Robert H. Rubin
Clinical transplantation has undergone an extraordinary transformation over the past four decades evolving from an interesting experiment in human immunobiology to the most practical means of rehabilitating individuals with end-stage kidney, heart, liver, lung, and bone marrow disease. Despite these advances, the major barriers to success remain the same: (1) rejection for solid organ transplant recipients and graft-vs-host disease (GVHD) for bone marrow transplant recipients, both examples of allogeneic reactions, and (2) infection. These two are closely linked; indeed, the therapeutic prescription for the transplant patient may be said to have two components: (1) an immunosuppressive program to prevent and/or treat rejection and GVHD and (2) an antimicrobial program to make it safe. Any manipulation or intervention that decreases the risk of infection will then permit the use of more intensive immunosuppression that will result in better control of rejection or GVHD; any manipulation or intervention that decreases the risk of these allogeneic reactions will decrease the risk of infection. The end result is the need to individualize therapy rather than use fixed regimens; (e.g., duration of antimicrobial therapy is “long enough,” with this being determined by microbial burden, clinical response, the intensity of the immunosuppression required, and the potential consequences of infection relapse [1,2,3]. See Figures 44-1, 44-2).
|
Figure 44-1 Progression of symptoms in patients with bacterial vs. viral infection. Note the rapid change in the deterioration, so there is relatively little time available to reverse the process once the threshold level of symptoms is reached. |
The transplant recipient remains a highly unusual patient because of the need for lifelong immunosuppression, the presence of chronic immunomodulating viral infection, ongoing rejection, and a susceptibility to a variety of microbial invaders.
These organisms can be divided into three general categories: (1) true pathogens, (2) sometime pathogens, and (3) nonpathogens. True pathogens (the classic plagues of mankind [e.g., influenza, plague, typhoid] have the genetic makeup necessary to cross fascial planes, produce damaging toxins, and invade normal tissue. Sometime pathogens are found primarily on mucocutaneous surfaces, where they are not harmful (e.g., Staphylococcus aureus, E. coli, Bacteroides fragilis); however, if there is a break in the integrity of these tissues, they can easily cause lethal disease. Nonpathogens are ubiquitous in the environment (e.g., Aspergillus species, Nocardia species, Cryptococcus neoformans) and rarely produce clinical disease in the nonimmunosuppressed host. The term opportunistic infection is used to describe invasive infection due to nonpathogens or invasive/disseminated infection due to organisms that cause a trivial infection in normal hosts (e.g., candidal vaginitis vs. disseminated candidiasis [1,2]).
P.758
In sum, a unique set of challenges is created in the transplant recipient [1,2,3]:
|
Figure 44-2 Effect of the immunosuppressed state on the microbial burden. The continuous increase in organisms means that the prognosis has to be guarded, more extensive antimicrobial therapy is needed, and the chance for both toxicity and resistance are increased. If the infection in question is transmissible, the increased microbial burden will increase the efficacy of transmission. |
Approximately 75% of transplant patients develop clinically significant infection. Not only are the opportunistic infections present, but also more severe clinical syndromes due to common pathogens (e.g., influenza and other community-acquired viral infections, legionellosis, and viral induced malignancies—EBV induced lymphoproliferative disease, squamous cell carcinomas from papillomavirus, and hepatocellular carcinomas) are the rule [1,2].
Risk of Infection in the Transplant Recipient
The risk of infection in the transplant patient is largely determined by the interaction among four factors: (1) the presence of anatomic/technical abnormalities, (2) an excessive exposure to environmental pathogens, particularly within the hospital, (3) the net state of immunosuppression, and (4) Darwinian pressures.
Anatomic/Technical Abnormalities in the Pathogenesis of Infection
Anatomic/technical factors can be divided into two categories: (1) those related to surgical misadventures at the time of the transplant that result in the creation of devitalized tissue, fluid collections, and/or ongoing urine or bile leaks; unless these abnormalities are promptly eliminated, secondary infection is inevitable, and (2) perioperative abridgement of mucocutaneous surfaces by vascular access devices, endotracheal tubes, drainage devices, and bladder catheters, which are associated with secondary infection unless they are cared for impeccably. Early removal of these devices is indicated whenever possible. The incidence of such infections is related to the nature of the transplant (small bowel = liver > lung = pancreas > heart > kidney), the complexity of the surgery, and the duration of time that “devices” that compromise the integrity of the skin and mucosal surfaces are required. Transplantation is one of the most unforgiving forms of surgery with a technical abnormality signaling a high risk for superinfection. Although any undrained fluid can be a problem, hematoma is a particular problem as a source of iron, a particularly important growth factor for Listeria, the Zygomycetes, and other microbes [1,2,3]. See Figure 44-3.
Environmental Factors
Although community-acquired infections can be an important issue for transplant patients, the more important
P.759
exposures are those that occur in the hospital where two important patterns—domiciliary and nondomiciliary—can be demonstrated. The term domiciliary is used to describe acquisition of organisms from the potable water and/or contaminated air, which occurs on the transplant ward or in the patient's room. Outbreaks in which infection is acquired in a domiciliary mode are usually characterized by clustering of cases in time and space and are therefore relatively easy to recognize. Domiciliary outbreaks of Pseudomonas aeruginosa(and other gram negative organisms), Legionella, and Aspergillus spp. infection are well documented [1,2,3,4,5].
|
Figure 44-3 Infection in the face of a technical/anatomic abnormality. Without antibiotics there is a progressive increase in the prevalence of infection. Antibiotics shift the curve to the right. If the anatomic abnormality can be corrected during this extra time period, then antibiotics are useful. If no change in the anatomic abnormality is accomplished then, resistance is induced. The most effective therapy in this situation is to combine repair of the underlying problem in conjunction with antimicrobial therapy. |
Nondomiciliary infection is acquired when the patient travels within the hospital for an essential procedure and is exposed to excessive levels of potential opportunistic pathogens present in the air, usually associated with construction, and/or areas of moisture that favor the growth of such molds as Aspergillus, Fusarium, and Scedosporium spp. Thus, invasive infection due to the molds, particularly Aspergillus species, has been well documented in radiology and endoscopy suites, in holding areas outside cardiac catheterization laboratories, the operating room, and a hospital area that is undergoing renovation. Nondomiciliary infection is probably more common than domiciliary infection, but because of the lack of clustering of cases in time and space can be more difficult to detect. The best clue to the presence of an environmental hazard is the occurrence of infection due to one of these opportunistic organisms when the net state of immunosuppression is not, under normal circumstances, great enough to allow such an infection to occur unless an environmental hazard is present [1,2,3,4].
A not infrequent problem is the person-to-person spread of respiratory viruses within the hospital. For example, when influenza is present in a community, great effort is needed to protect immunocompromised patients because vaccine and treatment with the neuroiminidase inhibitors are far less effective than in the immunologically normal patients. Transplant patients with influenza have a higher rate of both viral pneumonia and bacterial superinfection. Experience with the severe acute respiratory syndrome (SARS) and other viruses confirm that the impact of such infection is greater than that seen in the general population. Unfortunately, management of such problems is difficult, and prevention via a “quarantine” effort is greatly to be preferred [1,2,3,4].
An essential point to be emphasized is that immunosuppressed patients such as transplant recipients are like “sentinel chickens,” reflecting any excess traffic in microbes in the hospital environment (particularly with agents that cause opportunistic respiratory infection). Constant surveillance of infection among transplant patients is essential. In addition, in institutions undergoing major construction, transplant patients will benefit greatly from being housed in areas where the air quality is maintained by high-efficiency particulate air filters and from an ongoing assessment of routes of transport within the hospital [1,2,6].
The Net State of Immunosuppression
The net state of immunosuppression is a complex function determined by the interaction of a number of factors: host defense deficits caused by the underlying disease process (e.g., diabetes, systemic lupus erythematosis) and attempts at treating it with immunosuppression before transplant (e.g., chronic hepatitis, biliary cirrhosis, inflammatory lung disease); the dose, duration, and temporal sequence of immunosuppressive therapies administered; the presence or absence of damage to the mucocutaneous surfaces of the body (the primary host defense barriers to invasive infection); neutropenia, especially with an absolute granulocyte count <100/mm3 that is persisting; the presence of such metabolic abnormalities as protein-calorie malnutrition, uremia, or hyperglycemia; and the presence of infection with one or more of the immunomodulating viruses (e.g., cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, hepatitis viruses B or C, and the human immunodeficiency virus) [1,2,7].
The major determinant of the net state of immunosuppression is the nature of the immunosuppressive therapy. However, two other observations underline the principle that other factors are important as well: >90% of opportunistic infections in transplant patients occur in individuals with chronic viral infection with the 10% exceptions
P.760
almost invariably due to excessive environmental exposure; if the transplant population is stratified into two groups on the basis of a serum albumin > or <2.5 g/dl, those with the lower value have a 10-fold higher risk of life-threatening infection [1,2].
There is a semi-quantitative relationship between the patient's net state of immunosuppression and the environmental hazards that are encountered. If the patient's net state of immunosuppression is great enough, even trivial exposures to relatively avirulent organisms (nonpathogens) can produce life-threatening infection; conversely, if the exposure is great enough, even immunologically normal individuals can succumb to the infectious challenge [1,2].
Darwinian Pressures in the Transplant Patient
Several forms of Darwinian pressure affect the nature of infection in the transplant recipient. First, previous antimicrobial exposure, the normal flora on the skin, in the gut, and in the upper respiratory tract—is very much influenced by previous antimicrobial therapy, with an increase of the microbial burden of resistant bacteria and Candida species being an end result. Because these sites are the reservoirs from which invasive infection is derived, the clinician is obligated to modify antimicrobial regimens for initial therapy. Second is the availability of nutrients and growth factors. A number of organisms are very responsive to these Darwinian pressures: The availability of iron will greatly increase the possibility of infection with such organisms as the Zygomycetes, Listeria, and Staphylococcus aureus. Thus, the occurrence of wound infection following the transplant operation is several times greater if bleeding has complicated the procedure. Hyperglycemia will greatly increase the level of Candida colonization on the skin, in the gut, the pharynx, and the female genital tract. A relatively minor break in the integrity of these tissues (e.g., vascular access device, placement of drains and catheters) will lead to significant clinical Candida spp. infection because of the high organism load that is present. The third pressure is the presence of devitalized tissue and/or foreign body. If these are not corrected, antimicrobial therapy will lead only to microbial resistance because the ecologic niche is unchanged and more resistant flora will emerge, causing resistant infection [1,2,3].
Successful antimicrobial therapy in these patients, then, requires attention to Darwinian factors, a term that encompasses past exposures to antibiotics as part of this effort. Overgrowth of microbes is potentiated by metabolic derangement (e.g., Candida spp. overgrowth) and the presence of excessive amounts of growth factors (e.g., iron and the zygomcytes). It is then a small step to invasive infection [1,2,3].
Timetable of Infection After Organ Transplantation
The general pattern of infection is the same in all forms of organ transplantation, reflecting the use of similar immunosuppressive programs in all of these patients (Figure 44-4). Thus, a timetable can be defined (Figure 44-2) delineating when in the posttransplantation course a particular form of infection is likely to occur; that is, although a given infectious disease clinical syndrome, such as pneumonia, can occur at any point in the posttransplantation period, the microbial etiologies are very different in the different time periods. Application of this timetable to the clinical management of transplant recipients is useful in at least three different ways: in arriving at a differential diagnosis of the causes of a particular clinical presentation; in designing directed, cost-effective antimicrobial preventative strategies; and in recognizing epidemiologic hazards. Exceptions to the timetable are usually due to previously unrecognized environmental exposure, often within the hospital environment. In the organ transplant patient, the timetable is conveniently divided into three different time periods; the first month post-transplantation, the period 1 to 6 months post-transplantation, and the late period, more than six months post-transplantation [1,2,3,7].
P.761
Infection in the First Month Post-Transplantation
In the first month post-transplantation, there are three major causes of clinically important infection: (1) infection that was present in the recipient before the transplantation procedure and that was exacerbated by the surgery, anesthesia, the physical manipulations required, or the initiation of immunosuppression; (2) active infection conveyed with the allograft; and (3) the same wound-, catheter-, vascular access-related infection and pneumonia seen in nonimmunosuppressed patients subjected to comparable amounts of surgery.
|
Figure 44-4 Timetable of Infection following Organ Transplant. Infection in the Transplant Patient: Lessons from the bedside. Reprinted with permission from Rubin RH, Wolfson JS, Cosimi AB, et al. Infection in the renal transplant recipient. Am J Med 1981;70:405–411. |
Importance of Infection in the Recipient Before Transplantation
A cardinal rule of clinical transplantation is that all infectious processes should be under control before the transplantation procedure. Thus, before transplantation, every attempt must be made to identify and eradicate infection, such as tuberculosis, localized and systemic fungal infection, and strongyloidiasis (with particular infections to be considered based on a careful epidemiologic history). In patients awaiting heart, lung, and/or liver transplantation, acquisition of infection during an extended stay in intensive care units is quite common. The nature of these infections are as expected: vascular access bloodstream infection, infection related to the presence of ventricular assist devices, aspiration pneumonia, and so on [1,2,3].
In recent years, a relatively new entity, Pneumocystis pneumonia, has been encountered as have cryptococcosis and other opportunistic infections in the first few weeks following transplantation. In this instance, pretransplant immunosuppression was creating an environment appropriate for opportunistic infection, often in the setting of a desperate attempt to control the primary disease and thus avoid transplantation. These patients are coming to transplantation with active infection that is far more difficult to treat in the face of a fresh transplant [1].
As heart, lung, and liver transplantation are being used to treat an ever-increasing number of diseases, acute bacterial and fungal infection of clinical importance may be acquired during the wait for emergency transplantation. Examples include aspiration pneumonia in the patient his unable to protect his airway due to advanced hepatic encephalopathy; pneumonia and vascular sepsis in the patient with end-stage cardiac disease who is intubated and receiving life support from vasopressors delivered through central venous access and cardiac assist devices;
P.762
and bronchopulmonary infection or colonization with antibiotic-resistant gram-negative bacilli in the patient with end-stage pulmonary disease [1,2,3,4,5].
Importance of Infection in the Organ Donor
Infection to a recipient can be transmitted with an allograft. Of greatest concern is viral infection: the human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and cytomegalovirus (CMV) are all transferred with near 100% efficiency with transplantation [8,9,10]. As a result, pretransplant serologies provide a great help in avoiding such transmission. An important point that merits emphasis is that only “pedigreed” blood samples should be used. Transmission of HIV and HBV have been well documented in instances in which massive transfusions have been administered in an attempt to salvage a trauma victim before brain death is pronounced. At that point, a blood sample will reflect transfused blood and will be falsely negative, but the allograft itself will still carry infection to recipients [8,9,10,11,12].
Other infectious agents transmitted from the donor include systemic fungal and mycobacterial infection, fortunately an uncommon event [8,12,13,14]. In contrast, the protozoanToxooplasma gondii is a potential hazard primarily in patients undergoing cardiac transplantation. Transplantation of a heart from a donor seropositive for toxoplasmosis into a seronegative recipient is associated with >50% incidence of T. gondii myocarditis and disseminated infection. Accordingly, prophylaxis with trimethoprim-sulfamethoxazole or pyrimethamine and a sulfonamide is indicated for these individuals. Other forms of organ transplantation do not require antitoxoplasmosis prophylaxis [15,16,17,18,19,20,21,22,23,24,25].
A more difficult problem is the identification of immediately preterminal contamination of organs due to acute infection developing while the potential donor is in the intensive care unit. For example, unsuspected Pseudomonas aeruginosa bacteremia in an afebrile donor resulted in the infection of the two kidneys that were being transplanted. Both of these kidneys required emergency removal because of massive bleeding; examination of them revealed ruptured mycotic aneurysms at the suture line of the arterial anastamosis. Less commonly, organs may be secondarily contaminated during the harvesting process or during the transplant operation [1,2,3].
Technical Complications as a Risk Factor for Infection
The concept that technical complications lead to significant infectious problems applies to the perioperative period and the operation itself. Poor management of the airway leads to aspiration pneumonia; inadequate attention to vascular access devices, particularly central venous catheters, leads to septicemia; and drainage catheters can lead to infection of normally sterile sites. Infection occurring as a consequence of technical mishaps accounts for >95% of the infections that occur in the first month post-transplantation. The consequences of such infections can be far greater than in the normal host; for example, although transient vascular access–related candidemia carries a risk of visceral seeding of <10% in the nonimmunosuppressed patient, in the transplant patient the risk is >50%, and antifungal therapy is mandatory (in addition to removal of the contaminated vascular access device) [1,2,3,5,26,27,28].
Wound infection is the most important treatable infection occurring in the first month after transplantation. Its incidence is directly related to whether or not the transplant operation is free of vascular compromise and the creation of devitalized tissue, wound hematomas, fluid collections, and the need for re-exploration or prolonged use of drainage catheters. The particular technical challenges of liver transplantation, with a biliary anastomosis that is susceptible to ischemic injury, as well as four vascular anastomoses (superior and inferior vena cava, portal vein, and hepatic artery) all performed in patients with coagulopathies explain the high rate of intraabdominal infection that dominates the first month post-transplantation in these patients. Indeed, the major difference between liver transplant recipients and other allograft recipients is the higher incidence of technically related infection in and around the area of surgery [1,2,3,29,30].
There is considerable variability in the choice of perioperative antibiotics to prevent wound infection among different transplant centers. Two principles merit emphasis whatever the antimicrobial regimen is: (1) antimicrobial prophylaxis is not a substitute for technically impeccable surgery and (2) antimicrobial choice should be directed toward prevention of wound infection, not systemic sepsis. The author's center uses cefazolin for <72 hours, which has provided adequate protection without creating intensive pressure for the selection of resistant flora. In the special case of liver transplantation, some centers opt for the use of an elaborate program of nonabsorbable antimicrobials aimed at decreasing the amount of aerobic gram-negative flora and yeast colonizing in the gastrointestinal tract and then use a perioperative drug, such as cefotaxime, that leaves the anaerobic flora (and hence “colonization resistance”) intact. The author's group does attempt to eliminate yeast from the gastrointestinal tract but does not use the rest of the program. With these regimens, the post-transplantation intraabdominal infection rate of <5% has been achieved. Such results are primarily a testimony to the expert surgery being performed with the antibiotics playing an ancillary role [1,2,3,31,32,33,34].
Opportunistic Infection in the First Month Post-Transplantation
Noteworthy in this discussion of infections in the first month after organ transplantation is the absence of
P.763
opportunistic infection. Indeed, in this one-month “golden period,” the net state of immunosuppression should not be great enough to permit infection with such organisms asPneumocystis, Listeria, Legionella, or Aspergillus. This observation leads to two conclusions: the major determinant of the net state of immunosuppression is the duration of immunosuppressive therapy (“the area under the curve”) rather than the daily dose (indeed, the daily doses of immunosuppression are at their highest in this time period). Thus, the occurrence of opportunistic infection in the first month is an important clue to the presence of either an unsuspected environmental hazard or the presence of opportunistic infection pretransplant due to efforts to use immunosuppressive therapy to reverse the underlying disease [1,2,3].
Infection One to Six Months Post-Transplantation
In general, this is the period of greatest vulnerability to infection for the transplant recipient. Not only is sustained immunosuppressive therapy exerting an increasing effect, but also this is the time period when the immunomodulating viruses (cytomegalovirus [CMV], human herpesvirus-6 [HHV-6], Epstein-Barr virus [EBV], hepatitis viruses B and C [HBV and HCV], and the human immunodeficiency virus [HIV]) become important. In this period, the net state of immunosuppression is significantly increased because of these two factors. Clinically, the infections that are important fit into two general categories: (1) the direct effects of one or more of these viruses, for example, two-thirds of the fevers occurring in this time period are due to the direct effects of CMV alone, and (2) opportunistic infection occurs not because of unusual environmental exposures but is attributable to the increased net state of immunosuppression [1,2,3,6,35].
Impact of Viral Infection on the Transplant Recipient
When clinical infection due to viral pathogens occurs in nonimmunosuppressed patients, the patient usually recovers or succumbs to the direct effects of the virus (although chronic infection can occur with HBV and HCV). In the transplant recipient, the direct effects of viral invasion and proliferation are frequently superseded by the indirect effects. Thus, the consequences of viral infection in this patient population can be particularly broad [1,2,3,36,37]:
o The production of a state of immunosuppression in addition to that induced by the antirejection therapy being administered so that the patient is at increased risk of invasive infection with such opportunistic pathogens as Pneumocystis, Listeria, and Aspergillus in the absence of an excessive epidemiologic exposure.
o The initiation of a series of events that lead to allograft injury.
o The participation of these viruses in the process of oncogenesis.
Effects of Immunosuppressive Therapy on the Occurrence of Infection
The major determinants of the net state of immunosuppression are the dose, duration, and temporal sequence in which the immunosuppressive regimen is administered. Of all the drugs used in transplant patients, corticosteroids have the most global effects, and the thrust of modern antirejection efforts is “steroid sparing” therapy in which other drugs that exert their effects through other mechanisms can be used to achieve the desired level of immunocompromise but with reduced adverse events [1,2,3,38].
The effects of corticosteroids can be divided into two categories: an immunosuppressive effect and an anti-inflammatory one. The key immunosuppressive effect of corticosteroids is the inhibition of T-cell activation and proliferation (thus blocking clonal expansion in response to antigenic stimulation). This is accomplished through the suppression of interleukin-2 and other proinflammatory cytokines. The end result is a striking inhibition of cell-mediated immunity. The infections promoted by this impairment include herpes group viruses, the hepatitis viruses, the fungi and mycobacteria, and bacteria that persist intracellularly (e.g., Listeria and Salmonella) [1,2,3,39].
The anti-inflammatory effects of corticosteroids include the following: inhibition of proinflammatory cytokines; inhibition of the ability of polymorphonuclear leukocytes to accumulate at sites of infection and inflammation; inhibition of the proinflammatory arachidonic acid metabolites (prostaglandins, thromboxane, leukotrienes, and platelet activating factor); inhibition of mediators of vasodilatation, including the inducible form of nitric oxide synthase, thus decreasing macrophage nitric oxide production, endothelial permeability, and microvascular leak [1,2,3,38,39].
From an infectious disease point of view, the most important adverse effects of corticosteroids have to do with their inhibition of the inflammatory response to microbial invasion. The consequences of this suppressed inflammatory response are twofold: the signs and symptoms of infection, as well as the X-ray findings, will be greatly blunted until late in the clinical course, and the microbial burden at the site of infection is likely to be far higher than that observed in normal hosts [1,2,3,38,39].
The standard of care for organ transplant recipients is a multidrug regimen consisting of a calcineurin inhibitor (cyclosporine or tacrolimus), prednisone, and either
P.764
azathioprine or mycophenolate. In addition, antithymocyte globulin (ATG, a polyclonal anti-T cell drug) or OKT3 (a monoclonal anti-T cell drug) can be used as induction therapy or to treat steroid-resistant rejection. The calcineurin inhibitors are the cornerstones of modern antirejection therapy. These exert their effects through a complex signaling pathway that results in the inhibition of the transcriptional activation of genes required for T-cell activation, proliferation, and function. This results in the inhibition of a large number of proinflammatory cytokines, with the most important of these effects being the blockade of essential functions of interleukin-2 (IL-2). The infectious disease consequences of these drugs are direct results of these mechanisms: a dose-related inhibition of microbial specific T-cell cytotoxic activity, thus promoting the herpes group viruses, fungal, mycobacterial, and other intracellular infections. The key toxicities of the calcineurin inhibitors are injury to the kidneys and hypertension [1,2,3,38,40,41].
Azathioprine and mycophenolate should be thought of as mediating their immunosuppressive effects by depleting purine stores and inhibiting RNA and DNA synthesis. Actively dividing lymphocytes are particularly susceptible to these effects. In recent years, the rate-limiting step in the metabolism of azathioprine has been shown to be the function of the enzyme thiopurine methyltransferase with significant genetic heterogeneity in the activity of this enzyme. Thus, it is likely that there have been important effects of this enzyme in clinical transplantation due to drug over- or underdose and that azathioprine is probably a more useful drug than was recognized. The toxicities of these two drugs are very different: bone marrow and hepatic toxicity for azthioprine and gastrointestinal toxicity (diarrhea and cramps) for mycophenolate [1,38,42].
ATG and OKT3 are the most potent therapies for steroid resistant rejection. The administration of these agents is associated with fever and rigors due to “cytokine storm.” These side effects are important not only because of the patient's discomfort but also because of secondary effects on herpes viruses. Reactivation of latent viruses due to tumor necrosis factor (TNF) release plays an important role in the pathogenesis of herpes group virus infection, particularly CMV and EBV. Interest in the anti-IL-2 monoclonal antibodies in part is related to the lack of the initial cytokine release seen with ATG or OKT3. However, the clinical roles of these newer antibodies (daclizumab and basilixmab) in transplantation are still being defined [2,43,44].
The final immunosuppressive therapy to be considered here is rapamycin (sirolimus), which has a mechanism of action separate from cyclosporine and tacrolimus. Whereas cyclosporine and tacrolimus initiate their effects by binding to specific cell surface immunophilins, rapamycin's targets include RAFT1/FRAP proteins in mammalian cells, which are associated with cell cycle phase G1. Rapamycin is less potent than the other drugs in terms of inhibition of cytokine synthesis but has potentially useful activity in inhibiting immunoglobulin synthesis and growth factor synthesis, potentially useful effects in protecting against chronic allograft injury. At present, the primary use of rapamycin is in combination with cyclosporine, thus permitting lower doses of cyclosporine with less renal toxicity [45,46,47]. Major difficulties in the use of rapamycin include pulmonary toxicity, aphthous ulcers, and significant drug–drug interactions [48,49,50].
Infection More Than 6 Months Post-Transplantation
Patients with functioning allografts more than 6 months post-transplantation can be divided into three general categories in terms of their infectious disease problems [1,2,3]:
o Community-acquired respiratory infections, with influenza, respiratory syncytial virus, parainfluenza, and other viruses having a particular impact on these patients. In general, the rate of both viral pneumonia and secondary bacterial pneumonia associated with these infections is higher than that in the general population; that is, the etiology is the same, but the incidence of severe disease is increased. It is not surprising, then, that such unusual pulmonary processes as SARS and Legionella will have a greater impact on the transplant patient than the general population.
o Community-acquired gastrointestinal infection after the ingestion of contaminated food or water, due to Salmonella species, L. monocytogenes, Campylobacter jejuni, and others. In general, the duration of disease and the incidence of bacteremia and metastatic infection are longer/greater in the transplant patient than for individuals in the general population [1].
o Exposure in the community to one of the geographically restricted systemic mycoses or tuberculosis, which, as previously stated, has a higher incidence of systemic spread than in the general population.
Because therapies of these infections are not ideal, transplant recipients are cautioned to avoid exotic travel or undue exposure to infection within the community. Disease prevention with vaccine administration is less successful in transplant patients as well, making the avoidance of exposure particularly important.
P.765
of hepatocellular carcinoma; EBV can initiate posttransplantation lymphoproliferative disorder (PTLD); and HIV infection progresses to AIDS—all occurring at a more rapid and higher rate than in any populations other than those individuals with progressive immune deficiency due to HIV infection unrelated to transplantation.
Infections of Particular Importance in the Transplant Recipient
Cytomegalovirus
Cytomegalovirus is the single most important cause of infectious disease morbidity and mortality in transplant patients with evidence of active viral replication being found in 50% to 75% of transplant recipients. Three patterns of CMV transmission, each with a different risk for clinically overt disease, may be observed [1,2,3,51,52,53,54,55,56,57,58,59,60,61,62]:
Whatever form of CMV infection is operative, clinically overt infectious disease syndromes classically present in the time period 1 to 4 months post-transplantation. Three exceptions to this pattern may be observed. First, an individual who is still CMV seronegative after this period can acquire primary CMV disease because of acquisition of the virus in the community after intimate contact. Second, an occasional seropositive patient with severe bacterial infection, such as urosepsis or bacteremic pneumococcal disease, can acquire symptomatic CMV disease 3 to 4 weeks later because of cytokine release (the “second wave phenomenon”), particularly release of TNF release during the septic episode. Third, late CMV disease can occur many months post-transplant due to incomplete protection from prophylactic antiviral therapy. In this instance, the incubation period is greatly prolonged as a partial effect of the antiviral regimen, thus delaying the onset of CMV disease [1,2,3,63,64,65,66,67,68,69,70,71,72,73].
The general pattern of clinical disease due to CMV is similar in all forms of organ transplantation with one notable exception: The organ transplanted is far more vulnerable than are native organs—for example, CMV hepatitis is a significant problem only in liver transplant patients, CMV myocarditis in heart transplant patients, and CMV pancreatitis in pancreas transplant patients—whereas the attack rate for CMV pneumonia is many times higher in lung and heart–lung transplant patients [1,30]. The spectrum of clinical illness produced by CMV includes asymptomatic shedding of virus (most common in patients with reactivation infection), a mononucleosis-like illness that has been termed the CMV syndrome, and life-threatening disease affecting such organs as the lungs and the gastrointestinal tract [1,2,3].
The role of proinflammatory cytokines has been well studied in recent years. TNF-alpha appears to be the mediator of reactivation of the virus from latency. Other inflammatory mediators appear to be responsible for inflammatory symptoms that are part of the direct effects of the virus as well as the indirect effects. Presently, another
P.766
piece of the pathogenic puzzle has been elucidated. Toll-like receptors (TLR) are stimulated by pattern recognition of unique motifs of different pathogens. This leads to the induction of antimicrobial activity and an inflammatory cytokine response through the activation of intracellular signaling pathways. The TLR-pathogen interaction plays a key role in the functioning of innate immunity. Ten different TLRs have been identified in humans, and extensive genetic polymorphisms have been shown to occur with increasing evidence that the nature of the TLR-pathogen infection is a major determinant of the clinical syndrome that is operative in particular patients [74,75,76,77,78].
The CMV syndrome typically refers to a prolonged episode of otherwise unexplained fever associated with constitutional symptoms in concert with such laboratory abnormalities as leukopenia (with or without thrombocytopenia), a mild atypical lymphocytosis (usually <10% of the circulating leukocytes and often not seen), and a mild, usually transient hepatitis. Severe CMV disease consists of severe leukopenia and thrombocytopenia, pneumonia, gastrointestinal ulcerations and perforation, and, in the liver transplant patient, severe hepatitis. Not infrequently, opportunistic superinfection with other pathogens further complicates the course of severe CMV infection. CMV chorioretinitis is a late manifestation of systemic CMV infection, presenting 4 months or more post-transplantation. Chorioretinitis may follow earlier clinical manifestations of CMV infection or be the first manifestation of CMV disease [1,30]. A unique clinical syndrome of interstitial pneumonitis is observed in the bone marrow transplant recipient after marrow engraftment. Although many of these forms of pneumonitis are idiopathic, up to 50% are observed in CMV seropositive recipients and are preventable with empiric antiviral therapy. This disease likely reflects both CMV infection and the emerging T-cell, cytotoxic response to CMV antigens. Both in bone marrow transplants and solid-organ transplants, the degree of MHC mismatch appears to contribute to the incidence and severity of disease [79,80,81,82].
The most valuable diagnostic test for managing clinical CMV disease is the demonstration of viremia (although invasive biopsies of tissue are even more specific but are usually not available until relatively late in the disease course). Viremia is usually present as early as 5 to 7 days before the onset of clinical disease and continues until effective treatment is initiated. At present, quantitative polymerase chain reaction (PCR) and the CMV antigenemia assays are quite useful with a sensitivity and specificity of >90%. Demonstration of “shed” virus in respiratory secretions and urine may be found in many transplant patients and, hence, correlates poorly with clinical events. Similarly, serial measurements of antibody not only correlate poorly with clinical events (“diagnostic rises” in antibody titers or the appearance of IgM antibody) but also are too delayed to allow for use in clinical decision making. Hence, the major use of antibody testing is to characterize donor and recipient at the time of transplant in an effort to guide preventative strategies.
Although still somewhat controversial, there is increasing evidence that CMV contributes to the pathogenesis of allograft injury (as well as to GVHD in bone marrow transplant patients). CMV infection has been particularly linked to accelerated coronary artery atherosclerosis in cardiac allograft recipients, to bronchiolitis obliterans in lung transplant recipients, to certain forms of hepatic injury in liver transplant patients, and to an unusual glomerulopathy in renal transplant patients, as well as to more conventional patterns of rejection. The problem has been that each of these lesions has also been observed in patients without viral infection. Cytokines elaborated in the course of CMV infection (and other processes) affect the display of histocompatibility antigens and thus modulate the immune response to the allograft. A similar array of proinflammatory cytokines are elaborated in response to rejection, infection, and key forms of infection. Thus, CMV is not the only way to cause these reactions but is just a common way. A report in which allograft dysfunction was successfully treated with the antiviral drug ganciclovir, not increased immunosuppression, is particularly interesting in this regard [83,84,85,86].
As discussed previously, the nature of the immunosuppressive therapy administered has a major influence on the course of CMV infection. TNF and other proinflammatory cytokines play a key role in reactivating CMV from latency, the critical first step in the pathogenesis of CMV-related events. The excessive rate of CMV infection induced by antilymphocyte antibody administration has now been shown to be largely related to the release of TNF. It is clear that the occasional cases of CMV disease that follow other circumstances in which TNF is released (e.g., severe allograft rejection and urosepsis) are due to the same mechanism [1,2,3].
The proposed linkage between rejection and CMV disease appears to be mediated by cytokines as well and seems to be bidirectional: in addition to the TNF–CMV activation mechanism, it is now apparent that gamma-interferon (and presumably other cytokines) elaborated in response to CMV infection upregulate the display of histocompatibility antigens on the allograft, thus promoting rejection [1]. Finally, CMV disease appears to be a significant risk factor in the occurrence of EBV-related PTLD with a greater than 7-fold increase in PTLD in patients with CMV, probably because of the effects of growth factors and cytokines elaborated in the course of the CMV infection but also because GVHD, allograft rejection, and immune suppression are major activators of latent viral infection [1,2,3].
Given the myriad of effects due to CMV, considerable effort has been directed at controlling it. Intravenous ganciclovir, at a dose of 5 mg/kg twice daily (with dosage correction in the face of renal dysfunction), for 2 to 3 weeks is quite effective in treating symptomatic disease. Relapse,
P.767
which may develop several times after seemingly effective treatment, occurs in ~10% of seropositive individuals and in >60% of those with primary infection. MHC antigen mismatch will significantly add to the occurrence of relapse. Based on apparent success in several cases with multiple relapses, we now routinely add oral ganciclovir at a dose of 2 to 3 g/day or valganciclovir for 10 weeks to the conventional intravenous course of therapy for those with primary infection [1,2,3]. Far less clear is the appropriate way to prevent CMV disease, which would be preferable to the treatment of tissue invasive disease.
|
TABLE 44-1 |
||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||
Two forms of preemptive therapy have been described: (1) monitoring patients for preclinical viremia and treating on that basis without any prophylaxis and (2) the administration of ganciclovir during antilymphocyte antibody therapy. Both offer considerable protection, and the concept of linking a particular antimicrobial strategy to the type of immunosuppression used is especially appealing [1,2,3,87,88]. See Table 44-1.
Human Herpesvirus-6
HHV-6 is a β herpesvirus closely related to CMV (66% DNA sequence homology). HHV-6 infects and replicates within a wide array of leukocytes, most notably CD4 positive lymphocytes. An important effect of HHV-6 replication is the elaboration of proinflammatory cytokines, most importantly TNF and interferon-χ. Primary HHV-6 infection usually occurs in the first year of life; as a consequence, 90% of adults harbor latent infection (and are seropositive). In normal children, HHV-6 is the cause of a febrile exanthema known as roseola. The consequences of HHV-6 reactivation and subsequent replication, particularly in the immunocompromised host, are several: mononucleosis syndrome with and without hepatitis and/or interstitial pneumonia, bone marrow suppression, and encephalitis. Dual infection with CMV and HHV-6 is common, and it has been suggested that such patients are sicker than those with single virus replication. Diagnosis of HHV-6 is best done with a PCR or antigenemia assay. It is likely that many of the direct and indirect effects of HHV-6 are similar to those seen with CMV and a clearer view of the impact of HHV-6 infection will emerge over the next few years. HHV-6 is susceptible to both ganciclovir and foscarnet, and it is probable that antiviral programs designed for one of these is modulating the course of other herpes group viruses [89,90,91,92,93].
Epstein-Barr Virus
Active EBV replication is present in 20% to 30% of organ transplant patients on maintenance immunosuppression (slightly higher than the general population), rising to >80% during antilymphocyte antibody therapy of acute rejection. Although a mononucleosis-like syndrome (usually heterophile negative in this patient population) comparable to that produced by CMV has been shown to be due to EBV in some patients, the critical impact of EBV is in its role in the pathogenesis of PTLD [1].
PTLD is a B-cell lymphoproliferative process that ranges in severity from a benign polyclonal process that responds to a decrease in immunosuppressive therapy
P.768
(± antiviral therapy) to a highly malignant monoclonal process resistant to all forms of treatment. It is frequently totally extranodal in presentation with brain involvement, invasion of the allograft, gastrointestinal tract disease, and liver invasion being not uncommon. The pathogenesis of this process is related to the effects of immunosuppressive therapy on the usual mechanisms for preventing the outgrowth of EBV-infected, immortalized B cells. As with CMV, the cornerstone of this defense is virus-specific, MHC-restricted, cytotoxic T cells, which destroy the EBV-infected B cells. Cyclosporine and FK-506 have a dose-related inhibitory effect on this defense and, thus, on the incidence of PTLD. OKT3 and ATG contribute to the pathogenesis of PTLD at two levels: they inhibit the surveillance mechanism, but, even more important, as with CMV, are their potent effects in reactivating latent EBV, thus increasing the potential for outgrowth of immortalized B cells. Other risk factors for PTLD include primary EBV infection, high levels of virus replicating in the oropharynx, and, as previously discussed, preceding CMV disease [1,94].
Other than decreasing immunosuppression, which will result in regression of 20–30% of these processes, therapy of PTLD remains unclear. Most groups use high-dose acyclovir or ganciclovir in hope that EBV is still driving the process, although evidence that infection susceptible to antiviral therapy is present at the time of development of PTLD is lacking. Patients not responding to these measures are usually treated with an anti-B cell antibody. For refractory patients, some combination of chemotherapy, radiation therapy, and surgery usually is prescribed with disappointing results. Other experimental therapies include interferon, an anti–B-cell antibody, and, perhaps most interesting, the adoptive transfer of activated cytotoxic T cells [95,96,97,98,99,100].
Clearly, this process would best be prevented. Both antivirals commonly used in transplant patients, ganciclovir and acyclovir, can inhibit EBV replication. The critical question is whether this will interrupt the pathogenesis of PTLD either directly through effects on EBV replication or indirectly through effects on CMV [1,95,96,97,98,99,100].
Viral Hepatitis
The course of both HBV and HCV infection is accelerated in these immunosuppressed patients compared with the general population, with both progressive liver failure and cirrhosis with hepatocellular carcinoma occurring as consequences of these infections (see Chapter 42). With modern serologic testing, it is now uncommon for patients to acquire HBV infection at the time of transplantation from either the donor of the organ or from blood. This is fortunate because the acquisition of HBV at the time of transplantation has a relatively high incidence of acute hepatic failure. The bigger problem clinically is the question of disease progression in HBV-infected individuals after transplantation. By 10 years post-transplantation, more than half of these individuals will have progressed to end-stage liver disease or hepato-cellular carcinoma [1,101,102,103].
Both HBV and HCV are modulated by the immunosuppressive therapy, particularly corticosteroids, which appear to have a direct stimulatory effect on the level of virus replication. In HBV infection, this is manifest by a rapid increase in HBV DNA polymerase activity, HBeAg levels, HBV DNA, and HBsAg levels. These findings are in contrast to the gradual decrease in HBV production that often is observed in viral carriers not receiving immunosuppressive therapy [1,2,3].
Hepatitis B has a particularly detrimental effect on liver transplant recipients. Recurrent HBV infection occurs in 80–90% of patients undergoing liver transplantation, and 1-year survival in these patients has been 50–60% (significantly less than the 80% to 85% survival seen in other patient groups). Recurrent disease is rare in patients being transplanted for fulminant hepatic failure due to HBV or in those with simultaneous delta virus infection. The range of clinical disease that results from recurrent HBV infection is quite broad: mild, persistent hepatitis to aggressive, chronic hepatitis and fulminant liver failure [1,104,105,106,107,108].
Two major advances have had a significant effect on the outcome of transplantation in patients with chronic HBV infection: (1) the effectiveness of long-term immunoprophylaxis with anti-HBs hyperimmune globulin and (2) the potency of lamivudine as an anti-HBV drug. The administration of 10,000 units of hyperimmune anti-HBV immunoglobulin during the anhepatic phase followed by daily administration for 6 days and then administration at ~3- to 6-week intervals to maintain the anti-hepatitis B surface antigen titer at >1:100 IU appears to provide significant protection against recurrent liver disease and to increase patient survival. However, the indefinite need for this therapy adds $15,000 to $25,000 to the first-year costs (and continues to be a significant cost thereafter) [1].
Lamivudine is a nucleoside analogue that is a powerful inhibitor of the HBV polymerase/reverse transcriptase. This drug has been extremely effective in lowering HBV levels and improving hepatic function in the full range of HBV clinical syndromes, including the devastating fibrosing, cholestatic hepatitis form of HBV disease. The major disadvantage of lamivudine is the emergence of drug resistance in the virus (usually in a highly conserved region of the reverse transcriptase called the YMDD motif). These mutants begin to emerge approximately 1 year after the drug is initiated with an increasing incidence over time. The higher the viral load, the more likely and the more quickly resistance mutants will emerge. After the first year of therapy, 15–30% of patients receiving lamividine will have resistant virus; this rises to ≥40% after two years of therapy. It is clear that combination drug therapy or the combination of hyperimmune globulin with antiviral(s) will be necessary to control this infection [1,2,3,107,108,109,110,111,112,113,114].
P.769
HCV is the cause of >80% of end-stage liver disease and is the most common indication for liver transplantation in much of the world. Both transfusion and transplantation are highly efficient means of transmitting HCV to another individual. In liver transplant recipients who are infected with HCV, re-infection of the allograft is the rule. Re-infection is accomplished by HCV-infected peripheral blood mononuclear cells [115,116,117].
A series of risk factors has been defined in patients with HCV re-infection that are correlated with increased morbidity and mortality: viral load—the higher the viral load, the greater is the risk of serious disease and/or the more accelerated the course; intensity of immunosuppression—especially excessive amounts of corticosteroids (both pulse doses to treat acute rejection and sustained high daily doses to prevent rejection); ideally, patients with HCV infection are maintained on “steroid sparing regimens.” In addition to steroids, OKT3 therapy and mycophenolate use have been associated with significant increases in HCV viral load; allograft rejection—cytokines, chemokines, and growth factors produced in the rejection process will increase viral load; the additional immunosuppression required to control the rejection process will likewise add to the viral burden; HCV genotype—genotype 1b infection is associated with higher viral loads, a more accelerated course, and a poorer response to interferon-based therapeutic regimens; the presence of quasispecies—the greater the heterogeneity in the virus present, the greater difficulty the patient has in containing the infection; CMV viremia—there is a bidirectional effect between HCV and CMV, with chemokines and cytokines produced in response to one virus causing an increase in the level in the other virus; iron overload—which decreases the patient's cytotoxic T cell response to HCV, thus allowing the viral burden to increase; donor and recipient class II HLA matching—associated with re-infection and allograft injury; and, finally, donor tumor necrosis factor gene—the donor TNF-α promoter genotype may influence the inflammatory response to HCV infection of the graft and the extent of subsequent allograft injury [118,119,120,121,122,123,124,125,126,127,128,129,130].
A potentially devastating consequence of HCV infection in the transplant recipient is an uncommon clinical syndrome, fibrosing cholestatic hepatitis. Also seen with HBV infection, this is a syndrome characterized by high levels of circulating virus, rapidly progressive hepatic failure, mildly elevated serum aminotransferase levels, and a pathologic picture of extensive periportal fibrosis, intense cholestasis, minimal inflammatory infiltrate, and no cirrhosis. The hepatocytes are choked with exceedingly high levels of virus, causing direct hepatocyte injury. This entity requires decreased immunosuppression and intensive antiviral therapy [133,134,135,136,137,138,139,140,141,142,143].
An additional potential complication of HCV infection is glomerulonephritis. The most common form of this is membranoproliferative glomerulonephritis with or without mixed cryoglobulinemia. Less common forms of renal injury associated with HCV are membranous glomerulonephritis, acute and chronic transplant glomerulopathy, and thrombotic microangiopathy with anticardiolipin antibody; management of these complications centers on antiviral therapy [137,138,139,140,141,142,143].
The presently available therapy of HCV includes a dramatic decrease of immunosuppressive therapy, control of CMV infection if it is present, and antiviral therapy. The best therapy currently available is the combination of ribovirin and pegolated versions of interferon-α (conventional interferon-α plus ribovirin regimens yield a 50% response with the pegolated form even better). Side effects are unfortunately common with such treatment: Interferon use is associated with fever, malaise, bone marrow dysfunction, and risk of rejection, and ribovirin can cause hemolytic anemia [144,145,146,147,148,149,150].
Approximately 5% of all organ donors are anti-HCV positive, with approximately half of these being positive by PCR assay for circulating viral RNA. Organs from PCR-positive individuals are extremely efficient at transmitting virus to the recipient. Given the relatively slow pace of HCV illness and the continuing shortage of donors, there has been great controversy about whether to accept anti-HCV-positive donors. Reserving these organs for anti-HCV-positive recipients results in superinfection with donor-strain HCV. The policy at the author's center is to reserve organs from anti-HCV-positive donors for critically ill heart and liver patients, for highly sensitized renal patients, and for older patients (with potentially shorter life spans during which the hepatitis would progress). Even in these circumstances, ethical considerations require full disclosure to the individuals involved regarding the potential consequences of such an action [1,2,3].
Mycobacterial Infections
Infection due to M. tuberculosis has been less of a problem after transplantation than might have been predicted. Despite immunosuppressive therapy, reactivation and dissemination of M. tuberculosis have been exceedingly uncommon in individuals whose only evidence of dormant tuberculosis is a positive tuberculin test. Conversely, patients with (1) a history of active tuberculosis (treated or untreated), (2) an abnormal chest radiograph, (3) noncaucasian racial background, (4) protein-calorie malnutrition, or (5) another immunosuppressing illness, in addition to a positive tuberculin test, are at significant risk for reactivating their tuberculosis. The approach at the author's center is to reserve antituberculous prophylaxis for those with added risk factors in addition to a positive tuberculin skin test. We have now followed more than 100 “low-risk” individuals post-transplantation for periods of up to 10 years without a single case of reactivation despite the positive tuberculin reaction; the high background rate of hepatocellular dysfunction in these patients makes the use of isoniazid or rifampin challenging; and antituberculous
P.770
drugs affect the pharmacokinetic profile of cyclosporine and tacrolimus, rendering the use of these drugs more difficult as well [1,2,3].
Atypical mycobacterial infection also may be observed in transplant recipients: Local or disseminated disease due to Mycobacterium kansasii and progressive skin infection due toMycobacterium marinum, Mycobacterium haemophilum, and Mycobacterium chelonei has been reported. These infections typically present initially at sites of cutaneous injury. Management usually involves surgery and chemotherapy based on in vitro antimicrobial susceptibility testing [1,2,3].
Fungal Infections
The fungal infections that affect transplant recipients can be divided into two general categories: (1) disseminated primary or reactivated infection with one of the geographically restricted systemic mycoses (histoplasmosis, blastomycosis, and coccidioidomycosis), and (2) invasive opportunistic infections with such organisms as Candida species, Aspergillusspecies, C. neoformans, and the Mucoraceae. The first category of disease should be considered in patients with a history of recent or remote travel to an endemic region who present with one of the following clinical syndromes: subacute respiratory illness, with focal, disseminated, or miliary infiltrates on chest radiograph; a nonspecific, systemic, febrile illness; unexplained pancytopenia; and an illness in which metastatic aspects of the infection predominate (e.g., mucocutaneous manifestations of histoplasmosis and blastomycosis or central nervous system manifestations in coccidioidomycosis or histoplasmosis) [1,2,3].
The opportunistic fungal infections have a far greater impact on the transplant patient than do the endemic mycoses. Primary infection, usually of the lungs but occasionally of the nasal sinuses, may occur in patients who inhale air contaminated with Aspergillus species, C. neoformans, or, particularly in diabetic patients, Mucoraceae. In addition, secondary infection of wounds and hematomas and intravenous lines by Candida or Aspergillus species may occur. Evidence of metastatic infection may follow either primary or secondary fungal infection with the skin and central nervous system being common sites of presentation. Fungal infection is a particular concern at the bronchial anastomotic site of lung transplant recipients with chronic infection and occasional dehiscence developing [1,2,3].
A revolutionary change in antifungal therapy has occurred in recent years. Although the only useful drug for many years was amphotericin deoxycholate, today there are three major classes of effective drugs available [1]:
Adverse effects of azoles are few, including hepatic dysfunction, skin rash, and drug–drug interactions. Voriconazole can cause visual disturbances that clear with cessation of the drug.
Pneumocystis Jirovici
Long considered a protozoan, P. jirovici has been shown by molecular taxonomic studies to be more appropriately regarded as a fungus. Regardless of this detail of classification, effective therapy thus far has been provided by drugs having antiprotozoan (as opposed to antifungal) profiles. The incidence of Pneumocystis pneumonia in organ transplant patients not receiving anti-Pneumocystis prophylaxis is 10–15%. Traditionally, such infections have
P.771
been regarded as immunosuppression-induced reactivation of infection acquired in childhood. However, the possibility of immunosuppressed person-to-immunosuppressed person spread (possibly by an aerosolized route) exists. It is the policy at the author's center, therefore, to isolate patients with P. carinii pneumonia from other immunosuppressed patients, including transplant recipients [1,2,3].
In transplant recipients, Pneumocystis infection typically occurs either in the period 1 to 6 months post-transplantation, often in association with CMV infection, or in the late period, typically in the subgroup of patients with poor allograft function, excessive immunosuppression, and chronic viral infection [1,2,3].
When Pneumocystis pneumonia does develop, it is a subacute disease characterized by fever, nonproductive cough, and progressive dyspnea with hypoxemia occurring over several days, and the presence of an interstitial infiltrate on chest radiograph. Administration of low-dose TMP-SMX (one single-strength tablet at bedtime) is effective in the prevention ofPneumocystis pneumonia and is routinely used in our transplant recipients. Alternative therapies are less effective but include monthly aerosolized or intravenous pentamidine, atovaquone, and clindamycin with pyrimethamine. Because treatment of confirmed Pneumocystis pneumonia with high-dose TMP-SMX or parenteral pentamidine in transplant recipients is associated with a high rate of side effects, particularly bone marrow and renal toxicity, the importance of prevention cannot be overemphasized [1,2,3].
Principles of Antimicrobial Therapy in Transplant Recipients
The Importance of Drug–Drug Interactions in Prescribing Antimicrobial Treatment in Transplant Patients
Interactions between the calcineurin inhibitors and certain antimicrobial agents are common and important in the transplant patient. Both cyclosporine and tacrolimus are metabolized by hepatic cytochrome P450 enzymes, which account for two of the three types of drug interactions observed [1,2,3]:
Sirolimus (rapamycin) has been a particular problem with most transplant centers not administering sirolimus and voriconazole to a transplant recipient. Recently, it has been shown that a sirolimus dose reduced by 90% will permit coadministration of the two drugs [50].
Problem-Directed Prophylactic Strategies
Antimicrobial therapy in transplant recipients presents several challenges. Many of the antimicrobial agents are themselves toxic and that toxicity frequently is exacerbated by cyclosporine and tacrolimus, the cornerstones of current immunosuppressive regimens. Prolonged courses of therapy with these toxic agents are required to achieve adequate treatment of clinically overt disease. Once disease has occurred, the infected tissue may become vulnerable to infection from other organisms (secondary infections).
The only way to avoid these difficulties is to shift the emphasis of infectious disease management of the transplant recipient to the prevention of infectious complications. This principle has led to development of prophylactic strategies directed toward specific problems, such as prevention of urinary tract infection in the renal transplant patient, prevention of procedure-related complications in the liver transplant recipient, prevention of toxoplasmosis in the heart transplant recipient, and prevention of Pneumcystis infection in all transplant recipients. All of these strategies have proved to be useful and cost-effective approaches to disease prevention [1,2,3].
The practice of routine prophylaxis is best illustrated by the use of TMP-SMX (one single-strength tablet daily) for 6 months or longer after transplantation. This practice presents a large series of common infections without perturbing the anaerobic flora of the gastrointestinal tract. Among the infections generally prevented are those due to P. jirovici, T. gondii, L. monocytogenes, N. asteroides, susceptible organisms involved in urinary tract infections
P.772
due to Enterobacteriaceae; sinopulmonary infections due to S. pneumoniae and H. influenzae; and gastrointestinal infections due to Salmonella and Shigella species. Four aspects of patient care are altered by the routine use of TMP-SMX: (1) infections, when they occur, are rarely due to these pathogens, (2) the presence of these pathogens in a compliant patient suggests an increased epidemiologic exposure or excessive immune suppression (e.g., high-dose steroids, drug-induced neutropenia, CMV infection), (3) in the absence of increased risk, technical/anatomic factors (obstruction, hematoma, lymphocele, indwelling stent, anastomotic leak) must be considered, and (4) infections, when they occur, are usually due to antibiotic-resistant, often nosocomially acquired, organisms. Initial clinical evaluations and therapies must be aggressive (e.g., invasive procedures, broad-spectrum antibiotics) to identify and reverse the infectious process and any predisposing factors and to obtain appropriate microbiologic data to guide further therapies [1,2,3].
Two examples of the limitations of prophylaxis are relevant. The use of daily quinolone prophylaxis in renal transplant recipients successfully prevents urinary tract infections in the absence of mechanical obstruction. However, a 10–14% incidence of Pneumocystis pneumonia is observed in these individuals. The routine use of fluconazole prophylaxis successfully prevents infections due to susceptible yeasts. However, these patients and these institutions experience, over time, a shift to colonization and infection with resistant yeasts (e.g.,Candida glabrata, Candida krusei) and filamentous fungi (e.g., Aspergillus and Mucorales species) Thus, individualized antifungal strategies (for those at greatest risk because of prolonged antibiotic use or those already colonized) may be preferred [1,2,3].
Preemptive Therapy
A newer mode of antimicrobial therapy, called preemptive therapy, has been described. Traditionally, antimicrobial therapy has been administered either prophylactically to a large number of patients at risk of disease before there is evidence of infection to prevent serious disease in a few or therapeutically to the few in whom tissue invasion and clinically overt disease are present. Typically, prophylactic regimens involve the administration of a nontoxic drug, often with less-than-ideal antimicrobial activity, for a prolonged period of time, whereas therapeutic regimens use the most effective medications, often at toxic doses, for shorter periods of time. Preemptive therapy combines the most desirable aspects of these two options: administration of highly effective therapy over a short period of time to a relatively small number of patients who are at risk of serious infection. The short duration of therapy reduces the potential toxicity, and clinical and laboratory markers may be used to determine predictors of serious infection. For example, preemptive therapy with low-dose ganciclovir administered in conjunction with OKT3 therapy to CMV-seropositive renal transplant recipients appears to be a promising approach to the prevention of CMV disease. Similarly, the early use of fluconazole to eradicate asymptomatic candiduria in renal transplant recipients and to prevent progression to urinary tract obstruction and pyelonephritis and the use of fluconazole in association with surgical manipulation of a pulmonary nodule due to Cryptococcus to prevent cryptococcal meningitis are other examples of preemptive therapy [1,2,3].
Future Trends
Given the therapeutic constraints imposed by the necessary immunosuppressive regimen and the devastation that infection may cause in the transplant recipient, appropriate emphasis is increasingly being placed on evaluation of predictors of serious infection. New technologies, including molecular hybridization and PCR, may allow the cost-effective screening and detection of at-risk individuals most in need of preemptive treatments. Development of clinical epidemiologic databases and appropriate laboratory markers will permit further major advances beyond the preemptive approach to infection in this ever-increasing and challenging population of patients.
References
P.773
P.774
P.775