Prevention of Opportunistic Infections in the Solid Organ Transplant Recipient

Opportunistic infections that occur early after solid organ transplant (SOT) may be de novo or may represent reactivation of latent infection (Figure). Common opportunistic infections include those caused by Cytomegalovirus (CMV), fungal pathogens such as Aspergillus and Candida, and bacterial pathogens such as Pneumocystis jiroveci and Mycobacterium tuberculosis. Knowing this, clinicians can institute preventive strategies in the setting of SOT (Table).

Figure -

Infections occur in a generally predictable pattern after solid organ transplant. The development of infection is delayed by prophylaxisand accelerated by intensified immunosuppression, drug-related toxicities that may cause leukopenia, or immunomodulatory viral infections suchas those caused by CMV, hepatitis C virus, or Epstein-Barr virus. At the time of transplant, a patient's short-term and long-term risk of infectioncan be stratified according to donor and recipient screening, the technical outcome of surgery, and the intensity of immunosuppression requiredto prevent allograft rejection. Subsequently, an ongoing assessment of the risk of infection is used to adjust both prophylaxis and immunosuppressivetherapy. (MRSA, methicillin-resistant Staphylococcus aureus; HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus;PCP, Pneumocystis pneumonia; CMV, Cytomegalovirus; SARS, severe acute respiratory syndrome; PTLD, posttransplant lymphoproliferativedisease.) (Adapted from Fishman JA. N Engl J Med. 2007.37 Used with permission.)

Table

Table

CMV infection
CMV infection in the SOT recipient is a cause of significant morbidity and mortality.¹ Disease is characterized by a febrile illness with or without direct end-organ damage. The term "CMV syndrome" refers to this febrile illness and may be the first sign of CMV infection in the SOT recipient. In addition, diverse effects, mediated by CMV infection, impact immune response. These effects may increase the risk of infection with other opportunistic pathogens during the posttransplant period.² They also may increase the risk of acute and chronic allograft injury.²

CMV infection is usually transmitted to the SOT recipient from the organ donor rather than it being a reactivation of a latent CMV infection in the organ recipient. Presence of CMV may represent isolated viremia (infection) or viremia associated with end-organ damage (disease). The serostatus of the donor and recipient will predict the risk of viremia posttransplant, which, in turn, will correlate with the risk of CMV disease.³ Infection risk is highest in a CMVseronegative recipient of an organ from a CMV-seropositive donor; however, even seropositive recipients are at increased risk for infection if the donor is also seropositive.

The level of risk for CMV disease- as defined by serological status- depends on the type of allograft received. Lung, pancreas, and small-bowel transplant recipients are at highest risk; liver and heart transplant recipients are at intermediate risk; and kidney transplant recipients are at lower risk. This may be related both to an increased risk of acquisition of CMV from donor organs with a potentially higher burden of latent virus and to the greater degree of immunosuppressive therapy used in some of these recipients. For any transplant recipient, risk will be significantly augmented by the use of specific immunosuppressive agents, which may increase the potential for reactivation of latent virus. These agents include antilymphocyte therapies (eg, antithymocyte globulin), muromonab-CD3, and alemtuzumab. In addition, rejection and its treatment may be linked to the development of CMV disease.⁴

Prevention of CMV disease has been shown to have a significantly positive effect on outcomes in SOT recipients. Two strategies have emerged: prophylaxis and preemptive therapy. Prophylaxis requires administration of antiviral agents to all at-risk SOT recipients before the development of detectable CMV infection. Preemptive therapy requires regular surveillance for CMV infection, with initiation of antiviral therapy for any patient in whom the virus is detected. Quantitative testing for CMV DNA by nucleic acid (ie, polymerase chain reaction) assay has replaced CMV antigen testing as the most common surveillance method because of its advantages in test characteristics and ease of use. In centers in which nucleic acid testing is not available, antigenemia can be used to monitor patients for the development of CMV infection.

Each strategy has advantages and disadvantages. Prophylactic therapy may be logistically simpler to follow, particularly outside the clinical trial environment. However, universal prophylaxis carries a potential risk of development of ganciclovir-resistant CMV.⁵ It also may prevent antibody formation and may delay the presentation of CMV infection. In addition, antiviral therapies may not be well tolerated; adverse effects include significant cytopenias. Preemptive therapy carries less risk of drug-related toxicities, but it leads to higher rates of asymptomatic CMV infection. Potentially, more virusmediated modulation of the immune system could occur.

A number of agents have proved to be effective for the prevention of CMV infection and disease. Acyclovir, valacyclovir, ganciclovir, and valganciclovir have all shown efficacy in prevention of CMV disease in select populations.^6,7 Before the release of valganciclovir, ganciclovir was the drug most frequently administered to the highest-risk patients. Ganciclovir is available in both intravenous and oral formulations; the oral formulation was often preferred despite the high pill burden and poor oral bioavailability.

Valganciclovir is a valine ester prodrug of ganciclovir with significantly improved oral bioavailability. In a prospective, randomized, double- blind trial comparing ganciclovir with valganciclovir for CMV prophylaxis among high-risk (donorpositive/ recipient-negative) SOT recipients, similar rates of CMV disease were seen in both groups at 6 and 12 months of follow-up.⁸ Valganciclovir has replaced ganciclovir for most prophylactic indications because of its increased bioavailability and the absence of associated resistance. However, in analysis of the liver transplant recipient subset of this trial, more tissue-invasive CMV disease was seen in the valganciclovir arm (14% vs 3%). As a result, valganciclovir was not approved by the FDAfor the prevention of CMV disease in liver transplant recipients, although some centers have continued to use it.⁹

Regardless of the agent used for prophylactic therapy, the duration of antiviral administration is not standardized. In most cases, prophylaxis is administered for a minimum of 100 days posttransplant. However, longer durations of prophylaxis also have been used, especially for the highest-risk recipients, and a comparative trial of 3 versus 6 months of prophylaxis is currently ongoing. Reintroduction of prophylaxis should be considered following treatment of rejection, especially when cytolytic therapies are used.2

Although most transplant centers use prophylaxis rather than preemptive therapy for prevention of CMV disease, few prospective trials compare these strategies. In a meta analysis of 3 trials that included 151 patients and compared either oral acyclovir or ganciclovir prophylaxis with either oral or intravenous (5 mg/kg twice daily) ganciclovir preemptive therapy, no difference was seen in rates of CMV disease, acute rejection, or all-cause mortality.¹⁰

In a recent trial, 98 kidney transplant recipients were randomly selected to receive either valganciclovir prophylaxis (900 mg/d) or preemptive therapy (900 mg twice daily). No difference was seen in rejection, allograft function, or mortality, although there was a trend toward increased symptomatic CMV disease in the prophylaxis group.¹¹ In another trial, 70 kidney transplant recipients were randomly selected to receive prophylactic valacyclovir (2 g 4 times daily) or preemptive valganciclovir (900 mg twice daily). Although there was also no difference in allograft function or mortality, a higher rate of acute rejection was seen in the preemptive therapy group.¹² Based on the findings from these relatively small single-center trials, the optimal strategy for the prevention of CMV disease has not been defined, and additional comparative trials are ongoing.

The use of immunoglobulin for the prevention of CMV disease has declined with the development of specific antiviral therapies for CMV. Initial studies of CMV immunoglobulin supported its use in limited populations, but drawbacks include cost and inconvenience of administration. Arecent meta-analysis found no additional benefit of antiviral therapy combined with immunoglobulin, compared with antiviral therapy alone.¹³ At some transplant centers, immunoglobulin may still be used, primarily in conjunction with antiviral therapies for those patients at highest risk.

Other viruses
The SOT recipient is also at risk for infection with or reactivation of her pes simplex virus (HSV), varicellazoster virus (VZV), Epstein-Barr virus (EBV), human herpes virus (HHV) 6, and HHV7. Prophylaxis against CMV infection also will offer protection against HSV and VZV infections. Patients not receiving CMV prophylaxis should receive either acyclovir or valacyclovir as prophylaxis against these pathogens.

EBV may mediate the development of posttransplant lymphoproliferative disease (PTLD). Although not yet definitely proved in clinical trials, it has been suggested that prophylaxis with ganciclovir may be protective against PTLD directly through activity against EBV and indirectly through the prevention of CMV disease.¹⁴

The clinical significance of HHV6, HHV7, and HHV8 viremia in the SOT recipient remains uncertain.¹⁵ For patients receiving ganciclovir or valganciclovir, infection with HHV7 may be relatively more common than infection with HHV6. In a comparison with infections in historical controls, infections with VZV, HHV6, and EBV may have declined with the use of ganciclovir or valganciclovir for prophylaxis against CMV infection.¹⁶ HHV8 viremia may be a consequence of reactivation of latent infection or donor-derived infection. There is no consensus on the role of donor screening or monitoring of SOT recipients for HHV8 infection.¹⁷

Fungal infection
Strategies for the prevention of fungal infections after transplant are less universally agreed on. In general, lung transplant recipients are at highest risk, followed by liver, pancreas, and small-bowel transplant recipients. Kidney and heart transplant recipients are at comparatively lower risk. There are few randomized trials that compare antifungal regimens, and many strategies have been developed based on observational data.¹⁸

Liver transplant recipients are at risk for both invasive aspergillosis and invasive candidiasis. Specific factors have been used to identify patients at high risk for invasive candidiasis. In an observational study of risk for invasive fungal infections in liver transplant recipients, high-risk patients were defined as having at least 2 of the following criteria: choledochojejunostomy anastamosis, retransplant, intraoperative administration of more than 40 units of blood products, return to the operating room for intra-abdominal bleeding, return to the operating room for anastomotic leak or vascular insufficiency, preoperative serum creatinine level greater than 2 mg/dL, and perioperative Candida colonization. Lowrisk patients-ie, those with no more than 1 of these criteria-may not require antifungal prophylaxis.^19,20

In a meta-analysis of prophylaxis for fungal infections in liver transplant recipients, prophylaxis with fluconazole decreased the incidence of invasive fungal infections by 75% but had no effect on total mortality.²¹ The decision to use fluconazole prophylaxis for high-risk patients also may depend on the prevalence of disease at an individual transplant center. Prophylaxis is usually not continued beyond 4 weeks posttransplant. It is uncertain whether there is a role for prophylaxis against invasive aspergillosis in the liver transplant recipient, and there is no established regimen that is recommended at this time.²²

Although lung transplant recipients are at increased risk for fungal infections, there are not yet universally agreed-on risk factors to guide the use of antifungal prophylaxis in this population. Observational studies have suggested a role for both aerosolized amphotericin B and itraconazole, but no prospective trials have evaluated individual regimens. ^23,24Arecent survey of centers performing lung transplantation found significant variation in the type of antifungal prophylaxis regimen used.²⁵ The appropriate duration of prophylaxis is also not well defined. Continuing prophylaxis for 4 to 6 months has been suggested to allow for suture healing and reduction of net immunosuppression. There may be a subset of patients who would benefit from extending prophylaxis to 1 year or beyond. The presence of Aspergillus in cultures of respiratory tract secretions should prompt investigation for invasive aspergillosis, with an institution of the appropriate treatment based on those results.²²

Recipients of a pancreas allograft (whether pancreas alone, simultaneous kidney-pancreas, or pancreas after kidney transplant) also are at high risk for invasive fungal infection. This risk approximates what is seen in liver transplant recipients. Specific risk factors include older age of donor or recipient, enteric drainage, and vascular graft thrombosis. The majority of infections in these patients are caused by Candida species. Fluconazole prophylaxis should be considered in high-risk patients. Duration of prophylaxis is not defined and may vary with the degree of ongoing risk.¹⁸

Guidelines on antifungal prophylaxis in other transplant recipients have not been established. Smallbowel transplant recipients are at considerable risk for invasive Candida infection, and although no controlled trials have been performed, experience with liver transplant and nontransplant small-bowel surgery has led to the common use of fluconazole prophylaxis.

The period of greatest risk is the first 2 months posttransplant. Prophylaxis in kidney transplant recipients should be limited to those with candiduria. Although patients with ventricular assist devices are at increased risk for invasive fungal infections, antifungal prophylaxis has not been systematically studied in this population and is not consistently recommended.¹⁸

P jiroveci pneumonia
Before trimethoprim/sulfamethoxazole (TMP/SMX) was routinely used in the SOT recipient, there was a high incidence of Pneumocystis pneumonia (PCP) posttransplant, especially between months 2 and 6 following transplant. The risk of PCP in the SOT recipient is also increased during periods of prolonged neutropenia and increased immunosuppression. It has been suggested that prophylaxis with TMP/SMX be limited to centers in which the incidence of PCP is greater than 3% to 5% or to any patient previously infected with Pneumocystis.²⁶ In practice, most centers continue to provide prophylaxis for all SOT recipients for at least a limited time after transplant.

For patients who are intolerant to TMP/SMX, alternative prophylactic agents include dapsone, atovaquone, pentamidine, and clindamycin with pyrimethamine. Activity of the glucose- 6-phosphate dehydrogenase (G6PD) enzyme should be measured before the use of dapsone. Even in patients with normal G6PD activity, a risk of dapsone-related hemolytic anemia and methemoglobinemia is present.²⁷ None of these alternative agents will have the additional antimicrobial activity of TMP/SMX, which includes activity against Nocardia and Toxoplasma, as well as activity against many community-acquired bacterial pathogens of the respiratory and urinary tracts. This may be particularly significant for heart transplant recipients, who are at increased risk for toxoplasmosis and in whom TMP/SMX is highly effective for toxoplasmosis prophylaxis.²⁸

In a review of 596 heart transplant recipients who received TMP/SMX prophylaxis for PCP for a minimum of 1 year posttransplant, no cases of toxoplasmosis were found.²⁹ As prophylaxis for PCP, TMP/SMX may be given 3 times weekly or once daily; it is unknown which of these dosing schedules is preferable.

Duration of prophylaxis for PCP will depend on the ongoing risk of infection. This risk is based on the patient's level of immunosuppression along with any history of previous Pneumocystis infection. For kidney, heart, and liver transplant recipients maintained on low levels of immunosuppression, prophylaxis may be discontinued at 1 year posttransplant. A longer duration of prophylaxis may be beneficial for lung transplant recipients, and lifelong prophylaxis is commonly used.^26,30

A retrospective review of 28 cases of PCP in lung transplant recipients at a single center identified 10 that occurred more than 1 year posttransplant. No cases of PCP were identified in patients receiving prophylaxis for Pneumocystis infection.³¹ All patients with a history of Pneumocystis infection and those patients who require significant ongoing immunosuppression- as in the treatment of chronic allograft rejection-should be evaluated for lifelong prophylaxis for Pneumocystis infection.

Latent tuberculosis
Although donor-derived tuberculosis infection may occur, most cases of tuberculosis following transplant represent reactivation of latent infection in the context of immunosuppression. The incidence of tuberculosis in SOT recipients, based on a review of published reports, is estimated to range from 0.35% to 15%, depending on the background prevalence of tuberculosis at the various study sites.³² In one large review, most cases (437 of 511) of tuberculosis were in kidney transplant recipients, and the median time to onset was 9 months posttransplant.³²

To identify latent infection before transplant, patients should undergo tuberculin skin testing. A positive skin test result is defined as induration greater than 5 mm. Two-step testing should be considered for all patients with initial negative results, with a repeat of the skin test approximately 2 weeks later.³³

Living donors who are related to the recipient also should be tested and treated for latent infection as indicated. All patients with positive skin test results should receive preventive therapy with isoniazid after active disease has been excluded. The treatment for latent tuberculosis in the SOT recipient, as in the general population, is isoniazid 300 mg/d for 9 months.³⁴ Because many transplant candidates may have cutaneous anergy, nonresponders should also receive isoniazid if they have any of the following: radiographic evidence of previous active tuberculosis without prior treatment or prophylaxis, a history of inadequately treated tuberculosis, close contact with an infectious patient or receipt of an allograft from a donor with previous inadequately treated tuberculosis. ³² There are no data on the use of ?-interferon tests for the diagnosis of latent tuberculosis in the SOT recipient.

Among kidney transplant candidates, and possibly lung transplant candidates, it may be best to complete treatment before the transplant is performed. Among liver transplant recipients, treatment may be deferred until hepatic function has stabilized.³⁵ Although the risk of isoniazid toxicity may be greater in a liver transplant recipient, abnormal liver enzyme levels after transplant may not be related to isoniazid. Liver transplant patients should undergo liver biopsy to check for enzyme abnormalities. It may be difficult to differentiate rejection, recurrent viral infection, and drug toxicity.³³

For patients intolerant to isoniazid, rifampin 600 mg/d for 4 months is an alternative therapy; however, caution should be used with rifampin in the SOT recipient. It affects the metabolism of many other agents, including the calcineurin inhibitors and target of rapamycin (TOR) inhibitors, which may result in suboptimal immunosuppression, allograft rejection, and possible loss of the organ; careful monitoring is critical.³⁶

Conclusion
Skillful prevention of opportunistic infection in the SOT recipient allows for the successful maintenance of immunosuppression and a much lower risk of complications related to allograft rejection. Because of a growing population of potential recipients, strategies for expanding the donor pool are being evaluated. These include the use of expanded criteria for donors to include those who may be a source of donor-derived infections and the use of more potent immunosuppressive strategies to minimize the risk of rejection in higher-risk transplant recipients. Ultimately, prophylactic measures may require adaptation to provide enhanced protection from both new and established pathogens in this evolving patient population.

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