CHAPTER 16: INFECTIONS IN TRANSPLANT RECIPIENTS

This chapter considers aspects of infection unique to patients receiving transplanted tissue. The evaluation of infections in transplant recipients involves consideration of both the donor and the recipient of the transplanted cells or organ. Two central issues are of paramount importance: (1) infectious agents (particularly viruses, but also bacteria, fungi, and parasites) can be introduced into the recipient by the donor; and (2) treatment of the recipient with medicine to prevent rejection can suppress normal immune responses, greatly increasing susceptibility to infection. Thus, what might have been a latent or asymptomatic infection in an immunocompetent donor or in the recipient prior to therapy can become a life-threatening problem when the recipient becomes immunosuppressed. The pretransplantation evaluation of each patient should be guided by an analysis of both (1) what infections the recipient is currently harboring, since organisms that exist in a state of latency or dormancy before the procedure may cause fatal disease when the patient receives immunosuppressive treatment; and (2) what organisms are likely to be transmitted by the donor, particularly those to which the recipient may be naïve.

PRETRANSPLANTATION EVALUATION

The donor

A variety of organisms have been transmitted by organ transplantation. Transmission of infections that may have been latent or not clinically apparent in the donor has resulted in the development of specific donor-screening protocols. Results from routine blood bank studies, including those for antibodies to Treponema pallidum (syphilis), Trypanosoma cruzi, hepatitis B and C viruses, HIV-1 and -2, human T-lymphotropic virus types 1 and 2 (HTLV-1 and -2), and West Nile virus (WNV), should be documented. Serologic studies should be ordered to identify latent infection with viruses such as herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), Kaposi’s sarcoma–associated herpesvirus (KSHV); acute infection with hepatitis A virus; and infection with the common parasite Toxoplasma gondii. Donors should be screened, when relevant, for viruses such as rabies virus and lymphocytic choriomeningitis virus as well as for parasites such as Strongyloides stercoralis and Schistosoma species. Clinicians caring for prospective organ donors should examine chest radiographs for evidence of granulomatous disease (e.g., caused by mycobacteria or fungi) and should perform skin testing or obtain blood for immune cell–based assays that detect active or latent Mycobacterium tuberculosis infection. An investigation of the donor’s dietary habits (e.g., consumption of raw meat or fish or of unpasteurized dairy products), occupations or avocations (e.g., gardening or spelunking), and travel history (e.g., travel to areas with endemic fungi) also is indicated and may mandate additional testing. Creutzfeldt-Jakob disease has been transmitted through corneal transplants. Whether it can be transmitted by transfused blood is not known. Variant Creutzfeldt-Jakob disease can be transmitted with transfused non-leukodepleted blood, posing a theoretical risk to transplant recipients.

The recipient

It is expected that the recipient will have been even more comprehensively assessed than the donor. Additional studies recommended for the recipient include evaluation for acute respiratory viruses and gastrointestinal pathogens in the immediate pretransplantation period. An important caveat is that, because of immune dysfunction resulting from chemotherapy or underlying chronic disease, serologic testing of the recipient may prove less reliable than usual.

The donor cells/organ

Careful attention to the sterility of the medium used to process the donor organ, combined with meticulous microbiologic evaluation, reduces rates of transmission of bacteria (or, rarely, yeasts) that may be present or grow in the organ culture medium. From 2% to >20% of donor kidneys are estimated to be contaminated with bacteria—in most cases, with the organisms that colonize the skin or grow in the tissue culture medium used to bathe the donor organ while it awaits implantation. The reported rate of bacterial contamination of transplanted stem cells (bone marrow, peripheral blood, cord blood) is as high as 17% but most commonly is ∼1%. The use of enrichment columns and monoclonal antibody depletion procedures results in a higher incidence of contamination. In one series of patients receiving contaminated stem cells, 14% had fever or bacteremia, but none died. Results of cultures performed at the time of cryopreservation and at the time of thawing were helpful in guiding therapy for the recipient.

Transplantation of hematopoietic stem cells (HSCs) from bone marrow or from peripheral or cord blood for cancer, immunodeficiency, or autoimmune disease most often results in a transient state of complete immunologic incompetence. Immediately after myeloablative chemotherapy and transplantation, both innate immune cells (phagocytes, dendritic cells, natural killer cells) and adaptive immune cells (T and B cells) are absent, and the host is extremely susceptible to infection. The reconstitution that follows transplantation has been likened to maturation of the immune system in neonates. The analogy does not entirely predict infections seen in HSC transplant recipients, however, because the stem cells mature in an old host who has several latent infections already. The choice among the current variety of methods for obtaining stem cells is determined by availability and by the need to optimize the chances of a cure for an individual recipient. One strategy is autologous HSC transplantation, in which the donor and the recipient are the same. After chemotherapy, stem cells are collected and are purged (ex vivo) of residual neoplastic populations. Allogeneic HSC transplantation has the advantage of providing a graft-versus-tumor effect. In this case, the recipient is matched to varying degrees for human leukocyte antigens (HLAs) with a donor who may be related or unrelated. In some individuals, nonmyeloablative therapy (mini-allo transplantation) is used and permits recipient cells to persist for some time after transplantation while preserving the graft-versus-tumor effect and sparing the recipient myeloablative therapy. Cord-blood transplantation is increasingly utilized in adults; two independent cord-blood units are typically required for suitable neutrophil engraftment early after transplantation, even though only one of the units is likely to provide long-term engraftment. In each circumstance, a different balance is struck among the toxicity of conditioning therapy, the need for a maximal graft-versus-target effect, short-term and long-term infectious complications, and the risk of graft-versus-host disease (GVHD; acute versus chronic). The various approaches differ in terms of reconstitution speed, cell lineages introduced, and likelihood of GVHD—all factors that can produce distinct effects on the risk of infection after transplantation (Table 16-1). Despite these caveats, most infections occur in a predictable time frame after transplantation (Table 16-2).

BACTERIAL INFECTIONS

In the first month after HSC transplantation, infectious complications are similar to those in granulocytopenic patients receiving chemotherapy for acute leukemia (Chap. 15). Because of the anticipated 1- to 4-week duration of neutropenia and the high rate of bacterial infection in this population, many centers give prophylactic antibiotics to patients upon initiation of myeloablative therapy. Quinolones decrease the incidence of gram-negative bacteremia among these patients. Bacterial infections are common in the first few days after HSC transplantation. The organisms involved are predominantly those found on skin, mucosa, or IV catheters (Staphylococcus aureus, coagulase-negative staphylococci, streptococci) or aerobic bacteria that colonize the bowel (Escherichia coli, Klebsiella, Pseudomonas). Bacillus cereus, although rare, has emerged as a pathogen early after transplantation and can cause meningitis, which is unusual in these patients. Chemotherapy, use of broad-spectrum antibiotics, and delayed reconstitution of humoral immunity place HSC transplant patients at risk for diarrhea and colitis caused by Clostridium difficile overgrowth and toxin production.

Beyond the first few days of neutropenia, infections with nosocomial pathogens (e.g., vancomycin-resistant enterococci, Stenotrophomonas maltophilia, Acinetobacter species, and extended-spectrum β-lactamase–producing gram-negative bacteria) as well as with filamentous bacteria (e.g., Nocardia species) become more common. Vigilance is indicated, particularly for patients with a history of active or known latent tuberculosis, even when they have been appropriately pretreated. A form of bacterial colitis among cord-blood recipients has occurred 90–300 days after transplantation, responds to antimicrobial agents such as metronidazole, and—as determined by polymerase chain reaction (PCR) of biopsy specimens—may be attributed to the bacterium Bradyrhizobium enterica (related to B. japonicum). Episodes of bacteremia due to encapsulated organisms mark the late posttransplantation period (>6 months after HSC reconstitution); patients who have undergone splenectomy and those with persistent hypogammaglobulinemia are at particular risk.

FUNGAL INFECTIONS

Beyond the first week after transplantation, fungal infections become increasingly common, particularly among patients who have received broad-spectrum antibiotics. As in most granulocytopenic patients, Candida infections are most commonly seen in this setting. However, with increased use of prophylactic fluconazole, infections with resistant fungi—in particular, Aspergillus and other non-Aspergillus molds (Rhizopus, Fusarium, Scedosporium, Penicillium)—have become more common, prompting some centers to replace fluconazole with agents such as micafungin, voriconazole, or posaconazole. The role of antifungal prophylaxis with these different agents, in contrast to empirical treatment for suspected infection that is based on a positive β-d-glucan assay or galactomannan antigen test, remains controversial (Chap. 15). Documented infection should be aggressively treated, ideally with agents of proven activity. In patients with GVHD who require prolonged or indefinite courses of glucocorticoids and other immunosuppressive agents (e.g., cyclosporine, tacrolimus [FK 506, Prograf], mycophenolate mofetil [Cellcept], rapamycin [sirolimus, Rapamune], antithymocyte globulin, or anti-CD52 antibody [alemtuzumab, Campath—an antilymphocyte and antimonocyte monoclonal antibody]), there is a high risk of fungal infection (usually with Candida or Aspergillus) even after engraftment and resolution of neutropenia. These patients are also at high risk for reactivation of latent fungal infection (histoplasmosis, coccidioidomycosis, or blastomycosis) in areas where endemic fungi reside and after involvement in activities such as gardening or caving. Prolonged use of central venous catheters for parenteral nutrition (lipids) increases the risk of fungemia with Malassezia. Some centers administer prophylactic antifungal agents to these patients. Because of the high and prolonged risk of Pneumocystis jirovecii pneumonia (especially among patients being treated for hematologic malignancies), most patients receive maintenance prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) starting 1 month after engraftment and continuing for at least 1 year.

PARASITIC INFECTIONS

The regimen just described for the fungal pathogen Pneumocystis may also protect patients seropositive for the parasite T. gondii, which can cause pneumonia, visceral disease (occasionally), and central nervous system (CNS) lesions (more commonly). The advantages of maintaining HSC transplant recipients on daily TMP-SMX for 1 year after transplantation include some protection against Listeria monocytogenes and nocardial disease as well as late infections with Streptococcus pneumoniae and Haemophilus influenzae, which stem from the inability of the immature immune system to respond to polysaccharide antigens.

With increasing international travel, parasitic diseases typically restricted to particular environmental niches may pose a risk of reactivation in certain patients after HSC transplantation. Thus, in recipients with an appropriate history who were not screened and/or treated before transplantation or in patients with recent exposures, evaluation for infection with Strongyloides, Leishmania, schistosomes, trypanosomes, or various parasitic causes of diarrheal illness (Giardia, Entamoeba, Cryptosporidium, microsporidia) may be warranted.

VIRAL INFECTIONS

HSC transplant recipients are susceptible to infection with a variety of viruses, including primary and reactivation syndromes caused by most human herpesviruses (Table 16-3) and acute infections caused by viruses that circulate in the community.

Herpes simplex virus

Within the first 2 weeks after transplantation, most patients who are seropositive for HSV-1 excrete the virus from the oropharynx. The ability to isolate HSV declines with time. Administration of prophylactic acyclovir (or valacyclovir) to seropositive HSC transplant recipients has been shown to reduce mucositis and prevent HSV pneumonia (a rare condition reported almost exclusively in allogeneic HSC transplant recipients). Both esophagitis (usually due to HSV-1) and anogenital disease (commonly caused by HSV-2) may be prevented with acyclovir prophylaxis. For further discussion, see Chap. 88.

Varicella-zoster virus

Reactivation of VZV manifests as herpes zoster and may occur within the first month but more commonly occurs several months after transplantation. Reactivation rates are ∼40% for allogeneic HSC transplant recipients and 25% for autologous recipients. Localized zoster can spread rapidly in an immunosuppressed patient. Fortunately, disseminated disease can usually be controlled with high doses of acyclovir. Because of frequent dissemination among patients with skin lesions, acyclovir is given prophylactically in some centers to prevent severe disease. Low doses of acyclovir appear to be effective in preventing reactivation of VZV. However, acyclovir can also suppress the development of VZV-specific immunity. Thus, its administration for only 6 months after transplantation does not prevent zoster from occurring when treatment is stopped. Administration of low doses of acyclovir for an entire year after transplantation is effective and may eliminate most cases of posttransplantation zoster, even among cord-blood recipients. For further discussion, see Chap. 89.

Cytomegalovirus

The onset of CMV disease (interstitial pneumonia, bone marrow suppression, graft failure, hepatitis/colitis) usually begins 30–90 days after HSC transplantation, when the granulocyte count is adequate but immunologic reconstitution has not occurred. CMV disease rarely develops earlier than 14 days after transplantation and may become evident as late as 4 months after the procedure. It is of greatest concern in the second month after transplantation, particularly in allogeneic HSC transplant recipients. In cases in which the donor marrow is depleted of T cells (to prevent GVHD or eliminate a T cell tumor) and in cord-blood recipients, the disease may manifest earlier. The use of alemtuzumab to prevent GVHD in nonmyeloablative transplantation has been associated with an increase in CMV disease. Patients who receive ganciclovir for prophylaxis, preemptive treatment, or treatment (see below) may develop recurrent CMV infection even later than 4 months after transplantation, as treatment appears to delay the development of the normal immune response to CMV infection. Although CMV disease may present as isolated fever, granulocytopenia, thrombocytopenia, or gastrointestinal disease, the foremost cause of death from CMV infection in the setting of HSC transplantation is pneumonia.

With the standard use of CMV-negative or filtered blood products, CMV infection should be a major risk in allogeneic transplantation only when the recipient is CMV-seropositive and the donor is CMV-seronegative. This situation is the reverse of that in solid organ transplant recipients. CMV reactivates from latent reservoirs present in the recipient at a time when donor T cells (especially cord-blood T cells) are too immature to control CMV replication. If the T cells from the donor have never encountered CMV and the recipient carries the virus, the patient is at maximal risk of severe disease. Reactivation disease or superinfection with another strain from the donor also can occur in CMV-positive recipients, but clinical manifestations are typically less severe, presumably because of CMV-specific memory in transplanted donor T cells. Most patients infected with CMV who undergo HSC transplantation excrete virus, with or without clinical findings. Serious CMV disease is much more common among allogeneic than autologous recipients and is often associated with GVHD. In addition to pneumonia and marrow suppression (and, less often, graft failure), manifestations of CMV disease in HSC transplant recipients include fever with or without arthralgias, myalgias, hepatitis, and esophagitis. CMV ulcerations occur in both the lower and the upper gastrointestinal tract, and it may be difficult to distinguish diarrhea due to GVHD from that due to CMV infection. The finding of CMV in the liver of a patient with GVHD does not necessarily mean that CMV is responsible for hepatic enzyme abnormalities. It is interesting that the ocular and neurologic manifestations of CMV infections, which are common in patients with AIDS, are uncommon in patients who develop disease after transplantation.

Management of CMV disease in HSC transplant recipients includes strategies directed at prophylaxis, preemptive therapy (suppression of silent replication), and treatment of disease. Prophylaxis results in a lower incidence of disease at the cost of treating many patients who otherwise would not require therapy. Because of the high fatality rate associated with CMV pneumonia in these patients and the difficulty of early diagnosis of CMV infection, prophylactic IV ganciclovir (or oral valganciclovir) has been used in some centers and has been shown to prevent CMV disease during the period of maximal vulnerability (from engraftment to day 120 after transplantation). Ganciclovir also prevents HSV reactivation and reduces the risk of VZV reactivation; thus acyclovir prophylaxis should be discontinued when ganciclovir is administered. The foremost problem with the administration of ganciclovir relates to adverse effects, which include dose-related bone marrow suppression (thrombocytopenia, leukopenia, anemia, and pancytopenia). Because the frequency of CMV pneumonia is lower among autologous HSC transplant recipients (2–7%) than among allogeneic HSC transplant recipients (10–40%), prophylaxis in the former group will not become the rule until a less toxic oral antiviral agent becomes available. Several are under study.

Preemptive treatment of CMV—that is, initiation of therapy with drugs only after CMV is detected in blood by a nucleic acid amplification test (NAAT)—is used at most centers. To limit variability between tests, the World Health Organization (WHO) has developed an international reference standard for measurement of CMV load by NAAT-based assays. Because of toxic drug side effects (e.g., neutropenia and bone marrow suppression), the preemptive approach has supplanted prophylactic therapy; it has also replaced treatment of all seropositive (recipient and/or donor) HSC transplants with an antiviral agent (typically ganciclovir). A positive test (or increasing viral load) prompts the initiation of preemptive therapy with ganciclovir. Preemptive approaches that target patients who have quantitative NAAT evidence of CMV infection can still lead to unnecessary treatment of many individuals with drugs that have adverse effects on the basis of a laboratory test that is not highly predictive of disease; however, invasive disease, particularly in the form of pulmonary infection, is difficult to treat and is associated with high mortality rates. When prophylaxis or preemptive therapy is stopped, late manifestations of CMV replication may occur, although by then the HSC transplant patient is often equipped with improved graft function and is better able to combat disease. Cord-blood transplant recipients are especially vulnerable to disease caused by members of the human herpesvirus family, including CMV. Implementation of the WHO standard for CMV load measurement will facilitate large-scale comparative studies and thus the establishment of optimal guidelines for distinct patient subsets.

CMV pneumonia in HSC transplant recipients (unlike that in other clinical settings) is often treated with both IV immunoglobulin (IVIg) and ganciclovir. In patients who cannot tolerate ganciclovir, foscarnet is a useful alternative, although it may produce nephrotoxicity and electrolyte imbalance. When neither ganciclovir nor foscarnet is clinically tolerated, cidofovir can be used; however, its efficacy is less well established, and its side effects include nephrotoxicity. A lipid-conjugate form of cidofovir and an oral antiviral agent, maribavir, are in clinical trials. Case reports have suggested that the immunosuppressive agent leflunomide may be active in this setting, but controlled studies are lacking. Transfusion of CMV-specific T cells from the donor has decreased viral load in a small series of patients; this result suggests that immunotherapy (e.g., banked T cells) may play a role in the management of this disease in the future. For further discussion, see Chap. 91.

Human herpesviruses 6 and 7

Human herpesvirus type 6 (HHV-6), the cause of roseola in children, is a ubiquitous herpesvirus that is reactivated (as determined by quantitative plasma PCR) in ∼50% of HSC transplant recipients 2–4 weeks after transplantation. Reactivation is more common among patients requiring glucocorticoids for GVHD and among those receiving second transplants. Reactivation of HHV-6, primarily type B, may be associated with delayed monocyte and platelet engraftment. Limbic encephalitis developing after transplantation has been associated with HHV-6 in cerebrospinal fluid (CSF). The causality of the association is not well defined; in several cases, plasma viremia was detected long before the onset of encephalitis. Nevertheless, most patients with encephalitis had very high viral loads in plasma at the time of CNS illness, and viral antigen has been detected in hippocampal astrocytes. HHV-6 DNA is sometimes found in lung samples after transplantation. However, its role in pneumonitis is unclear, as co-pathogens are frequently present. While HHV-6 is susceptible to foscarnet or cidofovir (and possibly to ganciclovir) in vitro, the efficacy of antiviral treatment has not been well studied. Little is known about the related herpesvirus HHV-7 or its role in posttransplantation infection. For further discussion, see Chap. 91.

Epstein-Barr virus

Primary EBV infection can be fatal to HSC transplant recipients; EBV reactivation can cause EBV–B cell lymphoproliferative disease (EBV-LPD), which may also be fatal to patients taking immunosuppressive drugs. Latent EBV infection of B cells leads to several interesting phenomena in HSC transplant recipients. The marrow ablation that occurs as part of the HSC transplantation procedure may sometimes eliminate latent EBV from the host. Infection can then be reacquired immediately after transplantation by transfer of infected donor B cells. Rarely, transplantation from a seronegative donor may result in a cure. The recipient is then at risk for a second primary infection.

EBV-LPD can develop in the recipient’s B cells (if any survive marrow ablation) but is more likely to be a consequence of outgrowth of infected donor cells. Both lytic replication and latent replication of EBV are more likely during immunosuppression (e.g., they are associated with GVHD and the use of antibodies to T cells). Although less likely in autologous transplantation, reactivation can occur in T cell–depleted autologous recipients (e.g., patients being given antibodies to T cells for the treatment of a T cell lymphoma with marrow depletion). EBV-LPD, which can become apparent as early as 1–3 months after engraftment, can cause high fevers and cervical adenopathy resembling the symptoms of infectious mononucleosis but more commonly presents as an extranodal mass. The incidence of EBV-LPD among allogeneic HSC transplant recipients is 0.6–1%, which contrasts with figures of ∼5% for renal transplant recipients and up to 20% for cardiac transplant patients. In all cases, EBV-LPD is more likely to occur with high-dose, prolonged immunosuppression, especially that caused by the use of antibodies to T cells, glucocorticoids, and calcineurin inhibitors (e.g., cyclosporine, tacrolimus). Cord-blood recipients constitute another high-risk group because of delayed T cell function. Ganciclovir, administered to preempt CMV disease, may reduce EBV lytic replication and thereby diminish the pool of B cells that can become newly infected and give rise to LPD. Increasing evidence indicates that replacement of calcineurin inhibitors with mTor inhibitors (e.g., rapamycin) exerts an antiproliferative effect on EBV-infected B cells that decreases the likelihood of development of LPD or unrelated proliferative disorders associated with transplant-related immunosuppression.

PCR can be used to monitor EBV production after HSC transplantation. High or increasing viral loads predict an enhanced likelihood of EBV-LPD development and should prompt rapid reduction of immunosuppression and a search for nodal or extranodal disease. If reduction of immunosuppression does not have the desired effect, administration of a monoclonal antibody to CD20 (e.g., rituximab) for the treatment of B cell lymphomas that express this surface protein has elicited dramatic responses and currently constitutes first-line therapy for CD20-positive EBV-LPD. However, long-term suppression of new antibody responses accompanies therapy, and recurrences are not infrequent. Additional B cell–directed antibodies, including anti-CD22, are under study. The role of antiviral drugs is uncertain because no available agents have been documented to have activity against the different forms of latent EBV infection. Diminishing lytic replication and virion production in these patients would theoretically produce a statistical decrease in the frequency of latent disease by decreasing the number of virions available to cause additional infection. In case reports and animal studies, ganciclovir and/or high-dose zidovudine, together with other agents, has been used to eradicate EBV-LPD and CNS lymphomas, another EBV-associated complication of transplantation. Both interferon and retinoic acid have been employed in the treatment of EBV-LPD, as has IVIg, but no large-scale prospective studies have assessed the efficacy of any of these agents. Several additional drugs are undergoing preclinical evaluation. Standard chemotherapeutic regimens are used if disease persists after reduction of immunosuppressive agents and administration of antibodies. EBV-specific T cells generated from the donor have been used experimentally to prevent and treat EBV-LPD in allogeneic recipients, and efforts are under way to increase the activity and specificity of ex vivo–generated T cells. For further discussion, see Chap. 90.

Human herpesvirus 8 (KSHV)

The EBV-related gammaherpesvirus KSHV, which is causally associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease, has rarely resulted in disease in HSC transplant recipients, although some cases of virus-associated marrow aplasia have been reported in the peritransplantation period. The relatively low seroprevalence of KSHV in the population and the limited duration of profound T cell suppression after HSC transplantation provide a plausible explanation for the currently low incidence of KSHV disease compared with that in recipients of solid organ transplants and patients with HIV infection. For further discussion, see Chap. 91.

Other (non-herpes) viruses

The diagnosis of pneumonia in HSC transplant recipients poses special problems. Because patients have undergone treatment with multiple chemotherapeutic agents and sometimes irradiation, their differential diagnosis should include—in addition to bacterial and fungal pneumonia—CMV pneumonitis, pneumonia of other viral etiologies, parasitic pneumonia, diffuse alveolar hemorrhage, and chemical- or radiation-associated pneumonitis. Since fungi and viruses (e.g., influenza A and B viruses, respiratory syncytial virus [RSV], parainfluenza virus [types 1–4], adenovirus, enterovirus, bocavirus, human metapneumovirus, coronavirus, and rhinovirus [increasingly detected by multiplex PCR]) also can cause pneumonia in this setting, it is important to obtain a specific diagnosis. Diagnostic modalities include Gram’s stain, microbiologic culture, antigen testing, and—increasingly—multipathogen PCR and mass spectrometry assays. M. tuberculosis has been an uncommon cause of pneumonia among HSC transplant recipients in Western countries (accounting for <0.1–0.2% of cases) but is common in Hong Kong (5.5%) and in countries where the prevalence of tuberculosis is high. The recipient’s exposure history is clearly critical in an assessment of posttransplantation infections.

Both RSV and parainfluenza viruses, particularly type 3, can cause severe or even fatal pneumonia in HSC transplant recipients. Infections with both of these agents sometimes occur as disastrous nosocomial epidemics. Therapy with palivizumab or ribavirin for RSV infection remains controversial. New agents, some host-directed, are under study. Influenza also occurs in HSC transplant recipients and generally mirrors the presence of infection in the community. Progression to pneumonia is more common when infection occurs early after transplantation and when the recipient is lymphopenic. The neuraminidase inhibitors oseltamivir (oral) and zanamivir (aerosolized) are active against both influenza A virus and influenza B virus and are a reasonable treatment option. Parenteral forms of neuraminidase inhibitors such as peramivir (intravenous) and several new oral agents remain in trial status. An important preventive measure is immunization of household members, hospital staff members, and other frequent contacts. Adenoviruses can be isolated from HSC transplant recipients at rates varying from 5% to ≥18%. Like CMV infection, adenovirus infection usually occurs in the first to third month after transplantation and is often asymptomatic, although pneumonia, hemorrhagic cystitis/nephritis, severe gastroenteritis with hemorrhage, and fatal disseminated infection have been reported and may be strain-specific. A role for cidofovir therapy has been suggested, but the efficacy of this agent in adenovirus infection remains to be determined. Banked virus-specific T cell therapy is under study for adenovirus infection (as well as for CMV and EBV infections).

Although diverse respiratory viruses can sometimes cause severe pneumonia and respiratory failure in HSC transplant recipients, mild or even asymptomatic infection may be more common. For example, rhinoviruses and coronaviruses are frequent co-pathogens in HSC transplant recipients; however, whether they independently contribute to significant pulmonary infection is not known. At present, the overall contribution of these viral respiratory pathogens to the burden of lower respiratory tract disease in HSC transplant recipients requires further study. Infections with parvovirus B19 (presenting as anemia or occasionally as pancytopenia) and disseminated enteroviruses (sometimes fatal) can occur. Parvovirus B19 infection can be treated with IVIg (Chap. 93).

Rotaviruses are a cause of gastroenteritis in HSC transplant recipients, more frequently in children. Norovirus is a common cause of vomiting and diarrhea, and symptoms can be prolonged in HSC recipients. The polyomavirus BK virus is found at high titers in the urine of patients who are profoundly immunosuppressed. BK viruria may be associated with hemorrhagic cystitis in these patients. In contrast to its incidence among patients with impaired T cell function due to AIDS (4–5%), progressive multifocal leukoencephalopathy caused by the related JC virus is relatively rare among HSC transplant recipients (Chap. 36). When transmitted by mosquitoes or by blood transfusion, WNV can cause encephalitis and death after HSC transplantation.

Rates of morbidity and mortality among recipients of solid organ transplants (SOTs) are reduced by the use of effective antibiotics. The organisms that cause acute infections in recipients of SOTs are different from those that infect HSC transplant recipients because SOT recipients do not go through a period of neutropenia. As the transplantation procedure involves major surgery, however, SOT recipients are subject to infections at anastomotic sites and to wound infections. Compared with HSC transplant recipients, SOT patients are immunosuppressed for longer periods (often permanently). Thus they are susceptible to many of the same organisms as patients with chronically impaired T cell immunity (Chap. 15, especially Table 15-1). Moreover, the persistent HLA mismatch between recipient immune cells (e.g., effector T cells) and the donor organ (allograft) places the organ at permanently increased risk of infection.

During the early period (<1 month after transplantation; Table 16-4), infections are most commonly caused by extracellular bacteria (staphylococci, streptococci, enterococci, and E. coli and other gram-negative organisms, including nosocomial organisms with broad antibiotic resistance), which often originate in surgical wound or anastomotic sites. The type of transplant largely determines the spectrum of infection. In subsequent weeks, the consequences of the administration of agents that suppress cell-mediated immunity become apparent, and acquisition—or, more commonly, reactivation—of viruses, mycobacteria, endemic fungi, and parasites (from the recipient or from the transplanted organ) can occur. CMV infection is often a problem, particularly in the first 6 months after transplantation, and may present as severe systemic disease or as infection of the transplanted organ. HHV-6 reactivation (assessed by plasma PCR) occurs within the first 2–4 weeks after transplantation and may be associated with fever, leukopenia, and very rare cases of encephalitis. Data suggest that replication of HHV-6 and HHV-7 may exacerbate CMV-induced disease. CMV is associated not only with generalized immunosuppression but also with organ-specific, rejection-related syndromes: glomerulopathy in kidney transplant recipients, bronchiolitis obliterans in lung transplant recipients, vasculopathy in heart transplant recipients, and the vanishing bile duct syndrome in liver transplant recipients. A complex interplay between increased CMV replication and enhanced graft rejection is well established: elevated immunosuppression leads to increased CMV replication, which is associated with graft rejection. For this reason, considerable attention has been focused on the diagnosis, prophylaxis, and treatment of CMV infection in SOT recipients. Early transmission of WNV to transplant recipients from a donated organ or transfused blood has been reported; however, the risk of WNV acquisition has been reduced by implementation of screening procedures. In rare instances, rabies virus and lymphocytic choriomeningitis virus also have been acutely transmitted in this setting; although accompanied by distinct clinical syndromes, both viral infections have resulted in fatal encephalitis. As screening for unusual viruses is not routine, only vigilant assessment of the prospective donor is likely to prevent the use of an infected organ.

Beyond 6 months after transplantation, infections characteristic of patients with defects in cell-mediated immunity—e.g., infections with Listeria, Nocardia, Rhodococcus, mycobacteria, various fungi, and other intracellular pathogens—may be a problem. International patients and global travelers may experience reactivation of dormant infections with trypanosomes, Leishmania, Plasmodium, Strongyloides, and other parasites. Reactivation of latent M. tuberculosis infection, while rare in Western nations, is far more common among persons from developing countries. The recipient is typically the source, although reactivation and spread from the donor organ can occur. While pulmonary disease remains most common, atypical sites can be involved and mortality rates can be high (up to 30%). Vigilance, prophylaxis/preemptive therapy (when indicated), and rapid diagnosis and treatment of infections can be lifesaving in SOT recipients, who, unlike most HSC transplant recipients, continue to be immunosuppressed.

SOT recipients are susceptible to EBV-LPD from as early as 2 months to many years after transplantation. The prevalence of this complication is increased by potent and prolonged use of T cell–suppressive drugs. Decreasing the degree of immunosuppression may in some cases reverse the condition. Among SOT patients, those with heart and lung transplants—who receive the most intensive immunosuppressive regimens—are most likely to develop EBV-LPD, particularly in the lungs. Although the disease usually originates in recipient B cells, several cases of donor origin, particularly in the transplanted organ, have been noted. High organ-specific content of B lymphoid tissues (e.g., bronchus-associated lymphoid tissue in the lung), anatomic factors (e.g., lack of access of host T cells to the transplanted organ because of disturbed lymphatics), and differences in major histocompatibility loci between the host T cells and the organ (e.g., lack of cell migration or lack of effective T cell/macrophage/dendritic cell cooperation) may result in defective elimination of EBV-infected B cells. SOT recipients are also highly susceptible to the development of Kaposi’s sarcoma and, less frequently, to the B cell–proliferative disorders associated with KSHV, such as primary effusion lymphoma and multicentric Castleman’s disease. Kaposi’s sarcoma is 550–1000 times more common among SOT recipients than in the general population, can develop very rapidly after transplantation, and can also occur in the allograft. However, because the seroprevalence of KSHV is very low in Western countries, Kaposi’s sarcoma is not common. Recipients (or donors) from Iceland, the Middle East, Mediterranean countries, and Africa are at highest risk of disease. Data suggest that a switch of immunosuppressive agents—from calcineurin inhibitors (cyclosporine, tacrolimus) to mTor pathway–active agents (sirolimus, everolimus)—after adequate wound healing may significantly reduce the likelihood of development of Kaposi’s sarcoma and perhaps of EBV-LPD and certain other posttransplantation malignancies.

KIDNEY TRANSPLANTATION

See Table 16-4.

Early infections

Bacteria often cause infections that develop in the period immediately after kidney transplantation. There is a role for perioperative antibiotic prophylaxis, and many centers give cephalosporins to decrease the risk of postoperative complications. Urinary tract infections developing soon after transplantation are usually related to anatomic alterations resulting from surgery. Such early infections may require prolonged treatment (e.g., 6 weeks of antibiotic administration for pyelonephritis). Urinary tract infections that occur >6 months after transplantation may be treated for shorter periods because they do not seem to be associated with the high rate of pyelonephritis or relapse seen with infections that occur during the first 3 months.

Prophylaxis with TMP-SMX for the first 4–6 months after transplantation decreases the incidence of early and middle-period infections (see Table 16-4, and Table 16-5).

Middle-period infections

Because of continuing immunosuppression, kidney transplant recipients are predisposed to lung infections characteristic of those in patients with T cell deficiency (i.e., infections with intracellular bacteria, mycobacteria, nocardiae, fungi, viruses, and parasites). A high mortality rate associated with Legionella pneumophila infection (Chap. 56) led to the closing of renal transplant units in hospitals with endemic legionellosis.

About 50% of all renal transplant recipients presenting with fever 1–4 months after transplantation have evidence of CMV disease; CMV itself accounts for the fever in more than two-thirds of cases and thus is the predominant pathogen during this period. CMV infection (Chap. 91) may also present as arthralgias, myalgias, or organ-specific symptoms. During this period, this infection may represent primary disease (in the case of a seronegative recipient of a kidney from a seropositive donor) or may represent reactivation disease or superinfection. Patients may have atypical lymphocytosis. Unlike immunocompetent patients, however, they rarely have lymphadenopathy or splenomegaly. Therefore, clinical suspicion and laboratory confirmation are necessary for diagnosis. The clinical syndrome may be accompanied by bone marrow suppression (particularly leukopenia). CMV also causes glomerulopathy and is associated with an increased incidence of other opportunistic infections. Because of the frequency and severity of disease, a considerable effort has been made to prevent and treat CMV infection in renal transplant recipients. An immune globulin preparation enriched with antibodies to CMV was used by many centers in the past in an effort to protect the group at highest risk for severe infection (seronegative recipients of seropositive kidneys). However, with the development of effective oral antiviral agents, CMV immune globulin is no longer used. Ganciclovir (or valganciclovir) is beneficial for prophylaxis (when indicated) and for the treatment of serious CMV disease. The availability of valganciclovir has allowed most centers to move to oral prophylaxis for transplant recipients. Infection with the other herpesviruses may become evident within 6 months after transplantation or later. Early after transplantation, HSV may cause either oral or anogenital lesions that are usually responsive to acyclovir. Large ulcerating lesions in the anogenital area may lead to bladder and rectal dysfunction and may predispose the patient to bacterial infection. VZV may cause fatal disseminated infection in nonimmune kidney transplant recipients, but in immune patients reactivation zoster usually does not disseminate outside the dermatome; thus disseminated VZV infection is a less fearsome complication in kidney transplantation than in HSC transplantation. HHV-6 reactivation may take place and (although usually asymptomatic) may be associated with fever, rash, marrow suppression, or rare instances of renal impairment, hepatitis, colitis, or encephalitis.

EBV disease is more serious; it may present as an extranodal proliferation of B cells that invade the CNS, nasopharynx, liver, small bowel, heart, and other organs, including the transplanted kidney. The disease is diagnosed by the finding of a mass of proliferating EBV-positive B cells. The incidence of EBV-LPD is elevated among patients who acquire EBV infection from the donor and among patients given high doses of cyclosporine, tacrolimus, glucocorticoids, and anti–T cell antibodies. Disease may regress once immunocompetence is restored. KSHV infection can be transmitted with the donor kidney and result in development of Kaposi’s sarcoma, although it more often represents reactivation of latent infection of the recipient. Kaposi’s sarcoma often appears within 1 year after transplantation, although the time of onset ranges widely (1 month to ∼20 years). Avoidance of immunosuppressive agents that inhibit calcineurin has been associated with less Kaposi’s sarcoma, less EBV disease, and even less CMV replication. The use of rapamycin (sirolimus) has independently led to regression of Kaposi’s sarcoma.

The papovaviruses BK virus and JC virus (polyomavirus hominis types 1 and 2) have been cultured from the urine of kidney transplant recipients (as they have from that of HSC transplant recipients) in the setting of profound immunosuppression. High levels of BK virus replication detected by PCR in urine and blood are predictive of pathology, especially in the setting of renal transplantation. JC virus may rarely cause similar disease in kidney transplantation. Urinary excretion of BK virus and BK viremia are associated with the development of ureteral strictures, polyomavirus-associated nephropathy (1–10% of renal transplant recipients), and (less commonly) generalized vasculopathy. Timely detection and early reduction of immunosuppression are critical and can reduce rates of graft loss related to polyomavirus-associated nephropathy from 90% to 10–30%. Therapeutic responses to IVIg, quinolones, leflunomide, and cidofovir have been reported, but the efficacy of these agents has not been substantiated through adequate clinical study. Most centers approach the problem by reducing immunosuppression in an effort to enhance host immunity and decrease viral titers. JC virus is associated with rare cases of progressive multifocal leukoencephalopathy. Adenoviruses may persist and cause hemorrhagic nephritis/cystitis with continued immunosuppression in these patients, but disseminated disease like that seen in HSC transplant recipients is much less common.

Kidney transplant recipients are also subject to infections with other intracellular organisms. These patients may develop pulmonary infections with Mycobacterium, Aspergillus, and Mucor species as well as infections with other pathogens in which the T cell/macrophage axis plays an important role. L. monocytogenes is a common cause of bacteremia ≥1 month after renal transplantation and should be seriously considered in renal transplant recipients presenting with fever and headache. Kidney transplant recipients may develop Salmonella bacteremia, which can lead to endovascular infections and require prolonged therapy. Pulmonary infections with Pneumocystis are common unless the patient is maintained on TMP-SMX prophylaxis. Acute interstitial nephritis caused by TMP-SMX is rare. However, because transient increases in creatinine (artifactual) and hyperkalemia (manageable) can occur, early discontinuation of prophylaxis, especially after kidney transplantation, is recommended by some groups. Although additional monitoring is indicated, the benefits of TMP-SMX in kidney transplant recipients may outweigh the risks; otherwise, second-line prophylactic agents should be used. Nocardia infection (Chap. 71) may present in the skin, bones, and lungs or in the CNS, where it usually takes the form of single or multiple brain abscesses. Nocardiosis generally occurs ≥1 month after transplantation and may follow immunosuppressive treatment for an episode of rejection. Pulmonary manifestations most commonly consist of localized disease with or without cavities, but the disease may be disseminated. The diagnosis is made by culture of the organism from sputum or from the involved nodule. As it is for P. jirovecii infection, prophylaxis with TMP-SMX is often efficacious in the prevention of nocardiosis.

Toxoplasmosis can occur in seropositive patients but is less common than in other transplantation settings, usually developing in the first few months after kidney transplantation. Again, TMP-SMX is helpful in prevention. In endemic areas, histoplasmosis, coccidioidomycosis, and blastomycosis may cause pulmonary infiltrates or disseminated disease.

Late infections

Late infections (>6 months after kidney transplantation) may involve the CNS and include CMV retinitis as well as other CNS manifestations of CMV disease. Patients (particularly those whose immunosuppression has been increased) are at risk for subacute meningitis due to Cryptococcus neoformans. Cryptococcal disease may present in an insidious manner (sometimes as a skin infection before the development of clear CNS findings). Listeria meningitis may have an acute presentation and requires prompt therapy to avoid a fatal outcome. TMP-SMX prophylaxis may reduce the frequency of Listeria infections.

Patients who continue to take glucocorticoids are predisposed to ongoing infection. “Transplant elbow,” a recurrent bacterial infection in and around the elbow that is thought to result from a combination of poor tensile strength of the skin of steroid-treated patients and steroid-induced proximal myopathy, requires patients to push themselves up with their elbows to get out of chairs. Bouts of cellulitis (usually caused by S. aureus) recur until patients are provided with elbow protection.

Kidney transplant recipients are susceptible to invasive fungal infections, including those due to Aspergillus and Rhizopus, which may present as superficial lesions before dissemination. Mycobacterial infection (particularly that with Mycobacterium marinum) can be diagnosed by skin examination. Infection with Prototheca wickerhamii (an achlorophyllic alga) has been diagnosed by skin biopsy. Warts caused by human papillomaviruses (HPVs) are a late consequence of persistent immunosuppression; imiquimod or other forms of local therapy are usually satisfactory. Merkel cell carcinoma, a rare and aggressive neuroendocrine skin tumor whose frequency is increased fivefold in elderly SOT (especially kidney) recipients, is causally linked to a novel polyomavirus, Merkel cell polyomavirus.

Notably, although BK virus replication and virus-associated disease can be detected far earlier, polyomavirus-associated nephropathy is clinically diagnosed in a median of ∼300 days and thus qualifies as a late-onset disease. With the establishment of better screening procedures (e.g., urine cytology, urine nucleic acid load, plasma PCR), disease onset is being detected earlier (see “Middle-Period Infections,” above) and preemptive strategies (decrease or modification of immunosuppression) are being instituted more promptly, as the efficacy of antiviral therapy is not well established.

HEART TRANSPLANTATION

Early infections

Sternal wound infection and mediastinitis are early complications of heart transplantation. An indolent course is common, with fever or a mildly elevated white blood cell count preceding the development of site tenderness or drainage. Clinical suspicion based on evidence of sternal instability and failure to heal may lead to the diagnosis. Common microbial residents of the skin (e.g., S. aureus, including methicillin-resistant strains, and Staphylococcus epidermidis) as well as gram-negative organisms (e.g., Pseudomonas aeruginosa) and fungi (e.g., Candida) are often involved. In rare cases, mediastinitis in heart transplant recipients can also be due to Mycoplasma hominis (Chap. 84); since this organism requires an anaerobic environment for growth and may be difficult to see on conventional medium, the laboratory should be alerted that its involvement is suspected. M. hominis mediastinitis has been cured with a combination of surgical debridement (sometimes requiring muscle-flap placement) and the administration of clindamycin and tetracycline. Organisms associated with mediastinitis may sometimes be cultured from pericardial fluid.

Middle-period infections

T. gondii (Chap. 128) residing in the heart of a seropositive donor may be transmitted to a seronegative recipient. Thus serologic screening for T. gondii infection is important before and in the months after cardiac transplantation. Rarely, active disease can be introduced at the time of transplantation. The overall incidence of toxoplasmosis is so high in the setting of heart transplantation that some prophylaxis is always warranted. Although alternatives are available, the most frequently used agent is TMP-SMX, which prevents infection with Pneumocystis as well as with Nocardia and several other bacterial pathogens. CMV also has been transmitted by heart transplantation. Toxoplasma, Nocardia, and Aspergillus can cause CNS infections. L. monocytogenes meningitis should be considered in heart transplant recipients with fever and headache.

CMV infection is associated with poor outcomes after heart transplantation. The virus is usually detected 1–2 months after transplantation, causes early signs and laboratory abnormalities (usually fever and atypical lymphocytosis or leukopenia and thrombocytopenia) at 2–3 months, and can produce severe disease (e.g., pneumonia) at 3–4 months. An interesting observation is that seropositive recipients usually develop viremia faster than patients whose primary CMV infection is a consequence of transplantation. Between 40% and 70% of patients develop symptomatic CMV disease in the form of (1) CMV pneumonia, the form most likely to be fatal; (2) CMV esophagitis and gastritis, sometimes accompanied by abdominal pain with or without ulcerations and bleeding; and (3) the CMV syndrome, consisting of CMV in the bloodstream along with fever, leukopenia, thrombocytopenia, and hepatic enzyme abnormalities. Ganciclovir is efficacious in the treatment of CMV infection; prophylaxis with ganciclovir or possibly with other antiviral agents, as described for renal transplantation, may reduce the overall incidence of CMV-related disease.

Late infections

EBV infection usually presents as a lymphoma-like proliferation of B cells late after heart transplantation, particularly in patients maintained on intense immunosuppressive therapy. A subset of heart and heart-lung transplant recipients may develop early fulminant EBV-LPD (within 2 months). Treatment includes the reduction of immunosuppression (if possible), the use of glucocorticoid and calcineurin inhibitor–sparing regimens, and the consideration of therapy with anti–B cell antibodies (rituximab and possibly others). Immunomodulatory and antiviral agents continue to be studied. Ganciclovir prophylaxis for CMV disease may indirectly reduce the risk of EBV-LPD through reduced spread of replicating EBV to naïve B cells. Aggressive chemotherapy is a last resort, as discussed earlier for HSC transplant recipients. KSHV-associated disease, including Kaposi’s sarcoma and primary effusion lymphoma, has been reported in heart transplant recipients. GVHD prophylaxis with sirolimus may decrease the risk of both rejection and outgrowth of KSHV-infected cells. Prophylaxis for Pneumocystis infection is required for these patients (see “Lung Transplantation, Late Infections,” below).

LUNG TRANSPLANTATION

Early infections

It is not surprising that lung transplant recipients are predisposed to the development of pneumonia. The combination of ischemia and the resulting mucosal damage, together with accompanying denervation and lack of lymphatic drainage, probably contributes to the high rate of pneumonia (66% in one series). The prophylactic use of high doses of broad-spectrum antibiotics for the first 3–4 days after surgery may decrease the incidence of pneumonia. Gram-negative pathogens (Enterobacteriaceae and Pseudomonas species) are troublesome in the first 2 weeks after surgery (the period of maximal vulnerability). Pneumonia can also be caused by Candida (possibly as a result of colonization of the donor lung), Aspergillus, and Cryptococcus. Many centers use antifungal prophylaxis (typically fluconazole or liposomal amphotericin B) for the first 1–2 weeks.

Mediastinitis may occur at an even higher rate among lung transplant recipients than among heart transplant recipients and most commonly develops within 2 weeks of surgery. In the absence of prophylaxis, pneumonitis due to CMV (which may be transmitted as a consequence of transplantation) usually presents between 2 weeks and 3 months after surgery, with primary disease occurring later than reactivation disease.

Middle-period infections

The incidence of CMV infection, either reactivated or primary, is 75–100% if either the donor or the recipient is seropositive for CMV. CMV-induced disease after solid organ transplantation appears to be most severe in recipients of lung and heart-lung transplants. Whether this severity relates to the mismatch in lung antigen presentation and host immune cells or is attributable to nonimmunologic factors is not known. More than half of lung transplant recipients with symptomatic CMV disease have pneumonia. Difficulty in distinguishing the radiographic picture of CMV infection from that of other infections or from organ rejection further complicates therapy. CMV can also cause bronchiolitis obliterans in lung transplants. The development of pneumonitis related to HSV has led to the prophylactic use of acyclovir. Such prophylaxis may also decrease rates of CMV disease, but ganciclovir is more active against CMV and is also active against HSV. The prophylaxis of CMV infection with IV ganciclovir—or increasingly with valganciclovir, the oral alternative—is recommended for lung transplant recipients. Antiviral alternatives are discussed in the earlier section on HSC transplantation. Although the overall incidence of serious disease is decreased during prophylaxis, late disease may occur when prophylaxis is stopped—a pattern observed increasingly in recent years. With recovery from peritransplantation complications and, in many cases, a decrease in immunosuppression, the recipient is often better equipped to combat late infection.

Late infections

The incidence of Pneumocystis infection (which may present with a paucity of findings) is high among lung and heart-lung transplant recipients. Some form of prophylaxis for Pneumocystis pneumonia is indicated in all organ transplant situations (Table 16-5). Prophylaxis with TMP-SMX for 12 months after transplantation may be sufficient to prevent Pneumocystis disease in patients whose immunosuppression is not increased.

As in other transplant recipients, EBV infection in lung and heart-lung recipients may cause either a mononucleosis-like syndrome or EBV-LPD. The tendency of the B cell blasts to present in the lung appears to be greater after lung transplantation than after the transplantation of other organs, possibly because of a rich source of B cells in bronchus-associated lymphoid tissue. Reduction of immunosuppression and switching of regimens, as discussed in earlier sections, cause remission in some cases, but mTor inhibitors such as rapamycin may contribute to lung toxicity. Airway compression can be fatal, and rapid intervention may therefore become necessary. The approach to EBV-LPD is similar to that described in other sections.

LIVER TRANSPLANTATION

Early infections

As in other transplantation settings, early bacterial infections are a major problem after liver transplantation. Many centers administer systemic broad-spectrum antibiotics for the first 24 h or sometimes longer after surgery, even in the absence of documented infection. However, despite prophylaxis, infectious complications are common and correlate with the duration of the surgical procedure and the type of biliary drainage. An operation lasting >12 h is associated with an increased likelihood of infection. Patients who have a choledochojejunostomy with drainage of the biliary duct to a Roux-en-Y jejunal bowel loop have more fungal infections than those whose bile is drained via anastomosis of the donor common bile duct to the recipient common bile duct. Overall, liver transplant patients have a high incidence of fungal infections, and the occurrence of fungal (often candidal) infection in the setting of choledochojejunostomy correlates with retransplantation, elevated creatinine levels, long procedures, transfusion of >40 units of blood, reoperation, preoperative use of glucocorticoids, prolonged treatment with antibacterial agents, and fungal colonization 2 days before and 3 days after surgery. Many centers give antifungal agents prophylactically in this setting.

Peritonitis and intraabdominal abscesses are common complications of liver transplantation. Bacterial peritonitis or localized abscesses may result from biliary leaks. Early leaks are especially common with live-donor liver transplants. Peritonitis in liver transplant recipients is often polymicrobial, frequently involving enterococci, aerobic gram-negative bacteria, staphylococci, anaerobes, or Candida and sometimes involving other invasive fungi. Only one-third of patients with intraabdominal abscesses have bacteremia. Abscesses within the first month after surgery may occur not only in and around the liver but also in the spleen, pericolic area, and pelvis. Treatment includes antibiotic administration and drainage as necessary.

Middle-period infections

The development of postsurgical biliary stricture predisposes patients to cholangitis. The incidence of strictures is increased in live-donor liver transplantation. Transplant recipients who develop cholangitis may have high spiking fevers and rigors but often lack the characteristic signs and symptoms of classic cholangitis, including abdominal pain and jaundice. Although these findings may suggest graft rejection, rejection is typically accompanied by marked elevation of liver function enzymes. In contrast, in cholangitis in transplant recipients, results of liver function tests (with the possible exception of alkaline phosphatase levels) are often within the normal range. Definitive diagnosis of cholangitis in liver transplant recipients requires demonstration of aggregated neutrophils in bile duct biopsy specimens. Unfortunately, invasive studies of the biliary tract (either T-tube cholangiography or endoscopic retrograde cholangiopancreatography) may themselves lead to cholangitis. For this reason, many clinicians recommend an empirical trial of therapy with antibiotics covering gram-negative organisms and anaerobes before these procedures are undertaken as well as antibiotic coverage if procedures are eventually performed.

Reactivation of viral hepatitis is a common complication of liver transplantation (Chap. 99). Recurrent hepatitis B and C infections, for which transplantation may be performed, are problematic. To prevent hepatitis B virus reinfection, prophylaxis with an optimal antiviral agent or combination of agents (lamivudine, adefovir, entecavir) and hepatitis B immune globulin is currently recommended, although the optimal dose, route, and duration of therapy remain controversial. Success in preventing reinfection with hepatitis B virus has increased in recent years. Complications related to hepatitis C infection are the most common reason for liver transplantation in the United States. Reinfection of the graft with hepatitis C virus occurs in all patients, with a variable time frame. Studies of aggressive pretransplantation treatment of selected recipients with antiviral agents and prophylactic/preemptive regimens are ongoing. However, early posttransplantation initiation of treatment for histologically documented disease with the classic combination of ribavirin and pegylated interferon has produced sustained responses at rates in the range of 25–40%. Several protease and polymerase inhibitors that block production of hepatitis C virus as well as regimens that spare interferon and a monoclonal antibody to the virus are undergoing preclinical and clinical trials for prevention and or control of infection after transplantation (Chap. 99).

As in other transplantation settings, reactivation disease with herpesviruses is common (Table 16-3). Herpesviruses can be transmitted in donor organs. Although CMV hepatitis occurs in ∼4% of liver transplant recipients, it is usually not so severe as to require retransplantation. Without prophylaxis, CMV disease develops in the majority of seronegative recipients of organs from CMV-positive donors, but fatality rates are lower among liver transplant recipients than among lung or heart-lung transplant recipients. Disease due to CMV can also be associated with the vanishing bile duct syndrome after liver transplantation. Patients respond to treatment with ganciclovir; prophylaxis with oral forms of ganciclovir or high-dose acyclovir may decrease the frequency of disease. A role for HHV-6 reactivation in early posttransplantation fever and leukopenia has been proposed, although the more severe sequelae described in HSC transplantation are unusual. HHV-6 and HHV-7 appear to exacerbate CMV disease in this setting. EBV-LPD after liver transplantation shows a propensity for involvement of the liver, and such disease may be of donor origin. See previous sections for discussion of EBV infections in solid organ transplantation.

PANCREAS TRANSPLANTATION

Pancreas transplantation is most frequently performed together with or after kidney transplantation, although it may be performed alone. Transplantation of the pancreas can be complicated by early bacterial and yeast infections. Most pancreatic transplants are drained into the bowel, and the rest are drained into the bladder. A cuff of duodenum is used in the anastomosis between the pancreatic graft and either the gut or the bladder. Bowel drainage poses a risk of early intraabdominal and allograft infections with enteric bacteria and yeasts. These infections can result in loss of the graft. Bladder drainage causes a high rate of urinary tract infection and sterile cystitis; however, such infection can usually be cured with appropriate antimicrobial agents. In both procedures, prophylactic antimicrobial agents are commonly used at the time of surgery. Aggressive immunosuppression, especially when the patient receives a kidney and a pancreas from different donors, is associated with late-onset systemic fungal and viral infections; thus many centers administer an antifungal drug and an antiviral agent (ganciclovir or a congener) for extended prophylaxis.

Issues related to the development of CMV infection, EBV-LPD, and infections with opportunistic pathogens in patients receiving a pancreatic transplant are similar to those in other SOT recipients.

COMPOSITE TISSUE TRANSPLANTATION

Composite tissue allotransplantation (CTA) is a new field in which, rather than a single organ, multiple tissue types composing a major body part are transplanted. The sites involved have included an upper extremity, the face, the trachea, the knee, and the abdominal wall. The numbers of recipients are limited. The different procedures and the associated infectious complications vary. Nevertheless, some early trends related to infectious complications have become apparent, as very intense and prolonged immunosuppression is typically required to prevent rejection. For example, in the early postoperative period, bacterial infections are especially frequent in facial transplant recipients. Perioperative prophylaxis is tailored to the organisms likely to complicate the different procedures. As in SOT recipients, complicated CMV infections have been observed in several CTA settings, particularly when the recipient is seronegative and the donor is seropositive. In some patients, anti-CMV immune globulin in addition to ganciclovir (as used in HSC transplant recipients with CMV pneumonia) was needed to control disease, and ganciclovir resistance requiring alternative therapies developed in several patients. Infectious complications from reactivation of other members of the human herpesvirus family and other latent viruses also caused significant morbidity, as discussed for SOT recipients. Prophylaxis for CMV infection, P. jirovecii infection, toxoplasmosis, and fungal infection is administered for several months on the basis of the limited studies available.

MISCELLANEOUS INFECTIONS IN SOLID ORGAN TRANSPLANTATION

Indwelling IV catheter infections

The prolonged use of indwelling IV catheters for administration of medications, blood products, and nutrition is common in diverse transplantation settings and poses a risk of local and bloodstream infections. Exit-site infection is most commonly caused by staphylococcal species. Bloodstream infection most frequently develops within 1 week of catheter placement or in patients who become neutropenic. Coagulase-negative staphylococci are the most common isolates from blood. Although infective endocarditis in HSC transplant recipients is uncommon, the incidence of endocarditis in SOT recipients has been estimated to be as high as 1%, and this infection is associated with excessive high mortality in this population. Although staphylococci predominate, the involvement of fungal and gram-negative organisms may be more common than in the general population.

For further discussion of differential diagnosis and therapeutic options, see Chap. 15.

Tuberculosis

The incidence of tuberculosis within the first 12 months after solid organ transplantation is greater than that observed after HSC transplantation (0.23–0.79%) and ranges broadly worldwide (1.2–15%), reflecting the prevalence of tuberculosis in local populations. Lesions suggesting prior tuberculosis on chest radiography, older age, diabetes, chronic liver disease, GVHD, and intense immunosuppression are predictive of tuberculosis reactivation and development of disseminated disease in a host with latent disease. Tuberculosis has rarely been transmitted from the donor organ. In contrast to the low mortality rate among HSC transplant recipients, mortality rates among SOT recipients are reported to be as high as 30%. Vigilance is indicated, as the presentation of disease is often extrapulmonary (gastrointestinal, genitourinary, central nervous, endocrine, musculoskeletal, laryngeal) and atypical; tuberculosis in this setting sometimes manifests as fever of unknown origin. Careful elicitation of a history and direct evaluation of both the recipient and the donor prior to transplantation are optimal. Skin testing of the recipient with purified protein derivative may be unreliable because of chronic disease and/or immunosuppression. Cell-based assays that measure interferon γ and/or cytokine production may prove more sensitive in the future. Isoniazid toxicity has not been a significant problem except in the setting of liver transplantation. Therefore, appropriate prophylaxis should be used (see recommendations from the Centers for Disease Control and Prevention [CDC] at www.cdc.gov/tb/topic/treatment/ltbi.htm). An assessment of the need to treat latent disease should include careful consideration of the possibility of a false-negative test result. Pending final confirmation of suspected tuberculosis, aggressive multidrug treatment in accordance with the guidelines of the CDC, the Infectious Diseases Society of America, and the American Thoracic Society is indicated because of the high mortality rates among these patients. Altered drug metabolism (e.g., upon coadministration of antituberculous medications and certain immunosuppressive agents) can be managed with careful monitoring of drug levels and appropriate dose adjustment. Close follow-up of hepatic enzymes is warranted. Drug-resistant tuberculosis is especially problematic in these individuals (Chap. 74).

Virus-associated malignancies

In addition to malignancy associated with gammaherpesvirus infection (EBV, KSHV) and simple warts (HPV), other tumors that are virus-associated or suspected of being virus-associated are more likely to develop in transplant recipients, particularly those who require long-term immunosuppression, than in the general population. The interval to tumor development is usually >1 year. Transplant recipients develop nonmelanoma skin or lip cancers that, in contrast to de novo skin cancers, have a high ratio of squamous cells to basal cells. HPV may play a major role in these lesions. Cervical and vulvar carcinomas, which are quite clearly associated with HPV, develop with increased frequency in female transplant recipients. The frequency of Merkel cell carcinoma associated with Merkel cell polyomavirus is also increased in transplant recipients; however, it is unclear whether recipients infected with HTLV-1 are at increased risk of leukemia. Among renal transplant recipients, rates of melanoma are modestly increased and rates of cancers of the kidney and bladder are increased.

(See also Chap. 5) In addition to receiving antibiotic prophylaxis, transplant recipients should be vaccinated against likely pathogens (Table 16-6). In the case of HSC transplant recipients, optimal responses cannot be achieved until after immune reconstitution, despite previous immunization of both donor and recipient. Recipients of an allogeneic HSC transplant must be reimmunized if they are to be protected against pathogens. The situation is less clear-cut in the case of autologous transplantation. T and B cells in the peripheral blood may reconstitute the immune response if they are transferred in adequate numbers. However, cancer patients (particularly those with Hodgkin’s disease, in whom vaccination has been extensively studied) who are undergoing chemotherapy do not respond normally to immunization, and titers of antibodies to infectious agents fall more rapidly than in healthy individuals. Therefore, even immunosuppressed patients who have not undergone HSC transplantation may need booster vaccine injections. If memory cells are specifically eliminated as part of a stem cell “cleanup” procedure, it will be necessary to reimmunize the recipient with a new primary series. Optimal times for immunizations of different transplant populations are being evaluated. Yearly immunization of household and other contacts (including health care personnel) against influenza benefits the patient by preventing local spread.

In the absence of compelling data as to optimal timing, it is reasonable to administer the pneumococcal and H. influenzae type b conjugate vaccines to both autologous and allogeneic HSC transplant recipients beginning 12 months after transplantation. A series that includes both the 13-valent pneumococcal conjugate vaccine (Prevnar) and the 23-valent pneumococcal polysaccharide vaccine (Pneumovax) is now recommended (according to CDC guidelines). The pneumococcal and H. influenzae type b vaccines are particularly important for patients who have undergone splenectomy. The Neisseria meningitidis polysaccharide conjugate vaccine (Menactra or Menveo) also is recommended. In addition, diphtheria, tetanus, acellular pertussis, and inactivated polio vaccines can all be given at these same intervals (12 months and, as required, 24 months after transplantation). Some authorities recommend a new primary series for tetanus/diphtheria/pertussis and inactivated poliovirus vaccines beginning 12 months after transplantation. Vaccination to prevent hepatitis B and hepatitis A (both killed vaccines) also seems advisable. A formal recommendation regarding immunization with the tetravalent HPV virus-like particle vaccine (Gardasil) after HSC transplantation has not been issued. However, HPV vaccination, which can prevent genital warts as well as specific cancers, is recommended through age 26 for healthy young adults who previously have not been vaccinated or have not received the full series. Live-virus measles/mumps/rubella (MMR) vaccine can be given to autologous HSC transplant recipients 24 months after transplantation and to most allogeneic HSC transplant recipients at the same point if they are not receiving maintenance therapy with immunosuppressive drugs and do not have ongoing GVHD. The risk of spread from a household contact is low for MMR vaccine. In parts of the world where live poliovirus vaccine is used, patients as well as contacts should be advised to receive only the killed vaccine. In the rare setting where both donor and recipient are VZV naïve and the recipient is no longer receiving acyclovir or ganciclovir prophylaxis, the patient should be counseled to receive varicella-zoster immune globulin (VariZIG) up to 10 days after an exposure to a person with chickenpox or uncovered zoster; such patients should avoid close contact with persons recently vaccinated with Varivax. A formal recommendation regarding Varivax immunization of such patients is not currently available. Neither patients nor their household contacts should receive vaccinia vaccine unless they have been exposed to smallpox virus. Among patients who have active GVHD and/or are taking high maintenance doses of glucocorticoids, it may be prudent to avoid all live-virus vaccines.

In the case of SOT recipients, administration of all the usual vaccines and of the indicated booster doses should be completed before immunosuppression, if possible, to maximize responses. For patients taking immunosuppressive agents, the administration of pneumococcal vaccine should be repeated every 5 years. No data are available for the meningococcal vaccine, but it is probably reasonable to administer it along with the pneumococcal vaccine. H. influenzae conjugate vaccine is safe and should be efficacious in this population; therefore, its administration before transplantation is recommended. Booster doses of this vaccine are not recommended for adults. SOT recipients who continue to receive immunosuppressive drugs should not receive live-virus vaccines. A person in this group who is exposed to measles should be given measles immune globulin. Similarly, an immunocompromised patient who is seronegative for varicella and who comes into contact with a person who has chickenpox should be given varicella-zoster immune globulin as soon as possible (optimally within 96 h; up to 10 days after contact); if this is not possible, a 10- to 14-day course of acyclovir therapy should be started immediately. Upon the discontinuation of treatment, clinical disease may still occur in a small number of patients; thus vigilance is indicated. Rapid re-treatment with acyclovir should limit the symptoms of disease. Household contacts of transplant recipients can receive live attenuated VZV vaccine, but vaccinees should avoid direct contact with the patient if a rash develops. Virus-like particle vaccines have been licensed for the prevention of infection with several HPV serotypes most commonly implicated in cervical and anal carcinomas and in anogenital and laryngeal warts. These vaccines are not live; however, no information is yet available about their immunogenicity or efficacy in transplant recipients.

Immunocompromised patients who travel may benefit from some but not all vaccines (Chaps. 5 and 6). In general, these patients should receive any killed or inactivated vaccine preparation appropriate to the area they are visiting; this recommendation includes the vaccines for Japanese encephalitis, hepatitis A and B, poliomyelitis, meningococcal infection, and typhoid. The live typhoid vaccines are not recommended for use in most immunocompromised patients, but an inactivated or purified polysaccharide typhoid vaccine can be used. Live yellow fever vaccine should not be administered. On the other hand, primary immunization or boosting with the purified-protein hepatitis B vaccine is indicated. Inactivated hepatitis A vaccine should also be used in the appropriate setting (Chap. 5). A vaccine is now available that provides dual protection against hepatitis A and hepatitis B. If hepatitis A vaccine is not administered, travelers should consider receiving passive protection with immune globulin (the dose depending on the duration of travel in the high-risk area).