Clinical Presentation

Cytomegalovirus disease is found most commonly one to four months after transplantation. Manifestations of CMV range from asymptomatic viremia to lethal disseminated disease. Mild to moderate disease presents with fever, malaise, headache, arthralgias and myalgias. Laboratory abnormalities include leucopenia and thrombocytopenia. End organ involvement usually correlates with the type of transplant, thus, hepatitis occurs in liver recipients, glomerulopathy in renal transplants, pancreatitis in pancreatic transplants, and pneumonitis in lung and heart-lung recipients. Other organs that can be affected are the gut (gastritis, esoph-agitis, colitis), central nervous system (encephalitis, polyradiculopathy), and retina (retinitis). Colitis usually presents with diarrhea that is occasionally bloody, and it may be complicated by the formation of ulcers and perforation. Retinitis is significantly less common in transplant recipients than in patients with HIV infection.

Laboratory abnormalities with CMV end-organ involvement depend on the affected organ system. CMV pneumonitis appears radiographically as bilateral interstitial, unilobar, and nodular infiltrates. Hepatitis manifests with elevated transaminases, alkaline phosphatase, and gamma-glutamyltransferase with minimal increases in bilirubin levels. The definitive diagnosis of CMV organ involvement often requires biopsy of the affected organ and pathologic demonstration of inclusion bodies or detection of CMV in tissue by immunohistochemistry or in-situ hybridization techniques.

To detect replicating virus in fluids or tissue, several techniques have been used including tube cell culture that demonstrates the cytopathic effect of the virus after 7-14 days of incubation and rapid shell-vial culture that uses fluorescent labeled antibodies and yields results in a shorter period of time, usually after 24-48 hours. Serologic testing is not reliable for the diagnosis of acute CMV infection.

Rapid tests that detect early disease are blood CMV antigenemia and PCR techniques. These two methods are used to determine which patients may benefit from preemptive administration of antiviral drugs in an effort to avoid the development of overt CMV disease.

Treatment

The currently available antivirals for the treatment and prevention of CMV disease are acyclovir, valacyclovir, ganciclovir, valganciclovir, foscarnet, and cidofovir. Acyclovir, valacyclovir, ganciclovir, and valganciclovir are available in oral formulations. CMV hyperimmune globulin is available in different preparations as well.

Treatment of established CMV disease currently relies on the intravenous administration of ganciclovir. Induction treatment at doses of 5 mg/kg twice daily are used, and maintenance doses are 5 mg/kg/daily. Duration of treatment varies depending on the severity of the disease; viremia may be treated with a regimen of 14 days at full doses whereas end-organ involvement usually requires longer courses. Oral ganciclovir has been used as maintenance therapy to prevent relapses of CMV. Valganciclovir offers improved oral bioavailability over GCV; however, limited clinical data are available to support its routine use for the treatment of transplant-related CMV infection. Side effects of GCV include bone marrow suppression, hemolysis, renal toxicity, rash, liver function abnormalities, and infusion site reactions.

D+R- patients with CMV infection who have received multiple courses of ganciclovir are at risk for the development of antiviral drug resistance. Ganciclovir resistance, usually caused by viral mutations in the UL97 gene, must be considered in patients with poor clinical response or persistent viral shedding during treatment.

The use of foscarnet in transplant recipients is less well studied. Side effects of this drug include nephrotoxicity, hyper- and hypophosphatemia, hyper- and hy-pocalcemia, nausea, vomiting, and seizures. Its use is reserved for patients who are intolerant of or have failed to respond to GCV.

Some centers advocate CMV hyperimmune globulin as an adjunctive therapy for CMV disease but other studies fail to confirm its effectiveness. Combination of this agent with GCV may be useful, especially in patients with severe life threatening disease, such as CMV pneumonitis.

Prevention

There are two main strategies for the prevention of CMV disease after transplantation. The first is the administration of antiviral prophylaxis to prevent the occurrence of CMV disease. The second approach is pre-emptive therapy, whereby patients at risk are monitored for laboratory evidence of subclinical CMV infection, usually by the CMV antigenemia or quantitative CMV PCR assay, and initiated on antiviral therapy if subclinical infection is detected. There is significant debate in the literature in regards to the effectiveness of these different approaches for the prevention of CMV disease, although both strategies are acceptable practices.

In general, the pre-emptive therapy strategy is effective in CMV-seropositive recipient groups. However, D+R- patients require oral GCV prophylactically. Because of improved oral availability, many centers now use valganciclovir instead of GCV, although clinical data is lacking. Data on renal transplant recipients sug gests that valacyclovir is an effective alternative in this population. Patients in any group, except D-R-, receiving OKT3 or anti-lymphocyte antibodies are considered candidates for GCV prophylaxis since their risk of CMV disease is substantially increased. Prophylaxis is continued for the first three months after transplantation. One exception to this approach is lung and heart-lung recipients that fall into the D+R- group; since they are at the highest risk, intravenous full dose GCV for two weeks and followed by maintenance doses to complete three months of prophylaxis after transplantation seem warranted to prevent severe disease.

For individuals in the D-R- group, CMV-negative blood products are administered if needed to prevent primary CMV infection and subsequent risk of disease.

Epstein-Barr Virus

Overview

Epstein-Barr virus infection plays an important role in the development of post-transplant lymphoproliferative disorder (PTLD). Most transplant recipients have been infected with EBV at some point during their lifetime, and the virus persists within the host in a latent state. The pathogenesis of PTLD involves the heightened replication of EBV-infected lymphocytes triggered by agents such as OKT3 and the polyclonal anti-lymphocyte globulins. In addition, immunosuppression impairs the ability of virus-specific cytotoxic T-lymphocytes to control the expression of EBV-infected transformed B-cells, leading to the polyclonal and monoclonal proliferation of lymphocytes that constitutes PTLD. EBV may be of donor origin in EBV-seronegative recipients who receive an organ from a seropositive individual.

The incidence of PTLD ranges from 1% to more than 20% depending on the organ transplanted: 1% in renal transplant recipients, 2% in liver recipients, 2-4% in heart recipients, 2-8% in lung recipients, 11% in kidney-pancreas recipients, 7-11% in intestine recipients, and 13-33% in multi-organ recipients. Risk factors associated with the development of PTLD include EBV-seronegativity prior to transplantation, OKT3 or polyclonal anti-lymphocyte antibody therapy, CMV seromismatch, and CMV disease. Primary EBV infection is a strong predictor of PTLD.

Clinical Presentation

Primary infection with EBV may cause a syndrome characterized by malaise, fever, headaches, and sore throat. PTLD may develop at any time posttransplantation manifesting as a mononucleosis syndrome with fever, adenopathy, and sore throat; fever of unknown origin; allograft dysfunction; respiratory symptoms with pulmonary infiltrates; and weight loss. The definitive diagnosis of PTLD relies on histopathologic examination of biopsy specimens. Quantitative PCR techniques may help determine patients at high risk for the development of this disease before overt signs and symptoms manifest; however, this approach remains experimental.

Treatment

Once PTLD is established, the effectiveness of antiviral treatment has been disappointing. The main therapeutic approach in these cases is reduction of immu-nosuppression to the extent possible. Multifocal disease with organ involvement carries the worst prognosis, and in this setting, chemotherapy or radiotherapy is usually indicated. An alternative option is immunotherapy based on sensitized T-lymphocytes obtained from patients before transplant and stimulated ex vivo; such therapy is under investigation and is showing promising results.

Prevention

In EBV-seronegative patients, the use of EBV-seronegative organs constitutes the best option to prevent PTLD, especially in high-risk groups such as lung, gut, and pancreas recipients. It is unclear whether GCV is effective for the prevention of EBV-associated PTLD. Some data suggest that intravenous GCV followed by oral acyclovir during the first three months following transplantation decreases the incidence of PTLD in liver, kidney, and kidney-pancreas EBV-seronegative recipients, but there is not enough data to recommend this approach.

Herpes Simplex Virus

Overview

Infection with HSV in transplant recipients most commonly represents reactivation of latent virus. Up to 80% of adult transplant recipients are seropositive for HSV, indicating prior infection. Following primary infection, HSV remains latent in sensory nerve ganglia, and reactivation often occurs during the first month post-transplantation in up to 40% of organ recipients. The use of OKT3 is associated with higher frequency of reactivation.

Clinical Presentation

HSV reactivation most often manifests as oral or genital mucocutaneous lesions. Because of depressed cell-mediated immunity, organ recipients are at risk for more severe disease, delayed healing of skin lesions, and occasionally, visceral or disseminated involvement such as pneumonitis, tracheobronchitis, esophagi-tis, or hepatitis.

Mucocutaneous involvement presents as painful vesicular and ulcerative lesions; the appearance may be different than that observed in immunocompetent individuals. Pneumonitis is rare and usually seen in conjunction with other pulmonary infections. Ulcerative esophagitis manifests as dysphagia and odynophagia and can resemble or occur concomitantly with candidiasis. Hepatitis may occur and be rapidly progressive and fatal. Disseminated HSV is occasionally reported. Encephalitis is not seen with greater frequency than in immunocompetent individuals.

The diagnosis of HSV is made by direct immunofluorescent antibody staining, Tzanck smear, or culture of tissue and body fluids. Serodiagnosis is possible if IgM is detected or a four-fold rise in IgG titers is noted. In the case of HSV pneumonitis, the definitive diagnosis relies on histopathologic examination of biopsy speci mens, since the recovery of HSV from tracheal secretions may represent reactivation of virus in the oropharyngeal cavity.

Treatment

Acyclovir is considered the treatment of choice for HSV infections. Oral administration of 200 mg five times daily is effective in mild disease. Alternative oral preparations with better bioavailability are valacyclovir and famciclovir. Serious cases with disseminated infection or organ involvement requires treatment with intravenous acyclovir. Acyclovir may cause nephrotoxicity due to the precipitation of drug crystals in the renal tubules; other serious side effects include confusion, delirium, and seizures. The dose of acyclovir is adjusted according to the creatinine clearance. Acyclovir resistance has occurred in organ transplant recipients with HSV infection; foscarnet is considered the drug of choice in this situation.

Prevention

The use of low-dose acyclovir (200 mg every six to eight hours) for the first month after transplantation is an effective prophylactic regimen in all seropositive transplant recipients. Other potential options are valacyclovir and famciclovir.

Varicella Zoster Virus

Overview

Post-transplantation, VZV causes herpes zoster in seropositive individuals (90% of the adult population). The remaining 10% of patients are at a risk for primary infection. Up to 13% of transplant recipients develop herpes zoster during the first six months post-transplantation.

Clinical Presentation

Typical dermatomal skin lesions are the usual presentation of herpes zoster. Disseminated disease occurs as well, with multiple dermatome involvement. Der-matomal pain without skin eruption has been described.

Primary VZV infection is transmitted via contact with infected individuals; it may occur at any time after transplant and is potentially serious with pneumonia, skin lesions, hepatitis, encephalitis, pancreatitis, and disseminated intravascular coagulation.

The diagnosis is most often made clinically, but culture of VZV and direct im-munofluorescent antibody staining or Tzanck smear of appropriate clinical specimens are used for confirmatory purposes.

Treatment

The treatment of localized dermatomal zoster is treated with oral acyclovir, valacyclovir, or famciclovir. In severe cases, disseminated disease, or primary infection, intravenous acyclovir is administered initially and patients are monitored carefully. The duration of treatment is usually ten days.

Prevention

Varicella immune-globulin is administered to VZV-seronegative recipients exposed to acutely infected individuals. Prophylactic low-dose oral acyclovir may prevent VZV infections although this has not been formally studied.

Other Viruses

Human herpesviruses 6 and 7 reactivate after transplantation. The role of these viruses in clinical disease is currently under active investigation, as well as their interactions with other pathogens such as CMV and role in allograft rejection. There are no standard assays available for the diagnosis of these infections.

Hepatitis B and C viruses are common causes of end-stage liver disease and important indications for liver transplantation. The risk of recurrent infection with either virus is more than 80% after transplantation and morbidity can be high, especially in the case of hepatitis B. Viral hepatitis may be transmitted to recipients by the organs of infected donors. There is considerable ongoing debate regarding the use of organs from infected donors (mainly hepatitis C) in emergent transplantation of live-saving organs, and consensus has not been reached.

The polyomaviruses, BK virus (BKV) and JC virus (JCV), are ubiquitous viruses that cause subclinical and latent infections in humans. 80% of the adult population is seropositive for each of these viruses. These viruses may reactivate in the setting of immunosuppression, resulting in distinctive clinical syndromes. BKV reactivation after renal transplantation may result in tubulointerstitial nephritis, leading to progressive allograft dysfunction and eventual graft loss. In addition, BKV reactivation may present as ureteral stenosis leading to obstructive nephropathy. The diagnosis of BK nephropathy is suggested by the presence of characteristic "decoy" cells on cytologic examination of urine. Because the histo-pathological findings may be confused with allograft rejection, the definitive diagnosis is established by the demonstration of polyomavirus inclusions in renal biopsy specimens. The use of PCR assays with blood and urine specimens for the diagnosis of BK nephropathy are being investigated. Progressive multifocal leu-koencephalopathy, caused by the JCV, is less commonly encountered in organ recipients than in patients with acquired immunodeficiency syndrome. Treatment for polyomavirus infections has generally focused on supportive care and reduction of immunosuppression. A variety of antiviral agents are under investigation, with cidofovir demonstrating some promise.

Transplant recipients are also at heightened risk of developing infection with the related human papillomaviruses. These viruses are associated with neoplasms such as squamous carcinoma of the cervix. An association with skin carcinomas has been suggested but not definitively confirmed.

Parvovirus B19 infection may cause profound aplastic anemia after transplantation. Other respiratory viruses with potential to cause severe disease in transplant recipients include the respiratory syncytial virus, the adenoviruses, and the influenza viruses.

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