12 patients), asymptomatic recurrent CMV viremia was noted in five cases, and CMV syndrome noted in one case (all cases in the first 2 months after the end of treatment). VGC was clinically well tolerated in all patients; however, laboratory abnormalities occurred in three cases (mild increase in transaminases, thrombocytopenia, and pancytopenia). This preliminary experience strongly suggests that therapy with VGC is effective against CMV in organ transplant recipients; however, the exact duration of therapy remains to be determined: a longer course may be necessary to prevent early recurrence.     

Diagnosis of disseminated cytomegalovirus infection and pneumonitis in a heart transplant recipient by skin biopsy: case report.

A pulmonary infection caused by both Toxoplasma gondii and cytomegalovirus (CMV) developed in a heart transplant recipient. A presumptive diagnosis of CMV pneumonitis was made on the basis of a skin biopsy finding demonstrating CMV inclusions. This diagnosis was later supported by a positive pleural fluid culture for CMV, a greater than fourfold increase in CMV IgG antibody, and a response to therapy with ganciclovir sodium. Biopsy of skin lesions in patients at risk for CMV infections may represent an important early diagnostic tool.     

Insidious course of cytomegalovirus infection in hand transplant recipient: case report, diagnostics, and treatment

Cytomegalovirus (CMV) infection is common in solid organ and composite tissue transplant recipients and so becomes an ever more important issue for clinicians of every specialty. In this article we describe a case of CMV infection in a hand transplant recipient, which led to an episode of acute rejection early posttransplantation that was unresponsive to antiviral therapy. Our observations support the guidelines of matching CMV-positive donors with CMV-positive recipients only; however, the possible consequences related to CMV disease make a strong point to advocate the use of CMV prophylaxis in all hand transplant recipients.     

Cellular Immune Responses to Cytomegalovirus in Renal Transplant Recipients

Control of CMV replication depends primarily on anti-CMV T lymphocyte activity. However, the functional T-cell responses to CMV in immunosuppressed solid organ transplant recipients are not well understood. In this study we employed cytokine flowcytometry (CFC) using pooled CMV peptides and viral lysates to detect CMV-specific T-cell responses in 17 healthy controls, 33 stable renal transplant recipients (Tx recipients) and 6 transplant recipients with active CMV infection (CMV(+)). We found that pooled peptides and lysates provide optimal detection of IFN gamma production in anti-CMV CD8(+) and CD4(+) T cells, respectively. In both healthy controls and Tx recipients, CMV-specific T-cell levels strongly correlated with serostatus. Seropositive Tx recipients have significantly higher levels of CMV-specific CD8(+) T-cell responses compared to healthy controls, which may signify an effort to control enhanced viral replication in immunosuppressed Tx recipients. In some individuals, absence of anti-CMV T-cell response may correlate with lack of viral clearance by ganciclovir therapy, even when CMV isolates are not ganciclovir resistant. Thus, monitoring cellular immunity with CFC along with viral load by PCR merits further exploration for identification of patients at the risk of developing CMV disease, tailoring prophylactic and therapeutic decisions and preventing complications.     

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.     

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.     

Clinical usefulness of plasma quantitative polymerase chain reaction assay: diagnosis of cytomegalovirus infection in kidney transplant recipients

Background

Preemptive therapy is used to prevent cytomegalovirus (CMV) disease in transplant recipients. The CMV antigenemia assay, which has been commonly used as a predictive marker for preemptive therapy, requires intensive labor and immediate processing. We compared the cutoff value of plasma CMV polymerase chain reaction (PCR) with CMV antigenemia in kidney transplant recipients.

Methods

We compared two diagnostic methods for CMV infection in kidney transplant recipients: quantitative PCR (qPCR) versus antigenemia. We evaluated the optimal cutoff value of plasma CMV qPCR by using receiver-operating characteristic curves for specific antigenemia values. All kidney transplant recipients from January 2004 to January 2005 were enrolled and followed with CMV antigenemia and plasma CMV qPCR.

Results

The analyses were performed on 899 samples collected from 111 patients in the early posttransplant period, matching 84.1% of patients for the results of CMV antigenemia and plasma CMV qPCR. For patients with symptomatic CMV infection and disease, who showed ≥25 positive cells in the antigenemia assay, the cutoff value for qPCR was 17.8 copies/μL with a sensitivity of 97.1%, a specificity of 89.1%, and a positive predictive value of 26.6%.

Conclusions

Diagnostic assays for CMV such as CMV antigenemia and quantitative plasma PCR, showed similar diagnostic values. They are the methods of choice for the diagnosis and monitoring of active CMV infection after kidney transplantation. However, because of the relatively low positive predictive value of qPCR, this test may lead to unnecessary preemptive treatment in kidney transplant recipients.     

Significance of cytomegalovirus prophylaxis strategies and development of cancer in kidney transplant recipients

Cytomegalovirus (CMV) infection is one of the most common complications among kidney transplant recipients; two approaches preventing this complication are currently available: universal prophylaxis (UP) and pre-emptive therapy (PT). Despite some differences, similar effectiveness and safety have been proven in several studies for both strategies. However, Spinner et al compared both treatments in 115 renal transplant recipients showing deaths were more likely to occur in patients who received UP. Most of these deaths (2/4 cases) occurred because malignancies developed. This finding is paradoxical because CMV is considered a potentially oncogenic virus and, therefore, UP (a longer therapy compared with the PT) should not be linked with the emergence of a greater number of tumors. New evidence suggests that changes in host immune response triggered by CMV infection may have a mitigating effect on the development of tumors. It is now known CMV infection produces a clonal expansion of gamma delta T lymphocytes which can elicit an aggressive response against neoplastic cells. Currently, UP is the therapy most frequently used in Colombian transplant centers; however, doses administered vary depending on several clinical and laboratory factors. There are no clinical cohorts treated with PT. Reviewing the impact of different length dosing schemes is important for creating an immune response affecting malignancy development in kidney transplant recipients.     

Incidence and outcomes of cytomegalovirus in pancreas transplantation with steroid‐free immunosuppression

Cytomegalovirus (CMV) is a common opportunistic infection encountered after pancreas transplantation. The records of 407 pancreas transplant recipients (226 simultaneous pancreas and kidney transplant (SPK), 101 pancreas transplant after kidney (PAK), and 97 pancreas transplants alone [PTA]) performed at a single center with at least 1‐yr follow‐up were reviewed. Immunosuppression included rabbit antithymocyte globulin induction, steroid withdrawal, and maintenance therapy of tacrolimus and sirolimus (± mycophenolate). In addition, PTA recipients received a single dose of rituximab. All recipients received valganciclovir prophylaxis. Donor (D)+/recipient (R)− recipients received 6 months of prophylaxis; all others received 3 months. The overall CMV infection rate was 12%. The cumulative incidences of CMV infection at 3, 6, 9, and 12 months after transplant were 0.25%, 3%, 7%, and 8%, respectively. CMV infection rates were 20.2% in the D+/R− group, 16.5% in the D+/R+ group, 5.0% in the D−/R+ group, and 2.8% in the D−/R− group. Infections were less common in SPK recipients. Most infections developed at least 3 months post‐transplant, and 24% demonstrated tissue‐invasive disease. Immunosuppression was NOT reduced in 72% of patients with infections. Ganciclovir‐resistant CMV occurred in four patients. No patients died or lost their allografts due to CMV‐related infection; one graft was lost due to chronic rejection associated with a reduction in immunosuppression. In many cases, CMV infections may be treated in pancreas transplant recipients without necessarily reducing immunosuppression.     

Infections following orthotopic liver transplantation.

The epidemiology of infections associated with orthotopic liver transplantation is summarized herein, and approaches to prophylaxis are outlined. Infection is a major complication following orthotopic liver transplantation, and more than half of transplant recipients develop at least one infection. The risk of infection is highest in the first month after transplantation, and the most common pathogens are bacteria and cytomegalovirus (CMV). Bacterial infections usually occur in the first month, arise in the abdomen, and are caused by aerobes. The peak incidence of CMV infection is late in the first month and early in the second month after transplantation. CMV syndromes include fever and neutropenia, hepatitis, pneumonitis, gut ulceration, and disseminated infection. Other significant problems are Candida intraabdominal infection, Herpes simplex mucocutaneous infection or hepatitis, adenovirus hepatitis, and Pneumocystis carinii pneumonia. Prophylaxis of infection in liver transplant recipients has not been well-studied. Several different regimens of parenteral, oral absorbable, and/or oral non-absorbable antibiotics active against bacteria and yeast have been used at various centers, but no randomized controlled trials have been conducted. Selective bowel decontamination appears to be a promising approach to the prevention of bacterial and Candida infections, while oral acyclovir may be a relatively convenient and effective agent for CMV prophylaxis.