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.
TABLE 16-4COMMON INFECTIONS AFTER SOLID ORGAN TRANSPLANTATION, BY SITE OF INFECTION ||Download (.pdf) TABLE 16-4 COMMON INFECTIONS AFTER SOLID ORGAN TRANSPLANTATION, BY SITE OF INFECTION
|INFECTED SITE ||PERIOD AFTER TRANSPLANTATION |
|EARLY (<1 MONTH) ||MIDDLE (1–4 MONTHS) ||LATE (>6 MONTHS) |
|Donor organ ||Bacterial and fungal infections of the graft, anastomotic site, and surgical wound ||CMV infection ||EBV infection (may present in allograft organ) |
|Systemic ||Bacteremia and candidemia (often resulting from central venous catheter colonization) ||CMV infection (fever, bone marrow suppression) ||CMV infection, especially in patients given early posttransplantation prophylaxis; EBV proliferative syndromes (may occur in donor organs) |
|Lung ||Bacterial aspiration pneumonia with prevalent nosocomial organisms associated with intubation and sedation (highest risk in lung transplantation) ||Pneumocystis infection; CMV pneumonia (highest risk in lung transplantation); Aspergillus infection (highest risk in lung transplantation) ||Pneumocystis infection; granulomatous lung diseases (nocardial and reactivated fungal and mycobacterial diseases) |
|Kidney ||Bacterial and fungal (Candida) infections (cystitis, pyelonephritis) associated with urinary tract catheters (highest risk in kidney transplantation) ||Kidney transplantation: BK virus infection (associated with nephropathy); JC virus infection ||Kidney transplantation: bacterial infections (late urinary tract infections, usually not associated with bacteremia); BK virus infection (nephropathy, graft failure, generalized vasculopathy) |
|Liver and biliary tract ||Cholangitis ||CMV hepatitis ||CMV hepatitis |
|Heart || ||Toxoplasma gondii infection (highest risk in heart transplantation); endocarditis (Aspergillus and gram-negative organisms more common than in general population) ||T. gondii (highest risk in heart transplantation) |
|Gastrointestinal tract ||Peritonitis, especially after liver transplantation ||Colitis secondary to Clostridium difficile infection (risk can persist) ||Colitis secondary to C. difficile infection (risk can persist) |
|Central nervous system || ||Listeria infection (meningitis); T. gondii infection; CMV infection ||Listerial meningitis; cryptococcal meningitis; nocardial abscess; JC virus–associated PML |
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.
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).
TABLE 16-5PROPHYLACTIC REGIMENS COMMONLY USED TO DECREASE RISK OF INFECTION IN TRANSPLANT RECIPIENTSa ||Download (.pdf) TABLE 16-5 PROPHYLACTIC REGIMENS COMMONLY USED TO DECREASE RISK OF INFECTION IN TRANSPLANT RECIPIENTSa
|RISK FACTOR ||ORGANISM ||PROPHYLACTIC DRUG ||EXAMINATION(S)b |
|Travel to or residence in area with known risk of endemic fungal infection ||Histoplasma, Blastomyces, Coccidioides ||Triazoles considered in context of clinical and laboratory assessment ||Chest radiography, antigen testing, serology |
|Latent herpesviruses ||HSV, VZV, CMV, EBV ||Acyclovir after HSC transplantation to prevent HSV and VZV infection or reactivation; ganciclovir to prevent CMV infection, with possible effect on EBV/KSHV/HHV-6 infections in some settings ||Serologic tests for HSV, VZV, CMV, HHV-6, EBV, KSHV; PCR |
|Latent fungi and parasites ||Pneumocystis jirovecii, Toxoplasma gondii ||Trimethoprim-sulfamethoxazole (or alternatives) ||Serologic test for Toxoplasma |
|History of exposure to active or latent tuberculosis ||Mycobacterium tuberculosis ||Isoniazid in patients with recent seroconversion or positive chest imaging and/or no previous treatment ||Chest imaging; TST and/or cell-based assay |
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 (>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.
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.
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.
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).
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.
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.
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.
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.
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 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.
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).
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.