American Journal of Kidney Diseases
April 2001 • Volume 37 • Number 4 • p659 to p676

Viral infections after renal transplantation

Stephen R. Smith, MD, David W. Butterly, MD, Barbara D. Alexander, MD, Arthur Greenberg, MD

Abstract

Viral infections are a leading cause of posttransplantation morbidity and mortality. A number of recent developments have altered our understanding and management of these disorders. The pathogenetic roles of several viruses, including human herpesviruses 6 and 8, have been newly established. Molecular-based diagnostic tests now make more rapid diagnosis possible. The licensing of new potent antiviral agents offers a wider choice of drugs for viral prophylaxis and treatment. The use of more potent immunosuppressive agents is responsible in part for the increasing incidence of some viral infections, but this varies among drugs, and individual viruses differ in their sensitivity to immunosuppressive agents. This review summarizes the natural history, diagnosis, prevention, and treatment of many common viral infections after renal transplantation.



Supplemental reference list appears only on the web site electronic pages (www.ajkd.org)

VIRAL INFECTIONS ARE a major complication of the postoperative course in renal transplant recipients.1 A number of highly specific laboratory tests with rapid turnaround times have greatly improved the ability of clinicians to diagnose viral infections in a timely fashion. Moreover, in the last several years, a number of new antiviral agents have received approval from the Food and Drug Administration, leading to changes in the strategy for treatment and prophylaxis. The use of more potent immunosuppressive therapies has also changed the spectrum of viral diseases. Concern about hepatitis B and C occurs before transplantation, when decisions are made to list infected individuals for transplantation or use organs from infected donors. Excellent reviews of this controversial area are available elsewhere.

Human herpesviruses


Herpesviruses are DNA viruses that characteristically become latent after primary infection and may cause disease years after initial exposure. Eight herpesviruses are known to be pathogenic in humans. Except for human herpesvirus 8 (HHV-8), all are widespread in industrialized societies. Serological diagnosis is therefore not useful except in documenting prior exposure.

 

HHV-1 and -2: Herpes simplex 1 and 2
In 50% to 66% of seropositive renal allograft recipients, viral shedding can be detected within 5 to 14 days after transplantation, but only 15% to 45% develop symptomatic ulcers or vesicles.2 Cutaneous lesions may persist for months, and dissemination to internal sites, including the esophagus, colon, and bladder, as well as ocular involvement with corneal and retinal infection, may also occur.3-5 Hepatitis from herpes simplex 1 (HSV-1) or HSV-2 is uncommon, but potentially life threatening. Most cases represent primary infection with donor virus, although fatalities from reactivation have been reported.6 Typically, HSV hepatitis occurs very soon after transplantation, with onset within 4 to 20 days. In solid-organ transplant recipients, the median time of onset was 18 days compared with a peak time of onset for cytomegalovirus (CMV) hepatitis of 35 days. With hepatitis, cutaneous manifestations are the exception rather than the rule. The mortality rate for this disorder is high, up to 67%.6 HSV meningoencephalitis is most often caused by HSV-1. The virus preferentially affects the temporal lobes, and hallucinations or focal neurological signs may be present. Magnetic resonance imaging may show hyperintensity on T2-weighted images in the same distribution. A single case of interstitial nephritis with allograft failure caused by HSV-1 has been reported.

The definitive diagnosis of active HSV infection relies on culture of vesicular fluid, mucosal swabs, cerebrospinal fluid (CSF), or urine. Polymerase chain reaction (PCR) testing can also be used; this technique is preferred for CSF.7 A positive Tzanck smear signifies herpesvirus infection but is not specific for HSV. Immunofluorescence staining with specific antisera is preferred.

Treatment regimens for mucocutaneous HSV infections in renal transplant recipients are similar to those used in immunocompetent individuals (Table 1).


Table 1. Antiviral Therapy


Indication

Normal Renal Function

GFR 10-50 mL/min

GFR < 10 mL/min

HD or PD*

Herpes simplex

 Initial genital†

ACY, 400 mg 5 × d, or VAL, 1 g 3 × d for 10 d

ACY, no change; VAL, every 12-24 h

ACY, every 12 h; VAL, 0.5 g every 24 h

HD: additional dose post-HD

 Recurrent genital†

ACY, 400 mg 5 × d, or VAL, 1 g 2 × d for 5 d

ACY, no change; VAL, 0.5 g every 24 h

ACY, every 12 h; VAL, 0.5 g every 24 h

HD: additional dose post-HD

CAPD: every 24 h

 Suppression of recurrent genital

ACY, 400 mg 2 or 3 × d or VAL, 1 g/d

ACY, no change; VAL, 0.5 g every 24-48 h

ACY, 50% every 12 h; VAL, 0.5 g every 48 h

HD: additional dose post-HD

CAPD: every 24 h

 Herpes labialis†

PCV, 1% topically every 2 h × 4 d or ACV, 400 mg 5 × d for 5 d

Topical, no change; ACY, no change

Topical, no change; ACY, every 12 h

HD: additional dose post-HD

 Encephalitis

ACY, 10-15 mg/kg IV every 8 h for 14-21 d

Every 12-24 h

Every 24 h

HD: additional dose post-HD

CAPD: 50% every 24 h

Varicella-zoster

 Varicella‡

ACV, 10 mg/kg IV every 8 h for 7-10 d

Every 12-24 h

Every 24 h

HD: additional dose post-HD

CAPD: every 24 h

 Zoster§

VAL, 1 g 3 × d, or ACY, 800 mg 5 × d for 7 d, or ACY, 10 mg/kg IV every 8 h for 7 d

VAL 1 g every 12-24 h; ACY, 800 mg every 8 h or IV every 12-24 h

VAL, 0.5 g every 24 h; ACY, 800 mg every 12 h or IV every 24 h

HD: additional dose post-HD

CMV

 Prophylaxis||

GAN, 5 mg/kg IV 2 × d (see note for duration), then 1 g 3 × d to complete 3 mon; VAL, 2 g 4 × d for 3 mon

GAN, 25%-50% IV every 24 h; GAN, 0.5-1 g every 24 h; VAL, 1.5 g 2-3 × d

GAN, 25% IV every 24 h; GAN, 0.5 g every 24 h; VAL, 1.5 g every 24 h

HD: administer daily dose post-HD

 Treatment

GAN, 5 mg/kg IV 2 × d for 14 d, then 1 g 3 × d to complete 6 wk

25%-50% IV every 24 h; 0.5-1 g every 24 h

25% IV every 24 h; 0.5 g every 24 h

HD: administer daily dose post-HD

Influenza

 Prophylaxis or treatment¶

Amantadine, 100 mg 2 × d

100 mg every 48 h

200 mg every 7 d

No supplement

Rimantadine, 100 mg 2 × d

100 mg 2 × d or every 24 h

100 mg every 24 h

No data

 Treatment¶

Zanamivir, 10 mg by inhalation 2 × d × 5 d

No adjustment, limited data 75 mg every 24 h

No adjustment, limited data

No adjustment, limited data

Oseltamivir, 75 mg 2 × d

No data

No data

Parvovirus

 Treatment

IV IgG, 0.4 mg/kg, every 24 h × 5-10 d

No adjustment

No adjustment

No adjustment


NOTE. See text for details. Dosages are for oral administration except as specified. Valacyclovir is currently two to three times more expensive than acyclovir. In choosing between these agents, the pharmacokinetic advantage of less frequent dosing should be weighed against the cost, based on individual patient requirements.
Abbreviations: ACV, acyclovir; GAN, ganciclovir; PCV, penciclovir; VAL, valacyclovir; HD, hemodialysis; PD, peritoneal dialysis; GFR, glomerular filtration rate; IV, intravenously; CAPD, continuous ambulatory PD.
*Dose for GFR less than 10 mL/min except as noted.
For severe mucocutaneous disease, ACV, 5 mg/kg, IV every 8 hours for 7 days is recommended.
VZIG prophylaxis, 1 vial/10 kg (maximum, 5 vials) should be used if less than 72 hours has elapsed since exposure. Discontinue azathioprine or mycophenolate.
§Initial hospitalization and IV therapy is recommended for disseminated disease. Oral therapy may be used in patients with no more than three involved dermatomes. VZV is also susceptible to GAN, which can be used alone if CMV and VZV are present simultaneously.
||Low-risk recipients (D–/R–) do not require prophylaxis. High-risk recipients (D+/R–) treated with antilymphocyte preparations for induction or acute rejection should be administered IV GAN for 3 weeks, followed by oral GAN. Intermediate-risk patients (D+/R– or D+/R+) administered antilymphocyte preparations for induction or acute rejection should be administered IV GAN while hospitalized, followed by oral GAN.
When used for treatment, these agents must be started within 48 hours of symptom onset. Data for zanamivir and oseltamivir are very limited. Annual vaccination is the mainstay of prophylaxis.


Valacyclovir and famciclovir have recently been approved for the treatment of HSV. Their increased oral bioavailability is an important advance over acyclovir, but the benefit of less frequent dosing is tempered for many patients by the significantly greater cost.

Primary oral or genital herpes and recurrences should be treated. Suppressive therapy is useful for frequent recurrences. For oral herpes prophylaxis, once-daily valacyclovir is efficacious in immunocompetent adults. No data are available in renal transplant recipients, and some caution is necessary because of several reports of thrombotic thrombocytopenia and/or hemolytic uremic syndrome in renal transplant recipients administered valacyclovir prophylaxis.8 Data on famciclovir use in transplant recipients are also lacking. Penciclovir is available for topical use; it has no apparent advantage over acyclovir. In transplant recipients, prophylaxis with acyclovir, 200 mg, three times daily or even once daily can prevent, delay, or lessen the severity of oral or genital HSV reactivation.9 Given these data, we use acyclovir or valacyclovir for treatment of acute episodes, but we prefer acyclovir for prophylaxis.

HHV-3: Varicella-zoster virus
Before effective antiviral therapy, varicella was frequently associated with an adverse outcome. In one study, 12% of 160 pediatric renal allograft recipients developed varicella after renal transplantation. Of these patients, 16% had reinfections and 42% had severe disease, defined as either persistence of fever and new vesicle development lasting longer than 6 days or mucosal involvement. There was one death. Complications in the severe-disease group included urinary retention caused by bladder nerve involvement, transaminase level elevations, and thrombocytopenia.10 Among renal transplant recipients, primary varicella is more severe in adults than children, but available studies are small and subject to reporting bias. Complications in adults include disseminated intravascular coagulation, hepatitis, and secondary bacterial or fungal sepsis. In one series, four of five adults died. However, only one patient was administered timely acyclovir treatment.11 The outcome is more favorable with acyclovir.12

After primary infection, varicella-zoster virus (VZV) becomes latent in spinal dorsal root or cranial nerve sensory ganglia. Reactivation leads to herpes zoster. In healthy individuals, only the primary dermatome is involved, and the major morbidity is postherpetic neuralgia. Renal transplant recipients may develop localized dermatomal herpes zoster involving one to three dermatomes (primary and two contiguous dermatomes), disseminated cutaneous zoster that crosses the midline or involves more than three dermatomes, or visceral zoster with lung or liver involvement. Up to 33% of untreated cases disseminate.13

Besides VZV hepatitis, Reye’s syndrome should also be considered in the differential diagnosis of hepatic dysfunction after varicella, particularly if hyperbilirubinemia is absent. Varicella pneumonia presents with diffuse pulmonary infiltrates and hypoxemia. However, aspiration and other forms of pneumonia may also occur in these critically ill patients.12,14 Cerebellar ataxia is the most common neurological complication, but VZV may also cause myelitis or meningoencephalitis. Seizures occur in 25% to 50% of the patients. Anogenital zoster can lead to transient bladder paralysis with urinary retention.15

VZV infections are usually diagnosed clinically; however, virus can be cultured from vesicular fluid or bronchial washings, and immunohistochemical staining of biopsy material can provide laboratory confirmation. VZV DNA can be identified in liver biopsy specimens in cases of VZV hepatitis. CSF findings in VZV meningoencephalitis resemble those in HSV encephalitis. PCR or the measurement of CSF antibody directed against VZV permits rapid diagnosis.16 CSF pleocytosis may be observed in uncomplicated zoster, presumably as a response to nerve root inflammation.

Vesicular fluid contains infectious viral particles, and patients should be isolated until after all cutaneous lesions have crusted. However, this will not completely limit exposure because varicella spreads through the respiratory route before the rash develops. The period of contagion extends from 2 to 3 days before through 5 days after onset of the rash. If administered within 72 hours of exposure, varicella-zoster immune globulin (VZIG) provides effective postexposure prophylaxis in renal allograft recipients because it prevents or lessens the severity of primary varicella.17 VZIG may extend the incubation period of varicella from the normal 2 weeks up to 4 weeks. Occasional cases of varicella have been reported in transplant recipients in whom the natural antibody titer has declined.10 Some authorities recommend VZIG as postexposure prophylaxis for all transplant recipients unless immune titers are positive.14 This approach has not been widely adopted. Titers often are unavailable at the time of exposure. We withhold VZIG if a patient gives a reliable history of prior varicella.

Children awaiting transplantation, like all other children, should be vaccinated. Immunization is highly efficacious in preventing varicella in renal transplant patients. At 1 and 10 years, 62% and 42% of vaccinated children still had protective antibody titers, respectively. Among vaccine recipients, protective antibodies were lost in 7.4% within 1 year after transplantation and 24% after 5 years. This contrasts with loss rates of 0.4% and 4.5% at 4 years in transplant recipients with natural immunity after varicella. Although 45% of varicella-naive children developed varicella, no child who became and remained seropositive after vaccination developed varicella after transplantation. The attack rate was intermediate (25%) in vaccinees without protective antibodies. Immunization also reduced the severity of varicella and the incidence of zoster.18

Vaccination uses the live attenuated Oka strain. In a small trial, 16 of 17 individuals vaccinated after renal transplantation developed and retained antibodies for at least 1 year. One patient developed mild varicella from the vaccine strain.19 However, the vaccine is not licensed for use in immunosuppressed patients, and vaccination after transplantation is contraindicated. Among healthy individuals, transmission of the vaccine strain to household contacts has been described, but VZIG is not recommended, even for immunosuppressed siblings of vaccinees.

Because it has been shown to lessen the severity of disease, acyclovir is indicated for renal transplant recipients with VZV infection. Controlled studies are mainly limited to comparative trials of immunocompromised cancer patients, but one report included a small subset of patients administered azathioprine and prednisone after renal transplantation.20 Compared with placebo, acyclovir markedly limited the rate of cutaneous or visceral dissemination.13,21 Uncontrolled descriptions of marked improvement after initiation of acyclovir therapy also support treatment.11 In a retrospective study, only one death occurred among 66 acyclovir-treated pediatric renal transplant recipients with varicella. Nine patients (13%) had severe disease with pneumonitis, encephalitis, or prolonged fever and rash. Azathioprine therapy was discontinued at the time of diagnosis, although cyclosporine and prednisone were continued.22 In an earlier study, the subgroup of individuals in whom azathioprine therapy was discontinued had a milder course.10 Because an increased incidence of varicella reactivation has been reported in pediatric renal allograft recipients treated with mycophenolate, it also seems prudent to discontinue this agent in patients with varicella.23

VZV is less sensitive to acyclovir than HSV; therefore, bigger doses are required. Patients with varicella and disseminated zoster should be administered high-dose intravenous acyclovir with hospital monitoring (Table 1 ). After the fever resolves, patients without visceral involvement may safely be switched to oral acyclovir therapy.24 Localized zoster can be managed with oral therapy without hospitalization. Prednisone and acyclovir have not eliminated or shortened the course of postherpetic neuralgia consistently.25 In immunocompetent individuals, valacyclovir modestly but significantly shortened the time to cessation of postherpetic pain and reduced the percentage of patients with persistent pain at 6 months. Thus, it is probably the preferred drug.8 Famciclovir may also have a similar advantage, but experience is more limited. Gabapentin, tricyclic antidepressants, carbamazepine, and capsaicin can be tried in patients with established postherpetic neuralgia.

HHV-4: Epstein-Barr virus
Epstein-Barr virus (EBV) is responsible for a number of disorders, but the major concern in renal transplant recipients is posttransplant lymphoproliferative disorder (PTLD).26 Acute infection with EBV leads to polyclonal activation of B cells with expansion of lymphoid tissues. Because the cellular immune responses provided by natural killer cells and major histocompatibility complex (MHC)-restricted cytotoxic T cells are critical to clearing the virus, the T-cell–targeted immunosuppression used in organ transplantation puts allograft recipients at risk for PTLD. Specific agents vary in their propensity to cause PTLD. Antilymphocyte globulins are by far the principal risk factor (discussed later).

Four disease patterns for PTLD have been identified: (1) uncomplicated infectious mononucleosis; (2) benign, polyclonal, polymorphic B-cell hyperplasia; (3) early malignant transformation of polyclonal polymorphic B-cell lymphoma; and (4) monoclonal polymorphic B-cell lymphoma.27,28 In the Cincinnati registry, PTLD comprised 22% of posttransplantation tumors.29 European data showed a high risk during the first year (224 per 100,000, or 37 times the expected incidence). The presentation is dichotomous. Younger patients present earlier with polyclonal disease at an average 9 months after transplantation or intensification of immunosuppression. Older patients present later at an average 6 years, with monoclonal extranodal disease.

Extranodal involvement is present in 70% of the patients, and the most frequent sites are the central nervous system, allograft, and gastrointestinal tract. Presenting features can include fever and lymphadenopathy or isolated gastrointestinal symptoms, including anorexia, abdominal pain, diarrhea, obstruction, or bowel perforation. The usual sites of digestive tract disease are the distal ileum and right colon.

Allograft involvement accounts for approximately 20% of patients and is greatest in lung transplant recipients. In approximately one third of the patients with allograft involvement, disease is confined to that site. Occasionally, a biopsy for presumed rejection instead shows PTLD, and it is critically important to differentiate these two clinical entities. Immunohistochemical analysis shows renal interstitial infiltrates related to EBV stain for B-cell markers rather than the standard T-cell infiltrates seen in acute rejection. Demonstration of EBV genome with in situ hybridization or immunohistochemical stains is diagnostic.

A number of modalities have been tried to facilitate PTLD diagnosis. Neither an increase in antibody titers nor an increase in viral shedding is useful. EBV-positive B cells increase 100- to 1,000-fold after transplantation, 50% to 60% of transplant recipients shed EBV asymptomatically, and the rate increases with increasing immunosuppression and treatment of rejection. The isolation of EBV DNA in serum rather than peripheral-blood lymphocytes, which signifies a high viral load, has recently been shown to separate transplant recipients with PTLD from those without. However, these results have not yet been confirmed, and their clinical utility remains to be shown.30 Because of these limitations, the diagnosis of PTLD rests on finding immunohistochemical evidence of EBV in tumor tissue.

Specific treatment recommendations for primary EBV with infectious mononucleosis are lacking. Temporary reduction of immunosuppression and avoidance of antilymphocyte globulin therapy seem appropriate. Hairy cell leukoplakia responds to acyclovir therapy. Beyond reduction or discontinuation of immunosuppression, there is no consensus on the treatment of PTLD. Patients presenting early in the postoperative course, as well as patients with polymorphic disease, are more likely to have a favorable course.28,29 Central nervous system lymphomas initially respond to radiation, although recurrences are common. Localized gastrointestinal malignancies can be managed with resection and immunosuppression reduction. Antiviral therapy with ganciclovir, acyclovir, or interferon has been used with limited utility; interferon can promote rejection. For more advanced cases and monomorphic disease, radiation therapy and cytotoxic chemotherapy are used. Treatment options, including a variety of novel immunotherapeutic approaches, have been extensively reviewed.26,31 Ganciclovir or acyclovir administered for CMV prophylaxis reduces the later occurrence of PTLD.32 However, preventive strategies have not been widely applied, and their cost-effectiveness is uncertain.

HHV-5: CMV
CMV is named for the characteristic swelling of infected cells, which often contain inclusions. The virus is highly associated with cells. Because there are many genetically different CMV strains, seropositivity does not imply immunity, and reinfection with a different strain can cause symptomatic CMV disease.

Seropositivity rates for CMV among different populations range from 40% to 80%. Clinically apparent CMV disease can arise from the recipient’s latent strain or from primary or superinfection with virus that originates in a transplanted organ or blood product from a seropositive donor. Seronegative recipients of a kidney from a seropositive donor (D+/R–) usually seroconvert within the first 6 months after transplantation. Without prophylaxis and in the absence of antilymphocyte antibody therapy, approximately half the D+/R– individuals develop symptomatic CMV disease. Antilymphocyte therapy with OKT3 is associated with a greater risk for primary symptomatic CMV infection and a 2- to 10-fold greater risk for reactivation in seropositive recipients.33 Seronegative patients administered a blood transfusion from a seropositive donor are at similar risk. Symptomatic CMV infection occurs in less than 10% of seropositive recipients, independent of donor serological status.34

In renal allograft recipients, the clinical course of CMV disease from a primary infection does not differ from that with reactivation or superinfection. Typically, a syndrome characterized by fever and fatigue beginning 1 to 6 months after transplantation and accompanied by leukopenia or thrombocytopenia occurs. Fever spikes may be dramatic and can be interspersed with periods without fever during which the patient feels well. This syndrome may be accompanied by signs and symptoms of tissue-invasive disease, most commonly including hepatitis, pneumonitis, and gastrointestinal ulceration.35 Gastrointestinal involvement may occur without other signs of CMV disease. Any part of the gastrointestinal tract may be involved; thus, patients may present with odynophagia, substernal or epigastric pain, diarrhea, and upper or lower gastrointestinal bleeding. The biliary tract and appendix are rare sites of involvement. Normal-appearing cells surrounding areas of erosion, hemorrhage, or ulceration may show CMV cytopatholytic effects on histological examination. Therefore, random biopsy specimens are sometimes helpful, but infected tissue usually has an abnormal gross appearance. The incidence of CMV gastrointestinal ulceration appears to be increased in patients administered mycophenolate.35 CMV can also cause migratory abdominal pain in association with mesenteric lymphadenitis.

Rare consequences of CMV infection in renal transplant recipients include adrenalitis, encephalitis, and, as a late event, chorioretinitis. CMV infection in the transplanted kidney is also uncommon. Inclusions typical of herpesviruses may be seen in tubular epithelial cells and glomerular cells, and they are sometimes but not always accompanied by an inflammatory response.36 CMV has been associated with glomerulopathy characterized by endothelial swelling with narrowing of capillary lumens, mononuclear cell infiltration, and mild segmental hypercellularity, but without inclusions. Some patients experienced improvement in renal function after a reduction in immunosuppression. The causal relationship has been questioned, and this controversy has been reviewed in detail.37

CMV is associated with an increased subsequent risk for acute rejection.38,39 Whether the risk is conferred by the reduction of immunosuppressive medication used to treat CMV infection or is a direct immune-modulating effect of the virus is not known. Cytokines produced by CMV infection increase class II MHC expression on endothelial cells, as well as endothelial and tubular cell intercellular adhesion molecule 1 expression. CMV also encodes a glycoprotein homologous to class I MHC antigens.

A causal link between CMV infection and chronic allograft rejection has not been established. However, the vascular changes of chronic rejection mirror changes in cardiac allograft coronary arteries, vanishing bile duct syndrome in liver transplants, and bronchiolitis obliterans in lung transplant recipients in whom the link to prior CMV infection is stronger but still unproved. CMV infection predisposes to subsequent opportunistic infection, particularly Pneumocystis carinii pneumonia and fungal infection. CMV and VZV may occur simultaneously.

Two approaches to the diagnosis and management of CMV disease are available. The conventional approach is to perform a diagnostic test when symptoms arise, confirm the diagnosis, and treat accordingly. In the preemptive approach, high-risk patients are screened serially in an attempt to identify individuals destined to become symptomatic with CMV disease, and this subgroup is treated to prevent disease altogether. The diagnosis of CMV disease is made by detection of the virus in the peripheral blood or when characteristic findings are noted on histological examination of infected tissue and confirmed by immunohistochemical staining. Urinary shedding alone does not imply clinically significant CMV disease. Likewise, bronchoalveolar lavage fluid cultures are not sensitive or specific for CMV pneumonitis. However, viral load in bronchoalveolar lavage fluid correlates with disease.40

Despite their drawbacks, the introduction of tests detecting CMV viremia in blood (Table 2) has greatly refined the diagnosis of CMV disease and simplified its clinical management.


Table 2. Peripheral-Blood Tests for CMV Viremia


Sensitivity

Specificity

Time Course of Positive Test

Other

Shell vial culture

Low

Medium

Poor correlation with symptoms

Rapid loss of specimen viability; long turnaround time

pp 65 antigen

Medium to high

High

Correlates well with symptoms, but can be falsely negative early in the course or with leukopenia

Rapid loss of specimen viability

DNA hybrid capture

High

High

Correlates well with symptoms, but can be falsely negative early in the course or with leukopenia

Can be run on stored sample; may be too sensitive, with detection of clinically insignificant viremia

PCR assays

High

Medium

Positive before symptom onset; persists after symptom resolution

Leukocyte tests more sensitive than plasma test; prone to specimen contamination


PCR tests may be too sensitive; when qualitative PCR is used as part of a prospective surveillance program, many patients with positive test results do not go on to have CMV disease and the test remains positive long after symptoms are gone.41 Quantitative PCR may be more helpful in following up response to therapy.42 Currently, we favor a direct test for CMV DNA by hybrid capture. Like the pp65 antigen test, it tracks well with symptoms, but it may be run on stored samples.40 Quantitative assessment of the viral load using these molecular tests is being refined and standardized and will likely prove useful in the preemptive approach to CMV disease.40

Several prevention strategies can be used to reduce the likelihood of CMV disease. When blood transfusion is needed in a seronegative renal transplant recipient, use of blood from a seronegative donor is optimal, but seronegative blood is in short supply and better reserved for other patient populations. The likelihood of CMV disease can be reduced with a leukocyte filter. It is estimated that allocation of kidneys to maximize the number of donor and recipient CMV-negative pairs would increase the complexity of the matching algorithm with minimal effect on graft and patient survival.43 In the case of evaluation of more than one potential living related donor for a seronegative recipient, CMV status should be considered as one factor, equivalent in magnitude to one HLA-DR match.44

Active immunization with the Towne strain of attenuated CMV affords protection against severe infection in D+/R– patients. However, mild CMV disease was not eliminated, and seropositive recipients showed no benefit. Currently, no vaccine is approved by the Food and Drug Administration for CMV. Passive immunization with CMV immune globulin reduced the rate of CMV disease in D+/R– patients from 60% in the placebo group to 21% in a randomized trial. Seroconversion rates were unaffected. When CMV immune globulin was used in combination with oral acyclovir, 600 mg/d, for 3 months in D+/R– patients, the rate of CMV disease was reduced to 10%.45 CMV immune globulin is expensive and cumbersome to use; it requires seven intravenous doses over 16 weeks. Polyimmune globulin has modest efficacy in the prevention of CMV disease in seropositive recipients.

Antiviral therapy has also been studied. High-dose oral acyclovir was initially reported to be useful in renal allograft recipients. However, three subsequent studies failed to confirm its benefit.46 Ganciclovir is much more active against CMV than acyclovir, owing in part to its much longer intracellular half-life.47 Intravenous ganciclovir administered coincidently with antilymphocyte therapy for induction or rejection reduces but does not eliminate the risk for CMV disease. In a randomized trial, CMV disease occurred within 6 months in 14% of seropositive transplant recipients treated with this therapy versus 33% of patients administered antilymphocyte therapy alone.48 The preemptive approach using weekly screening followed by intravenous ganciclovir in the event of a positive test result reduced the incidence of CMV disease only slightly.49

Prolonged treatment with oral ganciclovir, despite less than 10% bioavailability, is potent prophylactic therapy for CMV disease. Several randomized trials have documented that the rate of CMV disease during treatment with 3 to 4 months of oral ganciclovir in doses as low as 250 mg twice daily is less than 5%. Ganciclovir has been shown to be more effective than acyclovir in preventing CMV infection and disease. A strategy using intravenous ganciclovir during antilymphocyte therapy followed by 3 to 4 months of oral ganciclovir virtually eliminated CMV disease in these patients. As indicated in Table 1 , we use this strategy. An evidence-based set of clinical practice guidelines for CMV prophylaxis after renal transplantation is available.50

Valacyclovir, a prodrug of acyclovir, was recently shown to be effective compared with placebo. The rate of acute rejection in valacyclovir-treated D+/R– patients was half that of the placebo group.39 Oral ganciclovir has not been compared directly with valacyclovir. Valganciclovir, a ganciclovir prodrug with increased oral bioavailability, is currently under development.

No reliable measures can indicate whether CMV disease will resolve spontaneously or after reduction of immunosuppression alone. Thus, most or all patients with laboratory-confirmed CMV syndrome should be treated. Dosage recommendations for ganciclovir are listed in Table 1 . Other schemes are also available.51 Intravenous ganciclovir induces remission of CMV disease in renal transplant recipients in all but rare cases that are ganciclovir resistant.47 Ganciclovir alone is seldom the cause of leukopenia during CMV treatment; mycophenolate or azathioprine dosage should be reduced or discontinued when leukopenia develops. Occasionally, severe leukopenia requires brief treatment with granulocyte colony-stimulating factor. Fever and leukopenia typically improve or resolve within 3 to 4 days, and quantitative markers of viremia decrease markedly during the first 2 weeks of treatment.42 Qualitative tests for viremia (pp65 antigen or CMV DNA by hybrid capture) may still be positive after 2 weeks of therapy.40 Recurrence of CMV disease after treatment with intravenous ganciclovir occurs frequently, especially after primary infection. Therefore, oral prophylaxis is recommended for at least 3 months thereafter.1 CMV immune globulin is sometimes administered for severe CMV infection in addition to an antiviral agent, although controlled studies of kidney transplant recipients are lacking. Recurrence is only rarely caused by the development of resistance, but ganciclovir-resistant strains of CMV are generally sensitive to foscarnet, which is otherwise to be avoided because of nephrotoxicity.47 Combined use of low-dose ganciclovir and low-dose foscarnet may be a useful strategy to lessen foscarnet toxicity.

HHV-6
HHV-6 causes exanthema subitum, a febrile disease of infancy that may be associated with rash. Immunoglobulin G (IgG) seroprevalence for HHV-6 in adults in industrialized societies approaches 90%. The cell in which the latent virus resides has not been established.

Our understanding of HHV-6 as a cause of disease in immunocompromised patients is still evolving. HHV-6 has been isolated from circulating monocytes of renal transplant recipients. Based on serological criteria or virus isolation, reactivation of HHV-6 is observed in 20% to 55% of renal allograft recipients. However, a clear relationship to a clinical disorder is lacking.52 Sixty percent of renal transplant biopsy specimens contain HHV-6 antigen in distal tubular epithelial cells, but the prevalence is the same whether the biopsy diagnosis is rejection or cyclosporine nephrotoxicity.53

Several forms of clinical involvement have been noted. In bone marrow transplant (BMT) recipients, HHV-6 DNA has been localized to lung tissue of inpatients with pneumonitis, but its causative role is not definite. The virus probably can cause encephalitis. HHV-6 has the potential to suppress bone marrow. Leukopenia is most common, but thrombocytopenia and even aplastic anemia also may occur.54 HHV-6 was cultured from the blood of six patients who developed leukopenia and fever 17 to 90 days after liver transplantation. CMV cultures were negative and patients responded to ganciclovir or foscarnet.55 Similar findings have been reported after renal transplantation, in which HHV-6 infection was associated with fever, leukopenia, thrombocytopenia, and elevated serum alanine transaminase and -glutamyl transpeptidase levels.56 This syndrome tends to occur earlier than CMV disease. Simultaneous isolation of HHV-6 and CMV was also observed.56 Interstitial nephritis with allograft dysfunction was attributed to HHV-6 in a patient with fever, leukopenia, newly detected HHV-6 IgM, and negative CMV antigen and cultures who had a clinical response to ganciclovir.57

HHV-6 should be suspected in patients with typical CMV syndrome and negative CMV viral studies. A shell vial early antigen assay is highly specific and sensitive. Cultures are also specific, but the issue of asymptomatic shedding arises. Because of its ubiquity, attribution of clinical significance to HHV-6 genome recovered from tissue specimens by PCR is problematic. Immunostaining methods for tissue specimens that detect structural proteins present only when the virus is replicating are more specific.54

HHV-6 is sensitive to ganciclovir. Thus, patients presenting with seronegative CMV or combined CMV and HHV-6 infection who undergo therapy for CMV also receive appropriate coverage for HHV-6.

HHV-7
HHV-7 may cause a syndrome similar to exanthema subitum, with rash, splenomegaly, leukopenia, neutropenia, and relative lymphocytosis. Infectious mononucleosis syndrome with lymphadenopathy and seizures may also occur. Primary infection occurs somewhat later than with HHV-6.58

The significance of reactivation of HHV-7 in renal transplant recipients is only beginning to emerge. In one study, CMV was detected by PCR in 58% of renal transplant recipients, HHV-7 in 46%, and HHV-6 in 23%, with frequent overlap. Detection of HHV-7 replication was associated with an increase in rejection episodes and CMV disease. These findings await confirmation.59

HHV-8
HHV-8 is the etiologic agent for Kaposi’s sarcoma (KS). This virus was first identified when a search for foreign DNA sequences in the genome of KS tissue isolated from patients with human immunodeficiency virus (HIV) disclosed sequences homologous to but distinct from known herpesviruses. The DNA sequences were subsequently found in patients with KS not associated with HIV and up to 96% of KS tissue obtained from organ transplant recipients.

Seroprevalence for HHV-8 varies greatly with the population examined, ranging from nil in US blood donors to 50% in individuals from sub-Saharan Africa, where KS is endemic, and 100% in patients with HIV and KS. End-stage renal disease per se is not a risk factor for HHV-8 exposure because the seropositivity rate is similar in hemodialysis patients and blood donors.60 The incidence of KS in renal transplant recipients varies in parallel to the prevalence in the donor and recipient populations. In two high-prevalence areas, Saudi Arabia and Italy, the KS incidence rates among renal transplant recipients were 5.3% and 1.6%, respectively. KS accounted for 87.5% of secondary malignancies in Saudi Arabia in contrast to the 3.7% rate in the Cincinnati registry.61,62 Either the donor or recipient can serve as the source of HHV-8.63,64 The use of antilymphocyte globulin may contribute to subsequent development of KS.65

Both limited and invasive variants of KS occur in renal allograft recipients. The classic limited form has an indolent course characterized by the development of violaceous nodules predominantly localized to the skin of the lower extremities. Nodules may ulcerate or infiltrate the lymphatic system and cause lower-extremity edema. The aggressive form involves the viscera, including oropharynx, lung, and gastrointestinal tract, and may present with pulmonary symptoms or gastrointestinal hemorrhage or perforation. Nine Saudi Arabian patients (64%) and five Italian patients (38%) had limited KS. The remainder had multiple sites of cutaneous involvement or visceral involvement. In the Cincinnati Transplant Tumor Registry, the average age of presentation was 43 years and mean time of onset was 21 months (range, 1 to 225 months). Nearly half the cases (46%) occurred within 1 year after transplantation; most patients were renal transplant recipients. The male-female ratio was 3:1 in contrast to the 17:1 ratio observed in classic KS.66

Detection of anti–HHV-8 antibodies provides evidence for viral latency. However, diagnosis of KS is based on a biopsy or excisional specimen showing the typical histological findings. The tumor originates in the dermis and is characterized histologically by malignant spindle cells with vascular proliferation.

Initial treatment consists of reduction or cessation of immunosuppression. Among the 27 patients reported in the Saudi Arabian and Italian studies, 59% had complete remissions, 15% had partial remissions, and 26% died. A variety of treatments, including local irradiation, intralesional chemotherapy, and systemic chemotherapy, were used in patients who did not respond to reduction of immunosuppression alone.61,62 Interferon has been used in the nontransplantation setting, but its propensity to promote rejection is problematic. Patients administered ganciclovir as treatment for other viruses had a lower incidence of KS, but it is doubtful that long-term prophylaxis is a suitable approach.

Respiratory viruses


A number of respiratory viruses, including influenza, parainfluenza, respiratory syncytial virus (RSV), and adenoviruses, can affect renal transplant recipients. These viruses share a common presentation with upper respiratory symptoms and cough, but more serious complications can occur.67 Typically, clinicians are presented with a patient with a viral syndrome. If recovery is slow or pneumonia develops, identification of the virus responsible is necessary to determine whether specific therapy is available and limit evaluation for other causes.

Although definitive, virus cultures require several days, as well as specialized laboratories. More recently, rapid identification has become possible using direct enzyme-linked immunosorbent assay or immunofluorescence techniques that identify viral antigens in respiratory secretions. Thus, the diagnosis will most often be made by analysis of nasopharyngeal, bronchial, or bronchoalveolar fluid washing specimens. Nasal and throat swab specimens provide inferior results. At many hospitals, a rapid-turnaround respiratory virus panel can provide a quick diagnosis from these specimens.

Patients suspected of having one of these disorders should be placed in respiratory isolation.

 

Influenza
Influenza A and B are RNA viruses that cause respiratory infections from December to March. Major potential complications include the development of primary influenza or secondary bacterial pneumonia.

Although influenza causes substantial morbidity and mortality in the elderly and patients with significant comorbidities, data on outcome in immunocompromised patients are lacking because there have been few longitudinal studies. Several large series of infections involving more than 500 transplant recipients identified only rare cases of these viruses as transplant pathogens.67 One study spanning two influenza seasons identified 12 renal transplant recipients with influenza A. Complications included one case each of pneumonitis and bronchitis, but most individuals had mild and self-limited disease.68 Similarly, three renal transplant recipients with influenza B recovered within 5 days without treatment or complications.69

Annual vaccination remains the primary method of preventing and controlling influenza. Like the elderly, renal transplant recipients have lower response rates and develop lower antibody titers after vaccination than young healthy controls. However, the vaccine still lessens the complications and severity of infection.70 Therefore, all renal transplant recipients should be vaccinated annually, as should all persons in close contact, including household members and health care providers. Chemoprophylaxis with amantadine or rimantadine is effective in other high-risk groups and can also be used. However, it has never been studied in the transplant population.

In established disease, amantadine and rimantadine and the new neuraminidase inhibitors, zanamivir and oseltamivir, shorten symptom duration in healthy adults by approximately 24 hours if started within 48 hours of symptom onset. The possible benefits of amantadine or rimantadine in transplant recipients are unproven because no trials have been conducted in this group. Nevertheless, most authorities support their use in the treatment of complicated influenza A infection.71 It remains to be seen whether the new agents will be of value.

Parainfluenza
Prior infection with these ubiquitous RNA viruses does not confer immunity, although the severity of infection diminishes with age and exposure. Bronchiolitis or croup are more likely to occur in children, but adults have upper respiratory tract disease exclusively. Parainfluenza viruses are responsible for significant morbidity and mortality caused by pneumonia in BMT recipients, but disease is limited to pharyngitis and cough in adult renal transplant recipients.72 Infection is associated with an increase in the frequency of acute rejection episodes, but graft survival at 6 months is not affected. Prolonged shedding of parainfluenza viruses in the immunocompromised host has been documented.

The effectiveness of specific antiviral agents for parainfluenza virus infection has not been established. Clinical experience with inhaled ribavirin in the transplant population is limited to case reports and retrospective reviews, none of renal transplant recipients.

Adenoviruses
These double-stranded DNA viruses have been recovered from virtually every organ system of humans and associated with many clinical syndromes, including enteric infections, urinary tract infections, upper and lower respiratory tract disease, and conjunctivitis.

Evidence of adenovirus as a cause of serious disease in solid-organ transplant recipients is accumulating. A comprehensive review of more than 300 cases of adenovirus infection in the immunocompromised population showed that 11% of all transplant recipients become infected with adenoviruses. The infection frequently involves the organ transplanted, and infections are often more severe and of longer duration than in healthy hosts.73 Type of immunosuppression, patient age, and infecting virus serotype influence fatality rates. In renal transplant recipients, adenovirus infections are associated with a 17% fatality rate. The majority of infections in renal transplant recipients involve the urinary (hemorrhagic cystitis) or respiratory tract (pneumonia).

Diagnosis of acute infections can be accomplished by direct antigen detection, as well as culture. In addition, viral inclusions may be observed in tissue specimens. There are no well-defined treatment options for adenovirus infections. Case reports suggest the possible efficacy of ribavirin, vidarabine, immunoglobulin, and ganciclovir.74 None of these has proven efficacious during a clinical trial.

RSV
RSV is a single-stranded RNA virus that causes yearly outbreaks from November through April. Epithelial necrosis and airway inflammation may be sufficient to impede airflow, particularly during expiration, resulting in characteristic wheezing and air trapping. Patients with cellular immune deficiencies tend to have worse infection and prolonged viral shedding.

In BMT recipients, RSV is a significant pathogen with 45% to 100% mortality.67 Data for renal transplant recipients are sparse. In one report of two renal transplant recipients with RSV infection, only one patient developed pneumonia, and both recovered. In another report, one of four patients required mechanical ventilation, and all recovered. None of these patients was administered ribavirin.

Results of retrospective reviews suggest that treatment with aerosolized ribavirin decreases the mortality of RSV pneumonia in BMT recipients if they are identified and treated early. However, controlled studies are lacking. Considering the mild nature of RSV infections in renal transplant recipients and the expense and potential side effects of ribavirin, routine use of this drug cannot be recommended. Immunoglobulin also has been used to treat RSV, but its value is equally uncertain.67

Other viral infections

Polyomaviruses
Polyomaviruses are small DNA viruses. Oral or respiratory transmission occurs early in life; 60% to 80% of adults are seropositive. However, polyomavirus causes significant symptomatic disease only in immunocompromised patients.75,76

BK polyomavirus
Although the BK subtype of polyomavirus was first isolated from the urine of a renal transplant recipient in 1971, recognized infection was rare until recently. The use of more potent combination regimens, including mycophenolate and tacrolimus, is probably responsible. In a recent series, the incidence of clinically significant polyomavirus infection was 2.5%, with most occurrences in the first year posttransplantation. The virus is trophic for the urinary tract, including the epithelium of the bladder, ureter, and renal tubules. Clinical manifestations include hemorrhagic cystitis, ureteral strictures, and interstitial nephritis. Suspicion of polyomavirus infection should arise when a renal transplant recipient presents with gross hematuria, urinary tract obstruction, or a slowly increasing serum creatinine level.75,76

Diagnosis can be made by histological examination, immunoperoxidase staining of biopsy tissue, detection of viral inclusions containing decoy cells on urine cytology, or urine electron microscopy. Renal biopsy findings include viral cytopathic changes in tubular cells and a dense, variable, inflammatory infiltrate frequently containing numerous plasma cells. Affected areas are often sharply demarcated from surrounding tissue.75,76 Because such processes as acute rejection and CMV infection can also cause reactive tubular cell changes, the diagnosis requires confirmation by one of the methods listed. Electron microscopy of negatively stained urine provides a simple, rapid, and relatively inexpensive method to follow up the disease.76 Asymptomatic shedding of polyomavirus in the urine has been reported. However, in a recent series, no virus was detected in the urine of 23 patients with renal dysfunction for reasons other than polyoma infection.76 Recently, the combination of screening by urine cytology with diagnostic confirmation by plasma PCR has been proposed as an alternative to biopsy.77

No pharmacological agents currently available have activity against polyomavirus, and no known prophylactic strategies offer demonstrated efficacy. Because the histological picture is similar to that in acute rejection and polyomavirus interstitial nephritis can coexist with acute rejection, some patients have undergone treatment for acute rejection along with intensification of their maintenance immunosuppression. These individuals have done poorly, with graft loss in the short term in more than half. In two recent series, reduction in maintenance immunosuppression resulted in stabilization or improvement in graft function in the ma