SYMPOSIUM ON CARDIAC TRANSPLANTATION-Part III

Strategies for Prevention of Infection After Cardiac Transplantation

MICHAEL R. KEATING, M.D., MARK P. WILHELM, M.D., RANDALL C. WALKER, M.D., Division of Infectious Diseases and Internal Medicine

Infection remains a major cause of morbidity and mortality after cardiac transplantation. Most infections occur during tbe first few months after transplantation. Although late infection does occur, the risk of infection during maintenance immunosuppression is low in the absence of recurrent rejection that necessitates augmentation of suppression of the immune response. Before cardiac transplantation, the risk factors for infectious disease in potential candidates should be assessed. A detailed history of past infections should be elicited, and patients should'be screened for the presence of active indolent infection. In addition, potential donors must be thoroughly assessed for organtransmittable infection. Many common infections that may occur after cardiac transplantation can be prevented with the use of appropriate prophylactic regimens directed toward cytomegalovirus, Toxoplasma gondii, Pneumocystis carinii, and herpes simplex virus. Periodic surveillance serologic tests and cultures after cardiac transplantation facilitate early diagnosis and prompt institution of appropriate therapy.

Despite dramatic improvements in the procurement and preservation of donor organs, surgical technique, and immunosuppressive therapy, infection remains a major cause of morbidity and mortality among recipients of heart transplants. The modem era of cardiac transplantation began with the introduction of cyclosporine in the early 1980s. In addition to improving graft survival, cyclosporine has been associated with a lower rate of infectious complications and prolonged patient survival. I Recent data from the Registry of the International Society for Heart Transplantation indicate that 18% of early deaths and almost 40% of late deaths after cardiac transplantation are attributable to infection.' As the ability to diagnose and treat infections has progressed, the emphasis in the field of transplantation-related infectious Address reprint requests to Dr. M. R. Keating, Division of Infectious Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:676-684, 1992

diseases has shifted from management of established infection to prevention of infection. TIMING OF INFECTIONS The first 6 months after cardiac transplantation is the period of greatest risk for the development of infection.' During this period of induction immunosuppression, the risk of acute rejection necessitates augmented suppression of the immune response. In most patients, immunosuppression is not decreased to a maintenance level until 3 months or more after transplantation. The effects of early high-dose immunosuppression, however, persist beyond this 3-month period. Early after transplantation, the infectious complications, typically due to nosocomial bacteria and Candida species, are related to intensive medical care and surgical intervention. Such complications include wound infections, noso676

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comial pneumonia, infections of the urinary tract, and bacteremia associated with use of intravascular devices. Dummer' noted 2.1 episodes of bacterial infection per patient-year during the first month after transplantation but fewer than 1 infectious episode per patient-year after 2 months. In that reported series of patients, candidal infections tended to occur predominantly during the first 2 months after transplantation. In contrast, viral infections tend to occur most commonly during the second month after transplantation. The exception is stomatitis due to herpes simplex virus, which most frequently occurs 2 to 4 weeks after transplantation in seropositive patients.' Infections due to Pneumocystis carinii are most likely to occur from the second through the sixth month after transplantation, although sporadic late cases are occasionally encountered." Primary toxoplasmosis typically occurs during the first 6 months. I,? After 6 months, the incidence and types of infection in transplant recipients who have not experienced acute episodes of rejection or chronic rejection are similar to those in the general population." Late infectious complications among these patients include community-acquired pneumonia, influenza, cutaneous zoster, and, rarely, opportunistic infections. PRETRANSPLANTATION ASSESSMENT Prevention of posttransplantation infection begins with a comprehensive medical assessment of the patient before cardiac transplantation. This workup should include elicitation of a detailed history of past infections such as recurrent pneumonia, sinusitis, furunculosis, or infections of the urinary tract. Moreover, patients must be screened for the presence of active indolent infection. Inquiries should be made about a history of a positive tuberculin test or exposure to tuberculosis. The patient's travel history should be reviewed, and possible exposure to endemic mycoses should specifically be addressed. Travel outside of North America or to an endemic area in North America may have exposed the patient to Strongyloides stercoralis, which can remain asymptomatic for decades and cause serious morbidity and mortality during immunosuppression after transplantation.? The environmental and occupational exposures that are expected after transplantation can also be assessed at this time. The patient's immunization history should be reviewed, and adequate vaccination protection should be established for tetanus, hepatitis B, and Streptococcus pneumoniae. Because of the recent increase in the occurrence of measles, the patient's rubeola immune status should be established. Finally, any history of adverse reactions to antimicrobial agents should be carefully reviewed and documented.

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Table I.-Guidelines for Assessment of Recipient Before Cardiac Transplantation Serologic studies Herpessimplex virus Epstein-Barr virus Varicella-zoster virus Cytomegalovirus Hepatitis B Hepatitis C Humanimmunodeficiency virus Toxoplasma gondii

Fungi (endemic mycoses) Rapid plasmareagin Culture Urine-bacteria Stool-s-enteric pathogens Stool examination for ova and parasites Tuberculin test

Serologic testing before cardiac transplantation should be directed at establishing the presence of latent infection and determining the patient's susceptibility to the primary infections listed in Table 1. When the history suggests previous exposure to endemic mycoses, serologic tests for fungi may be warranted. Stool specimens should be examined for ova and parasites and cultured for enteric bacterial pathogens. A tuberculin test should be performed unless the patient is known to be tuberculin positive. ASSESSMENT OF DONOR Recipients of organ transplants are at risk for acquiring infection from the allograft; thus, before acceptance, potential donors must undergo assessment.'? Donors who are seropositive for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus should be excluded from consideration." Potential donors who have engaged in high-risk behavior for transmission of human immunodeficiency virus should also be excluded.P Although active bacterial infection is usually regarded as a criterion for excluding a donor, a recent report suggested that cardiac allografts from carefully selected donors with noncardiac bacterial infections may be used successfully." Additional screening of the donor for latent infections provides prognostic information that is useful in the management of the recipient. Included in this assessment are serologic tests for cytomegalovirus (CMV) and Toxoplasma" (Table 2). PERIOPERATIVE PROPHYLAXIS At the time of cardiac transplantation, the patient should be assessed for the presence of active infection. Although the existence of a minor infection usually should not jeopardize

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Table 2.-Guidelines for Assessment of Donor

Before Cardiac Transplantation Serologic studies Human immunodeficiency virus Hepatitis B Hepatitis C Toxoplasma gondii Cytomegalovirus Culture-samples from appropriate sites if infection is suspected clinically

or preclude proceeding with transplantation, the knowledge of such an infection could prove critical in the management of the patient after transplantation. Exclusion of a patient because of a minor active infection must be balanced against the risks of not proceeding as rapidly as possible with the transplantation. Perioperative antimicrobial prophylaxis should be based on the antibiotic susceptibilities of organisms that have caused postoperative infections at the transplantation center. In general, a parenterally administered antibiotic prophylactic regimen should be continued for no more than 1 or 2 days after cardiac transplantation. POSTTRANSPLANTATION PROPHYLAXIS Cytomegalovirus.-CMV is the most common cause of viral infection after cardiac transplantation. Typically, active CMV infection is initially encountered from 4 to 8 weeks after transplantation." CMV infection is defined as laboratory evidence of active viral replication. Many patients with CMV infection will remain asymptomatic. In contrast, patients with CMV disease have signs and symptoms attributable to infection with the virus. Three types of CMV infection and disease occurprimary infection, reactivation, and superinfection. Primary infection is the development of CMV infection in a CMV -seronegative recipient of a transplanted heart. In this setting, CMV is almost always acquired from the transplanted allograft harvested from a seropositive donor. Occasionally, primary infection can be acquired from transfused blood products. Reactivation of a CMV infection is the development of viral replication after transplantation in a seropositive recipient. In a seropositive patient who receives an organ from a seronegative donor, recovery of the virus implies reactivation. In contradistinction, a seropositive recipient of an allograft from a seropositive donor may have either reactivation of the recipient latent strain or superinfection with the strain transplanted with the allograft. Clinically, distinguishing superinfection from reactivation is seldom possible, but this distinction has little clinical importance.

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Of the three aforementioned potential types of infection, primary infection is associated with the greatest morbidity and mortality. Although disease associated with reactivation and superinfection can be severe, it frequently is mild. Among 160 recipients of transplants in one series, primary infection developed in 16 of 18 patients who had seronegative mismatches, and the mortality was 28%.J5 In contrast, CMV infection (but no subsequent death) developed in 19 of 32 seropositive recipients of a seropositive organ (59%) and 18 of 42 seropositive recipients of a seronegative organ (43%). CMV infection has been associated with several effects. It has been shown to depress the function of neutrophils, a result that may predispose to bacterial infections." In addition, natural killer cell activity and T-cell proliferation may be depressed. I? Other studies have shown that patients with active CMV infection are more susceptible than other patients to superinfection with opportunistic pathogens. IS Recently, CMV has been associated with an increased frequency of opportunistic fungal infections, acute allograft rejection, and accelerated atherosclerosis in the transplanted heart. 19 Consequently, most transplantation centers have developed strategies for prevention of CMV disease. Several options exist. The use of CMV-seronegative blood products has been shown to decrease the frequency of primary CMV infection in patients who are CMV negative." Therefore, for patients who are CMV negative, all blood products should be tested for CMV, and only seronegative blood products should be administered. Some transplantation physicians recommend that CMV-seronegative patients should receive only CMV-seronegative allografts." Although this precaution would prevent primary infection, practical considerations related to donor availability would seem to preclude this approach. Most transplantation centers rely on early diagnosis and treatment of CMV infection if prophylaxis fails. Immunization of seronegative candidates may be a means of attenuating disease due to primary CMV infection. A live attenuated strain of CMV has been studied in recipients of renal transplants.v-" In a double-blind, randomized, placebo-controlled trial that encompassed 10 years, the vaccine was found to be well tolerated, and no adverse effects were encountered." Recipients who were seronegative at the time of vaccination and who received a kidney from a seropositive donor had significantly less severe CMV disease than did recipients of placebo. Moreover, graft survival 3 years after transplantation was significantly increased among vaccinated recipients. These promising results suggest that vaccination may have an important role in future approaches to the prevention of CMV-related disease. Unfortunately, it currently remains an investigational modality.

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The use of immunoglobulins to prevent CMV infection after cardiac transplantation has been the focus of numerous clinical trials.":" These studies have involved CMV hyperimmune globulin and pooled polyclonal y-globulin preparations. Most of these studies, however, have been uncontrolled and have used a variety of preparations and dosing regimens; therefore, extracting meaningful conclusions is difficult. In a large, randomized, prospective, placebo-controlled study in which CMV hyperimmune globulin was used in recipients of renal transplants," a significantly decreased frequency of virologically confirmed CMV-associated syndromes and fungal or parasitic superinfection was noted among recipients of hyperimmune globulin in comparison with control subjects. In studies of patients who underwent cardiac transplantation in which historical control subjects were used for comparison, the prophylactic use of CMV hyperimmune globulin decreased the frequency and the severity of CMV disease." No randomized placebocontrolled studies have been reported in this patient population; until such studies are performed, the precise role of immunoglobulins in the prevention of CMV infection after cardiac transplantation remains unclear. Ganciclovir has been shown to be effective therapy for CMV retinitis and other end-organ disease in recipients of transplants.P-" Recent reports suggest that ganciclovir may help prevent CMV disease after transplantation. In one study in which prophylactically administered ganciclovir was compared with hyperimmune globulin, the frequency of CMV disease was significantly decreased in the ganciclovirtreated group." In a preliminary report from a second study in which use of ganciclovir was compared with no prophylaxis in a control group, the drug was associated with a significantly decreased frequency of CMV infection, seroconversion, viremia, and viruria.F In a large, multicenter, randomized, double-blind trial that compared prophylactically administered ganciclovir with placebo, the incidence of CMV disease was significantly less in the ganciclovirtreated group." Among recipients of bone marrow transplants, a prophylactic regimen of ganciclovir effectively prevented CMV pneumonitis in patients with positive CMV cultures from bronchoalveolar lavage fluid." These studies indicate that prophylactic use of ganciclovir may have an important role in preventing serious CMV disease after transplantation. Further study is needed to establish the optimal dosage and duration of prophylaxis and to determine whether prophylaxis will decrease the accelerated atherosclerosis that has been associated with CMV infection. In a study performed in recipients of renal transplants, high-dose orally administered acyclovir, when given at the time of transplantation and continued for 12 weeks, significantly decreased the frequency of both CMV infection and CMV disease." This effect was most pronounced in the

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group of seronegative recipients of a seropositive organ. Unfortunately, these findings have not been confirmed in other investigations or studied in recipients of other solid organ allografts. Toxoplasma gondii-Toxoplasmosis aftercardiac transplantation can be the result of reactivation or primary infection. As with primary CMV infection, the Toxoplasmaseronegative recipient of an organ from a Toxoplasma-seropositive donor is at risk for serious primary Toxoplasma infection. In one series of seven such mismatches, primary infection developed in four patients, two of whom died." In another series of four such mismatches, primary infection developed in three patients, and two died of disseminated toxoplasmosis." In contrast, reactivation of latent infection in a seropositive recipient is usually asymptomatic or associated with minimal morbidity. 37 Prophylaxis is indicated for Toxoplasma-seronegative recipients of an allograft from a Toxoplasma-seropositive donor. The optimal prophylactic regimen has not been determined. Among 15 such mismatched recipients treated with pyrimethamine (25 mg daily) for 6 weeks, no toxoplasmosis developed." Prophylactic use of spiramycin has resulted in failures, although such cases have not been associated with fatal disease." No published data have indicated the efficacy of alternative prophylactic regimens. Studies involving the activity of co-trimoxazole against T. gondii suggest that it is inferior to pyrimethamine, sulfadiazine, trisulfapyrimidines, and clindamycin, although one large transplantation center attributes the absence of cases of toxoplasmosis to routine prophylaxis with trimethoprim-sulfamethoxazole.v-" Further data are necessary to determine the optimal prophylactic agent and the duration of prophylaxis. Pneumocystis carinii-P. carinii pneumonia is the most common late pulmonary infection after cardiac transplantation. Currently, approximately 3% of recipients of heart transplants become infected with this organism." Most transplantation centers use some type of prophylaxis for Pneumocystis. The most widely studied prophylactic agent for P. carinii is trimethoprim-sulfamethoxazole. No controlled studies of recipients of heart transplants have been performed, although data on prophylaxis in patients with leukemia or acquired immunodeficiency syndrome (AIDS) indicate that various regimens, including one doublestrength tablet twice daily, every other day, or twice daily three times per week, are highly effective in preventing infections.v" The use of trimethoprim-sulfamethoxazole may yield benefits beyond the prevention of Pneumocystis pneumonia. Studies performed in patients who underwent renal transplantation have demonstrated a significantly decreased frequency of bacterial infections in those who received trimethoprim-sulfamethoxazole prophylaxis in comparison

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with control subjects." Although this combination drug is most effective in preventing infections of the urinary tractan uncommon problem in recipients of heart transplantsfewer bacteremias were also noted in patients who received prophylaxis. Moreover, infections due to Nocardia and Listeria may also be prevented." Patients who have a history of a serious reaction to sulfa drugs are not candidates for prophylaxis with trimethoprimsulfamethoxazole. In patients with AIDS, aerosolized pentamidine has been shown to prevent Pneumocystis pneumonia, although breakthrough infections do occur, particularly in the upper lobes of the lung." Aerosolized pentamidine has not been studied in patients who have undergone transplantation but is likely to be effective. Herpes Simplex Virus.-Stomatitis due to reactivated herpes simplex virus can occur in any patient seropositive for this virus after the introduction of immunosuppression. Untreated, stomatitis may become severe, and the risk of secondary infection exists. Rarely, reactivated herpes simplex infection may result in pneumonitis. Herpes simplex frequently reactivates during the first month after transplantation. Low-dose orally administered acyclovir (for example, 200 mg three times daily) has been shown to be effective in preventing reactivated herpes simplex stomatitis among recipients of kidney transplants." Such studies have not been performed in recipients of heart transplants; however, transplantation centers that use prophylactic regimens of acyclovir have rarely reported infections caused by herpes simplex. Fungi.- The frequency of fungal infections after cardiac transplantation varies widely among transplantation centers. In a report from Stanford of 72 patients who received a cyclosporine-based immunosuppressive regimen, aspergillosis developed in 11% and deep candidal infection developed in 6%.1 In a more recent report of 400 recipients of heart transplants at Stanford, aspergillosis developed in 14%.49 At the time of initial assessment, 36 of these patients had pneumonia and 19 had disseminated disease. Candida has been identified as a cause of infection of the urinary tract, pericardial infection, mediastinitis, and candidemia after cardiac transplantation. Mucosal and skin colonization with Candida frequently precedes infection; topical prophylaxis may substantially decrease the level of colonization. Among immunocompromised patients, both orally administered nystatin and clotrimazole effectively decrease oral colonization and prevent oropharyngeal candidiasis. One study in which these two agents were compared found equivalent efficacy, although clotrimazole was easier to administer and less expensive." Amphotericin B mouthwash has also been used for preventing Candida colonization." Strategies for preventing Aspergillus infection are more difficult to devise than are those for Candida. The airborne

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conidia of Aspergillus species are ubiquitous, and the respiratory tracts of patients may easily become colonized. Practices such as removing all ornamental plants and flowers from the transplantation unit and implementing measures to prevent the dissemination of contaminated air during construction may be beneficial.F The only proven means of protecting immunocompromised patients from aspergillosis has been the use of high-efficiency particulate air filters. Reports of aspergillosis in transplantation units that use such filters are extremely rare. 53 Nonetheless, nondomiciliary exposure may occur. Nebulized amphotericin B may help prevent invasive aspergillosis in patients with neutropenia. 52 Its use after organ transplantation has not been studied. Itraconazole, an orally administered triazole agent with in vitro activity against Aspergillus, is effective for treating aspergillosis. When used prophylactically, it decreases the incidence of infections due to Aspergillus in patients with neutropenia. 54 Its potential role in the prevention of Aspergillus infections in recipients of organ transplants has yet to be determined. OTHER CONSIDERATIONS Initial protocols at centers that pioneered cardiac transplantation included measures for protective and reverse isolation of recipients of heart transplants. 55 Although these measures conceptually should help prevent nosocomial infections, several studies have failed to demonstrate a benefit from protective isolation." Moreover, these protocols are timeconsuming and costly, and they may be detrimental to the patient's emotional well-being. Scrupulous hand-washing, a low-microbial diet, and appropriate decontamination of inanimate objects are beneficial." Most patients who undergo cardiac transplantation are extubated shortly after the transplant operation and do not require prolonged mechanical ventilation. Recent studies have suggested that patients who require intubation, prolonged mechanical ventilation, and extended care in the intensive-care unit may benefit from selective bowel decontamination with use of a solution that contains nonabsorbable orally administered antimicrobial agents. 58,59 In an unblinded, randomized, controlled trial of patients in an intensive-care unit for 4 or more days, those who underwent selective bowel decontamination experienced significantly fewer infections, including bacteremia and pneumonia." This solution, which contained gentamicin, polymyxin B sulfate, and nystatin, was well tolerated and cost-effective. Its use in patients who require prolonged intubation after cardiac transplantation may be warranted. At the time of dismissal from the hospital, recipients of heart transplants should receive instructional guidelines to diminish exposure to infections in the community. Recipients who are seronegative for varicella-zoster virus must be

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informed of the risk of severe primary infection after exposure to persons with chickenpox or zoster. If such exposure occurs, they are candidates for varicella-zoster immune globulin, which must be administered within 96 hours. Thus, the importance of timely reporting of exposure must be emphasized. Similarly, avoiding contact with persons who may have influenza or other viral respiratory infections is advisable. The benefit of use of a mask in the outpatient setting to prevent exposure to respiratory pathogens has not been studied. POSTTRANSPLANTATION SURVEILLANCE Of equal importance to efforts at preventing posttransplantation infections are efforts directed at the early diagnosis of an evolving infection and the prompt institution of appropriate therapy. Consequently, active surveillance can be helpful (Table 3). The development of rapid diagnostic techniques for the detection of CMV in clinical specimens has dramatically improved the ability to diagnose this important infection in patients who have undergone transplantation. The shell vial culture technique can yield a positive result within 24 hours in more than 85% of positive blood specimens and in virtually all urine specimens.f Newer techniques, such as the CMV antigen detection assay, may provide a result even more rapidly." Surveillance for CMV is particularly important in the seronegative mismatched patient. In this setting, recovery of the virus from the blood or urine indicates the presence of a primary infection and, often, the need for treatment. In contrast, the seropositive patient with asymptomatic reactivation may not require therapeutic intervention. We recommend weekly CMV surveillance cultures of blood and urine from the fourth through the eighth week after transplantation, the period when the incidence of clinical CMV infection is highest. Once CMV has been recovered from the urine, no further surveillance culturing from this site is necessary. Serologic surveillance of the Toxoplasma-seronegative recipient of a Toxoplasma-seropositive allograft may likewise facilitate early detection of primary infection. Because the recognition of primary toxoplasmosis is frequently based on serologic changes, weekly sampling during the first 2 months after transplantation and then monthly for an additional 4 months is indicated. Certain difficulties have been associated with the serodiagnosis of toxoplasmosis. Falsepositive reactions have been reported, and some investigators have recommended confirmation of the serologic changes with the Sabin-Feldman dye test.62•63 This dye test, considered the reference assay for Toxoplasma serologic analysis, also reportedly yielded a false-negative result in a case of primary toxoplasmosis.s' Because no means of serologic surveillance is infallible, monitoring the presence

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Table 3.-Microbiologic Surveillance After Cardiac Transplantation 1. Serologic tests for Toxoplasma gondii weekly for 8 wk and then monthly for 4 mo 2. Serologic tests for cytomegalovirus monthly for 6 mo in cytomegalovirus-seronegative recipients 3. Cultures of urine and blood for cytomegalovirus weekly from wk 4 through wk 8 4. Cultures of urine and sputum for bacteria and fungi weekly for 1 mo 5. Low threshold for supplementary serologic tests and cultures (appropriate specimens dictated by clinical course)

of Toxoplasma in the serum with an assay that detects both IgG and IgM and careful attention to the endocardial biopsy specimens for the possibility of toxoplasmosis seem the best approach clinically. The contribution of routine surveillance cultures for bacteria and fungi toward the early diagnosis of infection has not been evaluated critically in patients who have undergone transplantation. Nevertheless, surveillance cultures for fungi and bacteria are included in the posttransplantation protocols at some centers." Use of surveillance serologic tests for endemic mycoses is of doubtful benefit; their reliability after transplantation may be blunted because of immunosuppression. In contrast, the cryptococcal antigen test does not rely on host response, but the low incidence of cryptococcal infection after cardiac transplantation diminishes the importance of active surveillance. CONCLUSION The use of prophylactic antimicrobial regimens to prevent infection after cardiac transplantation has received considerable attention in the transplantation literature for the past decade. No studies, however, have determined the optimal prophylactic combination in recipients of heart transplants: As a result, considerable variability exists among transplantation centers. We recommend the following postoperative prophylactic regimens, pending the availability of more definitive data on prophylaxis. 1. For prevention of toxoplasmosis in the seronegative recipient of an allograft from a Toxoplasma-seropositive donor, daily oral administration of pyrimethamine or cotrimoxazole should be continued for 3 months in conjunction with serologic surveillance. 2. For the CMV-seronegative recipient of an allograft from a CMV-seropositive donor, immunoglobulin should be administered intravenously at weekly intervals for 3 weeks and bimonthly thereafter for 3 months, and an initial 2-week intravenous course of ganciclovir should be followed by oral administration of high-dose acyclovir for 3 months.

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3. For prevention of Pneumocystis pneumonia, administer trimethoprim-sulfamethoxazole daily for at least 6 months; in the sulfa-allergic patient, use aerosolized pentamidine monthly. 4. For prevention of herpetic mucocutaneous disease, administer low-dose acyclovir orally for 4 to 6 weeks. 5. For prevention of oral candidiasis, administer nystatin solution or clotrimazole troches daily for 4 to 6 weeks.

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