Late-onset cytomegalovirus disease in patients with solid organ transplant

PURPOSE OF REVIEW: To review existing data regarding late cytomegalovirus disease occurring after antiviral prophylaxis. RECENT FINDINGS: There is a continued debate as to the respective merits of the preemptive and the prophylactic approach to prevent cytomegalovirus disease after transplantation. Arguably, by allowing some infection, the preemptive approach helps build immunity in contrast to prophylaxis, explaining the occurrence of late cytomegalovirus disease in the latter approach. No study comparing directly both approaches is large enough to definitely determine whether the preemptive approach leads to a faster development of immune response protective from late disease nor whether late disease is clinically different after prophylaxis compared to early cytomegalovirus diseases. While risk factors for late cytomegalovirus disease all point to a delay in mounting immune responses, there are no identified markers that would help predict the risk for late disease at the time of prophylaxis discontinuation. Various approaches to prevent late cytomegalovirus disease have been developed: prolonged prophylaxis, microbiological surveillance and preemptive treatment after prophylaxis discontinuation. Considering the identifying risk factors for late disease, it would also make sense to envision vaccinating cytomegalovirus-seronegative recipients. SUMMARY: The best approach to prevent or manage late cytomegalovirus disease associated with cytomegalovirus prophylaxis remains to be defined.     

Clinical impact of ganciclovir-resistant cytomegalovirus infections in solid organ transplant patients

Clinical consequences of ganciclovir resistant cytomegalovirus (CMV) infections were studied during 2 large prophylactic trials consisting of 100 days of valganciclovir or ganciclovir prophylaxis in solid organ transplant (SOT) recipients. The first one involved 301 high-risk (CMV donor seropositive/recipient seronegative) SOT recipients excluding lung transplants followed for 12 months, whereas the second one involved 80 lung transplant patients evaluated over 6 months. Among the 7 patients (4 non-lung and 3 lung transplant patients) carrying viruses with known ganciclovir-resistance [corrected] mutations in blood, adverse clinical outcome was only observed in the lung transplant recipients. Additionally, no CMV resistance mutations were observed in non-lung transplant patients receiving valganciclovir.     

Phaeohyphomycotic infections in solid organ transplant patients

Phaeohyphomycoses are darkly pigmented fungi that rarely cause infection in immunocompetent persons. In the past 2 decades these fungi increasingly have been reported as pathogens that cause significant morbidity and mortality in the immunocompromised host, especially solid organ transplant recipients. Clinical manifestations range from superficial lesions to disseminated infections. Exophiala spp. and Alternaria spp. account for the great majority of these infections. Treatment should include complete surgical excision of the lesions that are accessible combined with antifungal therapy, especially when invasive or systemic infection is present. Itraconazole usually suffices if only subcutaneous lesions are present; however, if the infection is systemic or it involves the central nervous system, the addition of amphotericin B is required. New investigational azoles also should be considered in these types of infections. This is a very heterogenous group of fungi and as such the sensitivities to antifungal agents is variable. Therefore, sensitivities should be obtained on every fungal isolate.     

Epidemiology of fungal infections in solid organ transplant patients

The epidemiology of fungal infection in solid organ transplant patients is of concern due to the high mortality associated with this complication. Rates of fungal infections vary by type of transplant recipient. Most of these infections occur two to six months after transplantation. Liver transplant recipients are more likely to have early fungal infection which is often due to Candida species. Exogenous and endogenous Candida infection may occur in the immunosuppressed patient in the intensive care unit. Patients with chronic rejection are more likely to have late infection (after six months) which may be due to Aspergillus or endemic fungi such as Cryptococcus. Lung and heart–lung transplant recipients are more predisposed to infection with Aspergillus and other filamentous fungi, due to exposure of the transplanted organ to the external environment. Preventative measures such as environmental controls and chemoprophylaxis may be beneficial in high-risk patients. Emerging fungal pathogens such as the dematiaceous fungi may cause skin or soft tissue infection, or more serious systemic infections. Fungal infection should be ruled out in the solid organ transplant patient with early brain abscess. Characteristic risk factors in high-risk types of solid organ transplant recipients should be recognized for early diagnosis and treatment of these infections associated with high morbidity and mortality.     

Thalassemic patients are at high risk for transfusion-transmitted cytomegalovirus infections

The prevalence of total as well as IgM antibodies against cytomegalovirus (CMV) was determined by enzyme immunoassay in a group of 287 multitransfused thalassemia major patients aged 5-39 years and in another group of 1,220 healthy controls. A significantly higher prevalence of CMV antibodies was observed in thalassemic patients of all age-groups compared with controls. The prevalence among splenectomized thalassemia patients was higher than among nonsplenectomized thalassemics. It is concluded concluded that patients with thalassemia, especially if splenectomized, are at high risk for transfusion-transmitted CMV infections. The high prevalence of CMV infections might be responsible, at least in part, for the immunological disturbances and the susceptibility to other infections observed in thalassemic patients. On the basis of these results, it is suggested that safe blood should be provided for anti-CMV-negative thalassemics, with priority to anti-HIV-positives and those who are to receive bone marrow transplantation.     

Relapsing cytomegalovirus infection in solid organ transplant recipients

Abstract:: Efforts to prevent relapsed cytomegalovirus (CMV) disease among solid organ transplant (SOT) recipients present clinical challenges. Historically, SOT recipients treated with short courses of ganciclovir, without documented clearance of viremia, had relapse rates of 23–33%. Current treatment often includes much longer courses of valganciclovir, and persistence of viremia at the end of treatment is rare. We sought to determine the rate and risk factors for relapse under those treatment conditions. Records of 1760 SOT recipients from January 2003 to June 2007 were reviewed; 105 cases of CMV viremia were identified. Relapse occurred in 20/105 (19%); 50% had end‐organ disease at the time of relapse. Most patients received approximately 3 months of valganciclovir. Clearance of viremia was documented in 19/20 patients with relapse. Multivariable analysis identified receipt of a thoracic organ and diabetes mellitus as risk factors for relapse. Despite long treatment courses with valganciclovir and documented clearance of viremia, CMV relapse remains common among SOT recipients. Better understanding of the epidemiology of CMV among SOT recipients and validation of risk factors for disease relapse should be the focus of future prospective trials. Such trials should include different treatment durations and extended monitoring for relapse.     

Prevention of infections in solid organ transplant recipients

Solid organ transplantation has become an important therapeutic option for multiple chronic diseases. With the advent of newer and potent immunosuppressive regimens, graft survival has improved, but at the expense of an increased risk for the development of infections secondary to bacterial, fungal, viral and parasitic pathogens. Prevention of such infectious complications with effective, well tolerated, and cost-effective anti-microbials would be ideal to improve the outcome of transplanted patients. However, the emergence of multi-drug resistant pathogens, medication toxicity and drug-drug interactions need to be carefully evaluated. This review summarizes the most relevant data pertaining to our current understanding of infection prevention for solid organ transplant recipients. Specific recommendations are given for the prevention of each group of microorganisms and types of solid organ transplant ( Note Presented in part at the First World Congress of Transplant Infectious Disease, 1–4 April 1998, Orlando, Florida.
).     

Immunohistochemically proven cytomegalovirus end-organ disease in solid organ transplant patients: clinical features and usefulness of conventional diagnostic tests

We studied the main clinical features, outcome, and laboratory parameters in a group of solid organ transplant (SOT) patients with immunohistochemically proven cytomegalovirus (CMV) disease. Confirmed CMV cases were obtained through databases. Demographics, clinical data, transplantation type, immunosuppressive regimens, donor and recipient CMV serostatus, therapy, outcome and laboratory results, pp65 antigenemia, and qualitative polymerase chain reaction (PCR) for CMV were analyzed. From 1995 to 2004, 31 cases with complete medical records were identified. Disease appeared between 24 and 2538 days after transplantation but most cases presented in the first 100 days. Gastrointestinal CMV disease was the most frequent form (71%), while thrombocytopenia was present in 50% of cases, and leukopenia was less common (35.5%). CMV pp65 antigenemia was positive in 58% of patients, but its sensitivity increased to 71% if performed during the first 6 months. A qualitative CMV PCR technique gave similar results during this period (71.4%). Most patients were treated with intravenous ganciclovir (n=25; 80.6%). In 4 cases (19.4%), use of foscarnet alone or a sequential regimen with ganciclovir-foscarnet was deemed necessary. Surgical procedures were necessary in 5 patients (16%). The death rate reached 13%. CMV end-organ disease can be a life-threatening infection in SOT patients. Gastrointestinal disease was the most frequent end-organ disease. CMV antigen detection is best suited for the early period after transplantation.     

Valganciclovir prophylaxis in patients at high risk for the development of cytomegalovirus disease

BACKGROUND: Despite advances in antiviral therapies, cytomegalovirus (CMV) remains the leading opportunistic infection in the transplant population. Valganciclovir (VGC), the L-valyl ester prodrug of ganciclovir (GCV), provides an excellent oral alternative to GCV for the prevention of CMV in transplant recipients. We investigated the use of VGC for CMV prevention in high-risk renal and pancreas transplant recipients. METHODS: Patients at high risk for development of CMV disease were defined as either those who had donor positive, recipient-negative serostatus (D+/R-), or those who received antilymphocyte antibody (ALA) therapy for either rejection treatment or induction. A retrospective review was conducted of all kidney and pancreas transplants performed between August 2001 and December 2003. A total of 341 transplants were performed, of which 109 received VGC, and 88 were included in this analysis. RESULTS: The overall incidence of CMV disease was 5.7% (5/88). All of the CMV episodes were in patients who were D+/R- (17.2% [5/29] versus 0% [0/59], P<0.001). Of these patients, all the episodes of CMV were in patients who received VGC prophylaxis for<100 days post transplant (29% [5/17] versus 0% [0/12], P=0.06). The overall incidence of leukopenia was 11% and thrombocytopenia was 7%, with the incidence between the D+/R- group and the ALA group being similar. CONCLUSION: VGC is an effective agent in preventing CMV disease in kidney and pancreas transplant recipients who are at high risk for developing the disease. The optimal length of prophylaxis in D+/R- patients is still undefined, while 3 months of prophylaxis appears to be sufficient in patients who received ALA therapy.     

Endemic and opportunistic infections in Brazilian solid organ transplant recipients

Objective To evaluate the frequency and clinical features of endemic and other opportunistic infections in liver or kidney transplant recipients in four transplant centres in different geographical areas of Brazil. Methods Retrospective analysis of medical and laboratory records of four transplant centres on endemic and other opportunistic infections in liver or kidney transplant recipients. Analyses were performed with spss statistical software. Results From 2001 to 2006, 1046 kidney and 708 liver transplants were registered in all centres. The average age was 42 years. Among 82 (4.7%) cases with infections, the most frequent was tuberculosis (2.0%), followed by systemic protozoal infections (0.7%), toxoplasmosis (0.4%) and visceral leishmaniasis (0.3%). Systemic fungal infections occurred in 0.6%, of which 0.4% were cryptococcosis and 0.2% were histoplasmosis. Dengue was the only systemic viral infection and was registered in two cases (0.1%), of which one was classified as the classic form and the other as dengue haemorrhagic fever. Nocardiosis was described in one case (0.05%). The infectious agents most frequently associated with diarrhoea were Blastocystis sp., Schistosoma mansoni and Strongyloides stercoralis. Conclusions Opportunistic Infections in transplant patients have a wide spectrum and may vary from asymptomatic to severe infections with high mortality. A better understanding of the epidemiology of endemic pathogens and clinical manifestations can contribute to the establishment of an early diagnosis as well as correct treatment aimed at decreasing morbidity and mortality.     

Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophylaxis

Background: Optimal prophylaxis against cytomegalovirus (CMV) disease for organ transplant patients at risk for primary infection (donor seropositive, recipient seronegative, D+R?) remains to be determined. We hypothesized that prolonged oral ganciclovir therapy following intravenous therapy would provide increased protection. Methods: A total of 155 evaluable D+R? organ transplant recipients from 13 transplant centers were entered into the study: all received intravenous ganciclovir (5 mg/kg/day) for 5–10 days and then either oral acyclovir (400 mg tid) or oral ganciclovir (1 g tid) for an additional 12 weeks. Patients were assigned to their treatment groups at a central randomization site, with a separate randomization scheme for each of the organs transplanted (kidney, heart, or liver). In the case of kidney transplants, the patients were stratified according to source of the kidney (living related vs. cadaveric donor). The primary endpoint was the incidence of CMV disease in the first six months post‐transplant. Results: Treatment with oral ganciclovir was associated with a significant decrease in the incidence of symptomatic disease or viremia when compared with the oral acyclovir group (32% vs. 50%, P<0.05). This difference was most marked in terms of tissue invasive disease: only 3 of 15 symptomatic patients in the ganciclovir group vs. 10 of 21 in the acyclovir group developed tissue‐invasive infection (P<0.05). There was a significant difference in the time to CMV disease or viremia in the two groups: mean time 212±17 days post‐transplant for the acyclovir group vs. 291±13 days for the ganciclovir group (P<0.001). The incidence of allograft rejection was 34% in the ganciclovir group and 46% in the acyclovir group (P=NS). Leukopenia was more common in the ganciclovir group (P<0.05), but in no case did it require drug discontinuation. Ganciclovir resistance did not develop in this study. Conclusion: Prophylaxis with oral ganciclovir following a brief course of intravenous ganciclovir provides useful protection against primary CMV disease.     

The rapid diagnosis of pulmonary infections in solid organ transplant recipients

A rapid diagnostic team was formed to facilitate the diagnosis of pulmonary infections in solid organ transplant recipients. Seventy-seven renal and three liver transplant recipients developed 86 episodes of pneumonitis between 6 and 2,410 days posttransplant (median, 117 days). A diagnosis was established in all but seven patients. More than one diagnosis was established in 25. Cytomegalovirus (CMV) occurred in 51 episodes, bacterial pneumonia in 16 episodes, Pneumocystis carinii (PCP) in 11 episodes, fungal or Nocardia in 10 episodes, and Legionellosis in six episodes. Over half of the episodes of pneumonitis occurred in the period 1 to 4 months posttransplant. Bacterial pneumonia occurred significantly later than pneumonitis caused by PCP, Legionella, or CMV. Death occurred in 24 transplant recipients (31%) including 19 of 49 patients (39%) with CMV. Diffuse disease was the most common abnormality noted on initial chest roentgenogram (79 of 111, 71%). Interstitial infiltrates were the most common type of radiographic lesion observed, accounting for 62 of 111 (56%). Fiberoptic bronchoscopy was performed in 69 transplant recipients. Thirty-six of the 65 diagnoses made were established early, within 24 hours after bronchoscopy. Of the remaining diagnoses established later than 24 hours, all but one case of CMV was included. Bronchial alveolar lavage alone established 31 of the diagnoses. Bronchial brushings alone established only six cases, including five episodes of bacterial pneumonia and one case of CMV. We conclude that a team approach relying on fiberoptic bronchoscopy is useful in establishing the diagnosis of pulmonary infections in solid organ transplant recipients.     

The role of fibre-optic bronchoscopy in solid organ, transplant patients with pulmonary infections.

Organ transplantation is currently the standard therapy for patients with end-stage organ dysfunction. The immunosuppression caused by this therapy increases the rate of infection, particularly in the lungs. Early diagnosis is extremely important and fibre-optic bronchoscopy is a helpful tool in reaching diagnosis. Knowing the timing of various pathogens following transplantation, and the radiological picture as well as the prophylactic regimen, is helpful when specific pathogens are suspected. Bronchoscopy with bronchoalveolar lavage and transbronchial biopsies are particularly helpful in diagnosis of bacterial cytomegalovirus (CMV) and pneumocytosis carinii pneumocytosis, and is considered a safe procedure. Open lung biopsy is reserved for those who have negative bronchoscopy with a reasonable prognosis.