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Fungal infection in the organ transplant recipient
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS
C h a p ter
21
Fungal infection in the organ transplant recipient Robert H. Rubin
The remarkable success being achieved by organ transplantation today (e.g., >90% 1-year patient and graft survival following cadaveric kidney transplantation) has changed the approach to the care of patients with chronic, progressive organ failure. A few decades ago, transplantation was considered a last desperate therapy, marred by technical complications, systemic infection, rejection, and a broad array of complications of immunosuppression, particularly corticosteroids. Today, we recognize organ transplantation as the most effective means of rehabilitating patients with organ failure of diverse etiologies. This is not to say that all the problems have been solved; rather, an approach has been developed that increases the chances of success. Important principles have been developed that serve as a foundation for clinical efforts.1-3 Effective antimicrobial therapy in the transplant recipient is particularly challenging for a number of reasons. 1. Microbial load is a major determinant of the prognosis for a given patient with infection. The impaired inflammatory response to microbial invasion that is engendered by immunosuppressive therapy commonly results in an occult presentation: signs and symptoms are attenuated until late in the infection; radiologic findings are often more subtle; dermatologic manifestations are dampened so that classic findings are absent and skin lesions are often non-specific. The microbial load is invariably greater in the transplant patient than in the normal host with a similar illness. The blandness of the response to many fungal infections only adds to diagnostic difficulty. Since prognosis is directly related to how quickly the appropriate diagnosis is made and effective therapy prescribed, an aggressive approach to evaluation of the patient is mandatory. CT scan rather than conventional radiography is the appropriate response to chest symptoms and/or minimal findings on conventional radiology; skin lesions as well as chest nodules require biopsy; and unexplained fevers require extensive evaluation.1,3-5 2. A ntimicrobial therapy, particularly antifungal therapy, in the transplant recipient is likewise more complex than in other populations. There are three modes of therapy that need to be considered: prophylactic, therapeutic, and preemptive. Prophylactic therapy is administered to an entire population of uninfected patients when the risk of clinical disease is deemed great enough to justify the intervention. An example is the performance of a transplant in
the face of aerosolization of one of the endemic systemic mycoses. Antifungal prophylaxis provides protection against clinical disease. The therapeutic use of antifungal drugs is the treatment of invasive infection, often due to the failure of prophylactic regimens. Preemptive therapy is utilized when asymptomatic patients are regarded as being at increased risk of invasive infection on the basis of a laboratory or clinical observation. Antimicrobial therapy in transplant patients requires more prolonged therapy than in other patient populations because of the increased microbial burden and the continuing need for immunosuppression. As a result, toxicity is usually greater and antimicrobial resistance may be selected.1,3,5 3. The range of organisms to be considered is far broader than that causing similar clinical presentations in the normal host. In the transplant patient, not only are the usual bacteria (e.g., Staphylococcus aureus, a variety of streptococci, E. coli and other Gram-negative bacilli) and viruses (e.g., influenza, respiratory syncytial virus, and hepatitis B and C) of concern, but more unusual pathogens must be considered. These unusual pathogens include fungi, not only the traditional organisms such as Candida albicans but also opportunistic species such as Aspergillus and Cryptococcus. In addition, there is an increasing problem with what has been termed the “new and emerging” organisms (such fungi as Scedosporium, Fusarium, and the zygomycetes). Uncommon bacterial (Nocardia, Mycobacterial, and pathogenic corynebacterial) and viral infections (e.g., SARS and West Nile virus) add significantly to the management challenges faced by the clinician. On the one hand, the impact of traditional pathogens is greater in this patient population; on the other hand, the effects of newly introduced pathogens will be particularly threatening in transplant patients and other immunosuppressed hosts. They are truly “sentinels” for excess trafficking in potential pathogens in the environment.7 4. There is a direct link between early diagnosis and effective therapy. Indeed, the patient would be well served by considering diagnosis and therapy together as part of an infection management program, one that includes not only antimicrobial therapy but also diagnostics that inform the use of these drugs. Although culture techniques remain the cornerstone of disease management, new approaches such as antigen detection, polymerase chain reaction (PCR) detection of microbial nucleic acids, and newer radiologic 473
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient procedures hold great promise for early diagnosis and the deployment of effective therapy. In contrast, serologic diagnosis (the testing for specific antibodies in the serum), which is measuring the immunologic response to a particular antigen, is far less sensitive and is usually not part of the diagnostic evaluation in immunocompromised patients with active infection. The major application of serologic techniques is prior to transplant when these measurements can help assess the risk of particular infections. The key concept here is to forge the link between early diagnosis and the preventive and therapeutic use of antimicrobials.1,2
Risk of fungal infection in the organ transplant recipient The risk of fungal infection in the organ transplant recipient is determined by the interaction of four factors.
Net state of immunosuppression The net state of immunosuppression is a complex function that is made up of a number of factors; the level of immunosuppressive therapy being administered is the primary determinant but, in addition, other entities contribute to this function: neutropenia, protein calorie malnutrition (and, probably, other metabolic disturbances such as uremia and hyperglycemia); systemic infection with one or more of the immunomodulating viruses (cytomegalovirus (CMV), Epstein–Barr virus, human herpesvirus-6; hepatitis viruses B and C, and the human immunodeficiency virus); and other factors such as immune response genes. The importance of these additional contributors to the net state of immunosuppression is underlined by the following observations: transplant patients with a serum albumin level of <2.5 gm/dl have a 10-fold increase in the incidence of life-threatening infection; 90% of opportunistic infection occurs in the setting of viral infection. For those patients without viral infection, there is a high probability of an excessive environmental hazard being present to account for the invasive infection; that is,viral infection increases the net state of immunosuppression such that the individual is susceptible to invasive infection.1,2,4
Environmental exposures Excessive environmental exposures can occur within the community or in the hospital. In the community, aerosols can be created and inhaled during the course of construction, gardening or farm work. Hospital exposures of importance that can result in invasive fungal infection can be divided into two general categories: domiciliary and non-domiciliary. Domiciliary refers to the acquisition of infection on the ward where the patient is housed, with outbreaks of this type being marked by clustering of cases in time and space. Non-domiciliary exposures occur as a patient travels in the hospital for essential procedures. Exposures of this sort can occur in the halls of the hospital, the operating room, the radiology or bronchoscopy suites and elsewhere. Non-domiciliary outbreaks are not uncommon, with the clue of a possible hazard coming from the diagnosis of infection at a point in time when the net state of immunosuppression 474
should not have been great enough by itself for such infection to occur. Excessive amounts of infectious particles in the potable water and/or the air that is inhaled can produce invasive disease, particularly in the transplant situation in which the cellmediated response to fungal tissue invasion is most affected by the immunosuppressive therapy being administered.5-7 In recent years a growing problem has been the person-toperson spread of azole-resistant Candida infection (both resistant C. albicans and non-albicans ������� Candida strains being spread in this fashion), on the unwashed hands of medical personnel.1,5,7,10,11 The dimorphic fungi (Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum) grow in the soil as a mould composed of a mesh of septate hyphae bearing conidia (the infectious particles) that can be aerosolized when the ground bearing these organs is manipulated during urban renewal projects, “clean-up” efforts, and explorations of sites where the soil is “enriched” with bird and animal droppings (e.g., bat caves, chicken roosts, and beaver habitats). Inhalation of aerosolized conidia will initiate clinical infection in the lungs, with the tissue invasive form being yeast.1,2,8,9,12,13 The clinical consequences of tissue invasion by these organisms can be quite diverse. Primary infection occurs in the first month after exposure. This may be asymptomatic or be associated with a flu-like syndrome. In addition, hypersensitivity manifestations such as erythema multiforme, erythema nodosum, and reactive arthritis are common manifestations of primary infection and the development of immunity in a normal host. In transplant patients, such immune effects are uncommon, whereas progressive primary pneumonia and postprimary dissemination via the bloodstream are common. These dimorphic fungi have a similar epidemiology and pathogenesis: a pulmonary portal of entry after inhalation of the infectious aerosol; an initial host defense response of polymorphonuclear leukocytes and alveolar macrophages as a consequence of the pulmonary invasion; followed by the development of a specific humoral and cell-mediated immune response.1,9,12,13,15,16
Technical or anatomic abnormalities The presence of technical or anatomic abnormalities that lead to undrained fluid collections (blood, urine or bile, and/or lymph), devitalized tissues, and the need for the placement of drainage catheters and other foreign bodies that compromise mucocutaneous surfaces can contribute significantly to the risk of infection. Surgical misadventures, vascular access devices, and the need for prolonged respiratory support can all play a role here. Surgery in a transplant patient is the most unforgiving form of surgery that is encountered, with a surgical misadventure being highly associated with secondary invasive infection.1,2,5-7
Darwinian factors Darwinian factors are now being recognized as important contributors to the pathogenesis of certain infections. The most common example of this phenomenon is when broadspectrum antibacterial therapy has been given in the setting if an anatomic problem that has not been corrected. Candida superinfection is a common result, requiring surgical correction as well as systemic antifungal therapy. Another version of Darwinian influences is when excessive amounts of growth
Clinical timetable for the occurrence of fungal infection in transplant patients
factors are present, thus favoring microbial overgrowth. Thus, excessive amounts of iron can result in zygomycosis, listeriosis, and other life-threatening infections, as well as an increase in the microbial burden in the case of a local staphylococcal wound infection.1,2,6,10,11
infection will be influenced by prophylactic antimicrobial therapy. A not uncommon result when this effort fails is to prolong the incubation period without affecting the incidence. As a general rule, the incubation period may be extended 2–6 months.1,2,4,6
Summary
First month after transplant
Environmental exposures can occur within the community or in the hospital. In the community aerosols can be created and inhaled during the course of construction, gardening or farm work. Moulds such as Aspergillus can cause invasive disease following such exposures. In addition to such opportunistic infections, the endemic mycoses (B. dermatitidis, C. immitis, and H. capsulatum) can have a significant impact on the health of the transplant patient. These dimorphic fungi have a similar epidemiology and pathogenesis. They each are geographically restricted, growing in nature as a mould composed of a mesh of septate hyphae bearing conidia (the infectious particles) that are aerosolized during urban renewal projects, “clean-up” efforts, and explorations of sites where the soil is “enriched” with bird and animal droppings. Inhalation of aerosolized conidia will initiate clinical infection, with the tissue invasive form being yeast. The critical host defense is the cell-mediated response to tissue invasion, just that aspect of host defense most affected by the immunosuppressive drugs required for successful transplantation.9,12,16 Epidemiologic patterns of infection that occur are: primary infection, often with bloodstream dissemination; reactivation infection with the potential for secondary dissemination; and reinfection, again with the possibility of dissemination. Transplant patients are particularly vulnerable to reinfection, due to attenuation of previous immunity by the chronic immunosuppressive therapy.1,2,4 The net state of immunosuppression is a complex function that is made up of a number of factors. For those patients without viral infection, there is a high probability of an excessive environmental hazard that should be identified and corrected as quickly as possible, in order to prevent additional cases.1,2,4,6
There are three major causes of infection in this time period.
Clinical timetable for the occurrence of fungal infection in transplant patients There is an important temporal component to the infections that occur post transplant; that is, different infections occur at a particular time after the transplant procedure and initiation of immunosuppression. Ultimately, the net state of immunosuppression (and the development of infection) is related to sustained therapy, the area under the curve, rather than the daily doses. The point to be emphasized is not that pneumonia can only occur at a specific time but rather that the restricted time period applies to the etiology. The timetable can be useful in the following ways: in helping to generate a differential diagnosis in a patient who presents with a clinical illness that could be a manifestation of invasive infection; as a tool of infection control – exceptions to the timetable demand an explanation; and as the foundation of a variety of preventive strategies. The three time periods that have been defined do not include the impact of prophylaxis. Both CMV and fungal
1. Infection in the recipient that was not eradicated prior to the transplant operation, and may be further exacerbated by surgery and post transplant immunosuppression. Although every patient should be carefully screened for active infection prior to the procedure, particular attention should be paid to those individuals already receiving immunosuppression prior to transplantation. Thus, we have seen patients with conditions such as Crohn’s disease, primary biliary cirrhosis or a cardiomyopathy, in a desperate attempt to avoid transplantation, come to transplant receiving chronic corticosteroids, and with infection due to Pneumocystis or Cryptococcus already present. These infections can be a major problem in the early post transplant period. 2. Infection of donor origin, with bloodstream infection seeding the allograft prior to surgery. Parenchymal infection may contribute to infections such as histoplasmosis and the other endemic fungi in the recipient. 3. The most common infections in this time period are the same wound, pulmonary, vascular access or drainage catheter infections seen in normal hosts undergoing comparable surgery. The prime determinant is the technical skill with which the surgery and perioperative care are carried out. Notable by their absence during this time period are infections with opportunistic fungal pathogens such as Aspergillus. Indeed, when such infection occurs, this should trigger a search for excessive environmental dangers.1,2,4,6
One to six months after transplant In this time period the net state of immunosuppression is particularly high, because of the sustained immunosuppression and the effects of the immunomodulating viruses. As a result, infections such as those due to Aspergillus species can occur in the absence of an unusually intense exposure. The most common cause of febrile syndromes during this period are the herpes group viruses, particularly CMV and human herpesvirus-6. Since these predispose to opportunistic infections such as those caused by fungi, Listeria, and Nocardia, a careful assessment for dual or sequential infection should always be a part of the clinical review once CMV is diagnosed.1,2,4,6
More than six months after transplant In this period the patients may be regarded as fitting into one of two general categories in terms of fungal infection. Approximately 80% of organ transplant patients will have had a good result from their transplant: good allograft function, maintenance immunosuppression, and freedom from viral infection. This group is at minimal risk for invasive fungal infection unless 475
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient an excessive environmental exposure has occurred. Mucocutaneous candidal infection and, uncommonly, asymptomatic pulmonary nodules due primarily to Cryptococcus neoformans are the major fungal concerns. The remaining patients have had a poorer outcome from transplantation: less satisfactory allograft function, too much acute and chronic immunosuppression, and, often, chronic or recurrent viral infection. This group is often characterized as “chronic ne’er do wells.” They are at the greatest risk of any transplant patient for disseminated cryptococcal infection, invasive aspergillosis, and, if the epidemiologic history is appropriate, systemic infection with one of the endemic mycoses.
Fungal infections of particular importance for the organ transplant recipient The endemic mycoses As previously discussed, transplant patients are particularly vulnerable to the endemic mycoses if an exposure has occurred. The salient epidemiologic and clinical characteristics of the different infections in this group of patients are very similar: the organisms are dimorphic, growing in the soil over a limited geographic area as a mould with the infectious particles, the conidia, liberated from the mould in an aerosol following a variety of manipulations of the infected soil. Inhalation of the conidia is the key step in initiating the infection, with a pulmonary portal of entry being characteristic of these organisms. Tissue invasion is accomplished by yeast forms. There is an initial polymorphonuclear leukocyte and alveolar macrophage response to these events, with a subsequent humoral and cell-mediated response. The key host defense is a specific cytotoxic T cell response. The combination of the initial nonspecific inflammatory response with the specific response will limit the extent of the pulmonary infection, as well as access to the bloodstream and systemic infection. In transplant patients the attenuation of the specific immune response engendered by immunosuppressive therapy leads to an increased incidence and severity of progressive pulmonary and disseminated infection, as well as metastatic spread to sites such as the skin, the CNS, bones, and joints.8,9,12-17
Blastomycosis Blastomyces dermatitidis grows as a mould on decaying wood. The geographic distribution of these organisms is similar to that of H. capsulatum (the midwest and southeastern United States). Human infection results following the inhalation of a conidia-laden aerosols. Clinically, pulmonary symptoms (cough, sputum production, chest pain, and dyspnea) predominate. Radiologic findings include non-specific infiltrates and hilar adenopathy. Disseminated infection not uncommonly results in metastatic skin involvement, with large nodular skin lesions that undergo necrosis and fibrosis. Genitourinary and skeletal infection are the other common sites of metastatic spread. Blastomycosis is the least common of the systemic mycoses to infect the transplant recipient. Diagnosis usually requires biopsy for pathologic and cultural examination. Initial treatment usually requires an amphotericin preparation 476
a dministered intravenously, followed by oral itraconazole. The role of newer antifungals is still being defined.
Coccidioidomycosis Coccidioides immitis is a dimorphic fungus which grows as a mesh of septate hyphae bearing the arthoconidia that initiate clinical disease following inhalation of an aerosol laden with these infectious arthroconidia. Within the mammalian host maturation of the arthroconidia into spherules, the definitive tissue pathogen, takes place. The natural habitat of C. immitis is the desert soil of the Lower Sonoran life zone, an area whose climate features hot, dry summers and mild winters with moderate rainfall. Geographic areas that fit this description include the San Joaquin Valley of California, the southwestern United States, northern Mexico, and various sites in Central and South America. The arthroconidia can be so efficient at transmitting the infection that clinically important disease can occur many miles from an endemic area, due to wind or dust storm conditions, or exposure to dust on packages or clothing sent from the endemic sites. Major risk factors for serious clinical disease include the following: intensive immunosuppressive therapy, pregnancy, and non-Caucasian racial status. For example, on moving into an endemic area there is a 5% risk of developing primary infection during the first year of residence, with an additional annual infection rate of 2–3% per year. Dissemination, with a predominance of CNS infection, was noted in 75% of these individuals, with around two-thirds of these dying from this infection.6,8,16-20 A variety of clinical syndromes are associated with C. immitis infection. As previously discussed, primary infection in a nonimmunosuppressed individual will probably cause hypersensitivity reactions; in contrast, in a transplant patient receiving immunosuppressive therapy, the hypersensitivity reactions are uncommon, and progressive pneumonia and/or bloodstream infection due to invasive disease are the rule. The most important manifestation of infection in transplant patients is meningitis. Typically, a diffuse granulomatous meningitis encases the base of the brain, resulting in hydrocephalus and cranial nerve palsies. Headaches and an impaired state of consciousness are common. Vasculitis can occur, resulting in focal neurologic findings, including aphasia, hemianopia, and hemiparesis, aneurysms and subarachnoid hemorrhage. CNS disease caused by this organism can be the first or only evidence of coccidioidomycosis, and vice versa. Other sites of metastatic infection include the skin, the skeleton, and the genitourinary tract. The diagnosis of coccidioidomycosis can be difficult and should be regarded as being in a state of flux. Traditionally, KOH preparations of sputum, scrapings of skin or visceral tissues, or biopsies have yielded the diagnosis under the microscope. Cultures can be performed, but this approach is potentially dangerous if the diagnostic laboratory is inexperienced and/or appropriate protective biohazard equipment is not in place and utilized. Skin tests in immunosuppressed patients may be difficult to interpret. In contrast, rising titers of antibody, especially complement fixing antibody directed against C. immitis, are quite suggestive (although the possibility of cross-reacting antibodies can be seen with blastomycosis and histoplasmosis). Cerebrospinal fluid (CSF) in patients with meningitis usually reveals a lymphocytic pleocytosis, an elevated protein level and a low sugar (hypoglycorrhachia), and
Fungal infections of particular importance for the organ transplant recipient
increased intracranial pressure. Complement fixing antibodies in the CSF are of great diagnostic value. It is quite likely that in the next few years quantitative measurements of specific antigens and/or PCR detection of C. immitis nucleic acids will become the cornerstone of the diagnostic effort. Antifungal chemotherapy for coccidioidomycosis is also in evolution. High-dose amphotericin therapy has been, and continues to be the standard of care. However, because cure is unlikely and relapse to be expected, we advocate a different approach: gain control with amphotericin and then switch to high-dose azole therapy. For this purpose, itraconazole has been used successfully. We prefer fluconazole for this longterm maintenance therapy, because of the greater reliability of absorption, pharmacokinetics, and lesser amounts of interaction with cyclosporine and tacrolimus. Ideally, preemptive fluconazole therapy should be prescribed for transplant patients with a past history of coccidioidomycosis or when the transplant care is being given in an endemic region. Once initiated, the fluconazole should be maintained for an indefinite period.8,16-20
Histoplasmosis Histoplasma capsulatum, the dimorphic fungus, grows well in soil enriched by the droppings of chickens, starlings, and bats. In the United States the center of activity is found in the Ohio and Mississippi river valleys, extending eastward into Virginia and Maryland. The inhalation of aerosolized organisms results in a patchy bronchopneumonia with a neutrophilic inflammatory response. This is followed by the development of specific cell-mediated immunity and, finally, by the development of epithelioid granuloma with Langhans’ type giant cells, easily recognized on microscopic examination of the lung. Because of the impaired cell-mediated immune responses in transplant patients, systemic dissemination and/or progressive primary pneumonia are common, with infected mononuclear cells being efficient carriers of the infection to distant sites. Sites of extensive involvement are those organs with large numbers of reticuloendothelial cells: liver, spleen, lymph nodes, bone marrow, gut, and adrenal glands. In addition to these sites, mucocutaneous and CNS infection are not uncommon.5,6,8,9 Data presented by Wheat and his colleagues in Indianapolis, which is in the heart of the histoplasmosis belt, have shown that clinical disease occurs in 2–4% of renal transplant recipients, with a high percentage of these patients having disseminated disease. During an urban epidemic, this rate can exceed 10–15%. Although reactivation disease with secondary dissemination can occur, most such cases appear to be due to new exposures. Most clinical cases occur more than 6 months after transplant, particularly in those patients who have required greater than normal immunosuppression. Dissemination is the rule, with CNS infection, both parenchymal and meningeal, occurring in as many as one-quarter of cases. The clinical presentation of histoplasmosis is essentially identical to that of coccidioidomycosis: subacute onset of fever, respiratory complaints, metastatic infection, headache, and altered consciousness.8,9,12,14
Opportunistic fungal infection Aspergillosis Of the more than 200 species of Aspergillus, 95% of the clinical disease is caused by three species (A. fumigatus, A. flavus, and A. niger, with an occasional human case caused by
A. nidulans, A.terreus, A. oryzae, and A. versicolor). These organisms are ubiquitous in the environment and are particularly likely to cause infection in transplant patients in nosocomial or community settings in which construction activities result in the creation of an aerosol laden with Aspergillus conidia. There are several distinct clinical syndromes that can be produced following inhalation of the infectious aerosol.1,2,4 1. Hypersensitivity syndromes, including both asthma and extrinsic allergic alveolitis. 2. Colonization syndromes, in which the formation of fungal balls or mycetomas occurs in previously injured sinuses and, more commonly, in pulmonary cavities or sites of bronchiectasis. These fungal balls tend to cause irritation and inflammation. Life-threatening hemorrhage from the sites of the fungal balls can also occur. 3. Allergic bronchopulmonary aspergillosis is a clinical entity that combines aspects of both the hypersensitivity and colonization syndromes. Colonization of the tracheobronchial tree, an irritative cough, the appearance of “brown bits” in the sputum, and fleeting pulmonary infiltrates have been well described, including an 80% response to corticosteroids. 4. Invasive aspergillosis is the key response to this problem. Invasive aspergillosis is potentiated by steroids and/or neutropenia, and occurs only in patients who are significantly immunocompromised and/or exposed to a major environmental hazard. The consequences of invasive aspergillosis in this patient population are related to the vascular invasion that occurs: hemorrhage, infarction, and metastases. In a transplant patient, colonization with Aspergillus significantly increases the risk of subsequent invasion. 5. Semiinvasive aspergillosis is an uncommon entity in which true immunocompromised is not present but subtle findings of hyperglycemia, liver disease, influenza, etc. are present and are thought to be associated with the slow progression of this necrotizing process. Vascular invasion is a minor part of this syndrome. Surgical ablation under cover with an azole drug appears to be the treatment of choice. Other associations that merit comment include the presence of Aspergillus in marijuana, which can lead to invasive disease. Direct inoculation of damaged skin (e.g., vascular access sites, burns, and sites of inoculation) can likewise require treatment. In lung transplant recipients two additional forms of Aspergillus infection have been noted: infection of the suture line, with subsequent necrosis and disruption, and tracheobronchial disease. Invasive aspergillosis, then, primarily occurs in situations of poor leukocyte function or sustained exposure to steroids. However, even patients whose net state of immunosuppression is minimal can develop invasive aspergillosis if the environmental exposure is great enough. An important corollary to this observation is that a single case of invasive aspergillosis occurring in the first month post transplant (a “golden period” during which opportunistic infection only occurs under conditions of unusually intense environmental exposure) should trigger a search for environmental hazards before more cases occur.1,2,4-6 Whatever the portal of entry, blood vessel invasion is the hallmark of invasive aspergillosis, resulting in the three 477
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient characteristics of this entity: tissue infarction, hemorrhage, and metastatic spread through the cardiovascular system. Of all the Aspergillus species, A. fumigatus, A. flavus, and A. niger account for virtually all cases, with A. fumigatus causing the majority of these.1,2,4-6 Clinically, invasive aspergillosis of the lungs, the most common presentation of invasive disease, can occur as the primary event or as a superinfection after pulmonary injury due to virus or bacteria, or pulmonary infarction. In as many as 50% of cases, metastatic spread has already occurred by the time of diagnosis, and a site of metastasis may be the first presentation of invasive disease. The typical radiologic finding of invasive aspergillosis of the lungs is focal lung disease, with either a nodule or a consolidation being present, often with cavitation. Unlike the patient with leukemia and aspergillosis, halo signs and air crescent signs are uncommon in organ transplant patients. Specific diagnosis requires a biopsy procedure. Other diagnostic approaches such as the galactomannan assay appear to be quite promising. If the early promise is confirmed, then early preemptive therapy will become an important part of patient management.1,2,4-6 The traditional view of Aspergillus syndromes is that there is little overlap; that is, a colonization syndrome never turns invasive or allergic bronchopulmonary disease does not turn invasive. It is now clear that on occasion there is “overlap” “or crossover.” The availability of voriconazole now makes it possible to treat any evidence of invasive disease and, in many patients, avoid surgery. Combining voriconazole with surgery is also a useful strategy, preventing complications of surgical manipulation.1,2,4 The standard of care for invasive disease due to aspergillosis has long been a prolonged course of intravenous therapy. Sustained therapy of this sort was rendered difficult by the toxicities of this regimen: an acute infusion toxicity, with cytokine release, fever, rigors and malaise, chronic, progressive renal toxicity. Fortunately, there has been a major advance in the availability of alternative antifungal drugs.21-31 Lipid-associated amphotericin B products There are now three approved lipid-associated amphotericin products, whose use is approved by the Food and Drug Administration. The use of these drugs is clearly associated with a striking decrease in toxicity and a greatly increased cost. Issues such as optimal dose and duration and relative effectiveness are still being assessed. At present, a common strategy is to initiate therapy with conventional amphotericin and then switch to a lipid compound when the toxicity becomes evident, but is easily reversible. Amphotericin B, a polyene antifungal, acts by binding to fungal membrane sterols (most notably ergosterol) and causing a significant increase in fungal cell permeability, resulting in leakage of intracellular contents and cell death. Flucytosine Flucytosine is mentioned here because it can only be used in conjunction with amphotericin. It has synergistic antifungal activity against yeast in the presence of an amphotericin preparation. Flucytosine can be administered orally and has a very useful pharmacokinetic profile (including the ability to penetrate the CNS, eye, and urinary tract). Single-step mutation to resistance is common and is the reason for using amphotericin to protect the flucytosine. Flucytosine has therapeutic effects related to its effects on nucleic 478
acid synthesis. Toxicities include the bone marrow and liver. Its primary therapeutic use is in the treatment of serious cryptococcal and candidal infection. Therapeutic azoles These agents comprise the most important class of new therapeutic, antifungal drugs in the last two decades. Cytochrome P450-dependent 14-α-demethylase is the target of the azoles, causing a fungistatic effect on ergosterol synthesis. The first of the new fungal agents to gain FDA approval, ketoconazole was the first of these drugs to reach the marketplace. It is available only in an oral preparation. The spectrum of activity is attractive; unfortunately, the pharmacokinetic profile is difficult (requires an acid pH in the stomach for absorption). Penetration of the CNS, eye, and urinary tract is unreliable. Hepatic toxicity is common, and it is primarily a drug of historic interest whose major use these days is as a third-line agent for prostate cancer. Itraconazole requires gastric acidity for absorption and penetrates the CNS and urinary tract poorly. Formulation is an important aspect of the drug. Itraconazole in solution with β-hydroxydextrin is absorbed more reliably and completely than the parent drug. A dextrin formulation for parenteral use is now available. Itraconazole is reliably broad spectrum (including aspergillosis, “wrap-up” therapy for yeast and mould infection). Precise delineations of dose and duration are still being determined. Fluconazole is the “best behaved” of the azoles, limited primarily by a spectrum of activity that includes Candida spp. and Cryptococcus neoformans. In addition, it has been shown to be useful as “wrap-up” therapy in the management of C. immitis infection, particularly that involving the CNS. The volume of distribution is quite good, including the CNS, eye, and urinary tract. Fluconazole has excellent bioavailabiliy, with the same dose utilized orally and intravenously. Toxicity is less than with other antifungal drugs, consisting primarily of hepatic dysfunction and skin rashes. Fluconazole’s effect is primarily fungistatic. Therapy with an amphoterocin preparation to gain control, followed by a prolonged course of oral fluconazole, is a commonly used strategy. Voriconazole is a broad-spectrum azole, with useful activity against fluconazole-resistant Candida, Aspergillus, Fusarium, and Pseudallescheria. It is available both orally and parenterally, and should be considered the most effective drug currently available for aspergillosis. In addition to its utility against invasive aspergillosis, it can be useful against colonization syndromes as well, thus extending its range of clinical usefulness. There is also emerging evidence that combination therapy with other classes of anti-Aspergillus drugs may have value. Liver toxicity is more common than with fluconazole and needs to be carefully monitored. Particularly in patients being treated with high-dose intravenous therapy, a variety of transient visual complaints can occur, usually lasting a short period of time. These symptoms do not persist once the drug is discontinued and are thought to represent retinal dysfunction. In most respects this entity resembles the visual disturbances observed in some patients with digitalis toxicity. Posaconazole resembles voriconazole in activity, efficacy, and toxicity, with one additional quality. It appears to be useful, particularly in combination with surgical resection, in the management of zygomycosis. Since there is some
Conclusion
e vidence that zygomycosis is selected for by voriconazole, this property of posaconazole may be quite useful clinically. The full range of clinical uses for this drug is still being defined, as is the relative value of other azoles that are being studied. Echinocandins Echinocandins are potent inhibitors of fungal cell wall synthesis, by means of their effects on β1,3-glucan synthase. These agents bind rapidly to the fungal enzyme, causing rapid cell death of the fungus. The first of these, caspofungin, has been approved and appears to have useful activity against Aspergillus, Candida, some of the endemic fungi, and even Pneumocystis. Cryptococcal infection is not affected by the echinocandins. Whereas the other antifungal drugs exert their effects primarily through effects on ergosterol synthesis and function, thus affecting the fungal cell membrane, the echinocandins inhibit cell wall synthesis. Analogy has been made to the cell wall effects of penicillin in many bacteria. The hypothesis has been put forward that echinocandins are the “penicillins” of the antifungal world, and combination therapy with azoles and/or amphotericin formulations should increase penetration of the azoles and polyenes, and improve further antifungal efficacy. This hypothesis is currently being tested.21,22
drugs to be considered are the those utilized for the other fungal species.
Candidiasis
1. Primary infection of the skin at a site traumatized by an extravasated, intravenous event or pressure dressings contaminated by Rhizopus sporangioconidia. 2. Primary pulmonary infections following inhalation of sporangiospores. 3. Rhinocerebral zygomycosis in which the fungal aerosol establishes disease in the nasal sinuses, with progressive extension into intracranial structures.
Candidiasis is the most common form of fungal infection affecting the transplant recipient. The range of species and consequences of candidal replication are quite broad, ranging from mucocutaneous overgrowth to bloodstream infection and metastatic infection. There are three stages in the pathogenesis of candidal infection. 1. An increase in the Candida load in the gastrointestinal tract, mucocutaneous surfaces, and the female urogenital tract. The driving force is the level of glucose and glycogen at the site. This occurs in the face of broad-spectrum antibacterial therapy and in the setting of diabetes out of control, with the increased level of glucose functioning as an important growth factor. 2. A break in the mucocutaneous integrity at sites of glucose increase will promote bloodstream invasion. 3. Once penetration occurs, the key host defenses against candidal infection are adequate numbers of normally functioning polymorphonuclear leukocytes and intact cell-mediated immunity. Candida albicans and tropicalis are the most likely species to cause clinical disease. However, in the face of person-toperson spread on the hands of medical personnel or exposures to fluconazole without correction of the anatomic abnormality associated with the occurrence of the infection, reinfection with C. glabrata, C. krusei, and other resistant strains causing disease is common. Mucocutaneous infection, urinary tract infection, infection related to drains and catheters (including peritoneal dialysis catheters), and infection related to surgical procedures should be considered for anticandidal preemptive therapy, particularly when surgical manipulation is planned. Preemptive anti-candidal therapy should be considered when surgery is to be carried out in the presence of Candida. Similarly, vascular access devices, drainage catheters, and sites of a heavy microbial burden should also receive antifungal therapy. The
Cryptococcosis Cryptococcus is a ubiquitous organism that has a pulmonary portal of entry. Pulmonary disease, usually minimally symptomatic, is common and usually quite responsive to therapy. The lung findings vary from asymptomatic nodules to pneumonia. Postprimary dissemination via the bloodstream is common, with metastatic seeding of the meninges and/or the brain parenchyma (as well as sites such as the skin and skeletal system). CNS infection is the most important form of cryptococcal infection. Cryptococcal cellulitis may be the first evidence of disseminated infection. Most cases occur more than 6 months post transplant, particularly in patients who have been overimmunosuppressed, the chronic “ne’er do wells.” Therapy is given with an amphotericin preparation plus flucytosine, and then completed with fluconazole.
Zygomycosis (syn. mucormycosis) This is a rapidly progressive fungal infection that causes tissue infarction. This necrotizing infection is observed in the following situations.
The clinical hallmark of zygomycosis is rapidly progressive, necrotizing infection, often with eschar formation in the skin and mucosa overlying involved tissues. Risk factors include acidosis, particularly diabetic ketoacidosis, steroids, overimmunosuppression, and devitalized tissues that can be secondarily infected. Therapy is with posaconazole +/- ablative surgery.
Conclusion The invasive fungal infections remain a major problem for transplant recipients, causing pneumonia and bloodstream infection at a considerable cost and with greater consequences if early diagnosis and aggressive therapy have not been accomplished. There has been a major improvement in the treatment of fungal infection, with there being three separate classes of drugs (lipid-associated amphotericin drugs, antifungal azoles, and echinocandins) that can be utilized. Particularly appealing is the possibility that combination therapy, bringing together different mechanisms of action, will result in even better and more effective therapy. Early diagnosis, as with the galactomannan assay or a PCR-based technique, will improve the therapeutic results. Better diagnostics will also help. High-definition chest CT is proving to have a role in early diagnosis which is an example of utilizing existing technology in an innovative fashion. One word of caution: false-positive galactomannan assays are seen with piperacillin/tazobactam and amoxicillin/ clavulanate up to a week after discontinuing the antibiotics. 479
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient
References 1. Rubin RH. Infection in the organ transplant recipient. In: Rubin RH, Young LS (ed) Clinical Approach to Infection in the Compromised Host, 4th edn. Kluwer Academic/Plenum Publishers, New York, 2002 2. Rubin RH, Ikonen T, Gummert J, et al. The therapeutic prescription for the organ transplant recipient: the linkage of immunosuppression and antimicrobial strategies. Transplant Infect Dis 1: 29-39, 1999 3. Rubin RH. Infectious disease complications of renal transplantation. Kidney Int 44: 221-236, 1993 4. Fishman JA, Rubin RH. Infection in organ transplant recipients. N Engl J Med 338: 1741-1751, 1998 5. Paya C. Fungal infections in solid organ transplantation. Clin Infect Dis 16: 677-688, 1993 6. Hadley S, Karchmer AW. Fungal infections in solid organ transplant recipients. Infect Dis Clin North Am 9: 1045-1059, 1995 7. Rubin RH. The compromised host as sentinel chicken. N Engl J Med 317: 1151-1153, 1987 8. Chu JH, Feudtner C, Heydon K, et al. Hospitalizations for endemic mycoses. A national study. Clin Infect Dis 42: 822-834, 2006 9. Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am 17: 1-24, 2003 10. Levin AS, et al. Candida parapsilosis fungemia associated with implantable and s semi-implantable central venous catheters and the hands of healthcare workers. Diag Micro Infect Dis 30: 243-249, 1998 11. Pfaller MA. Nosocomial candidiasis; emerging species, reservoirs, and modes of transmission. Clin Infect Dis 22(suppl 2): S89-S102, 1996 12. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis. 2007 Update by the Infectious Diseases Society of America. Clin Infect Dis 45(7): 807-825, 2007 13. Kauffman CA. Endemic mycoses: blastomycosis. histoplasmosis, and sporotrichosis. Infect Dis Clin North Am 20: 645-662, 2006 14. Kennedy CC, Limper AH. Redefining the clinical spectrum of chronic pulmonary histoplasmosis. Medicine 86: 252-258, 2007 15. Chapman SW, Bradsher RW Jr, Campbell GD Jr, et al. Practice guidelines for the management of patients with blastomycosis. Clin Infect Dis 30: 679-680, 2000 16. Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guidelines for the treatment of coccidioidomycosis. Clin Infect Dis 30: 658-670, 2000
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17. Pappas PG, Threkeld MG, Bedsole GD, et al. Blastomycosis in immunocompromised patients. Medicine 72: 311-319, 1993 18. Galgiani JN. Coccidioidomycosis: a regional disease of national importance. Rethinking approaches for control. Ann Intern Med 130: 293-298, 1999 19. Stevens DA. Current concepts: coccidioidomycosis. N Engl J Med 332: 1077-1082, 1995 20. Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guidelines for the treatment of coccioidomycosis. Clin Infect Dis 30: 658-670, 2000 21. Dismukes WE. Antifungal therapy: lessons learned over the past 27 years. Clin Infect Dis 42: 1286-1296, 2006 22. Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection. Clin Infect Dis 44: 1289-1297, 2007 23. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients unresponsive to or intolerant of conventional therapy. Clin Infect Dis 44: 2-12, 2007 24. Maschmeyer G, Haas A. Voriconazole: a broad spectrum triazole for the treatment of fungal infection. Future Microbiol 1: 365-385, 2006 25. Maschmeye G, Haas A, Cornerl OA. Invasive asergillosis: epidemiology, diagnosis, and management in immjuncompromised patients. Drugs 67: 1567-1601, 2007 26. Hope WW, Shoham S, Walsh TJ. The pharmacology and clinical use of caspofungin. Expert Opin Drug Metab Toxicol 32: 263-274, 2007 27. Woods G, Miceli MH, Grazziutti ML, et al. Serum Aspergillus galactomannan antigen values strongly correlate with invasive aspergillosis. Cancer 110: 830-834, 2007 28. Vandewoude KH, Vogelaers D. Medical imaging and timely diagnosis of invasive pulmonary aspergillosis. Clin Infect Dis 44: 373-379, 2007 29. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis. Clin Infect Dis 44: 373-379, 2007 30. Verdaguer V, Walsh TJ, Hope W, et al. Galactomannan antigen detection in the diagnosis of invasive aspergillosis. Expert Rev Mol Diagn 7: 21-32, 2007 31. Tanriover MD, Metan G, Altun B, et al. False positivity for Aspergillus antigenemia related to the administration of piperacillin/tazobactam. Eur J Intern Med 16: 489-491, 2005
C h a p ter
21
Fungal infection in the organ transplant recipient Robert H. Rubin
The remarkable success being achieved by organ transplantation today (e.g., >90% 1-year patient and graft survival following cadaveric kidney transplantation) has changed the approach to the care of patients with chronic, progressive organ failure. A few decades ago, transplantation was considered a last desperate therapy, marred by technical complications, systemic infection, rejection, and a broad array of complications of immunosuppression, particularly corticosteroids. Today, we recognize organ transplantation as the most effective means of rehabilitating patients with organ failure of diverse etiologies. This is not to say that all the problems have been solved; rather, an approach has been developed that increases the chances of success. Important principles have been developed that serve as a foundation for clinical efforts.1-3 Effective antimicrobial therapy in the transplant recipient is particularly challenging for a number of reasons. 1. Microbial load is a major determinant of the prognosis for a given patient with infection. The impaired inflammatory response to microbial invasion that is engendered by immunosuppressive therapy commonly results in an occult presentation: signs and symptoms are attenuated until late in the infection; radiologic findings are often more subtle; dermatologic manifestations are dampened so that classic findings are absent and skin lesions are often non-specific. The microbial load is invariably greater in the transplant patient than in the normal host with a similar illness. The blandness of the response to many fungal infections only adds to diagnostic difficulty. Since prognosis is directly related to how quickly the appropriate diagnosis is made and effective therapy prescribed, an aggressive approach to evaluation of the patient is mandatory. CT scan rather than conventional radiography is the appropriate response to chest symptoms and/or minimal findings on conventional radiology; skin lesions as well as chest nodules require biopsy; and unexplained fevers require extensive evaluation.1,3-5 2. A ntimicrobial therapy, particularly antifungal therapy, in the transplant recipient is likewise more complex than in other populations. There are three modes of therapy that need to be considered: prophylactic, therapeutic, and preemptive. Prophylactic therapy is administered to an entire population of uninfected patients when the risk of clinical disease is deemed great enough to justify the intervention. An example is the performance of a transplant in
the face of aerosolization of one of the endemic systemic mycoses. Antifungal prophylaxis provides protection against clinical disease. The therapeutic use of antifungal drugs is the treatment of invasive infection, often due to the failure of prophylactic regimens. Preemptive therapy is utilized when asymptomatic patients are regarded as being at increased risk of invasive infection on the basis of a laboratory or clinical observation. Antimicrobial therapy in transplant patients requires more prolonged therapy than in other patient populations because of the increased microbial burden and the continuing need for immunosuppression. As a result, toxicity is usually greater and antimicrobial resistance may be selected.1,3,5 3. The range of organisms to be considered is far broader than that causing similar clinical presentations in the normal host. In the transplant patient, not only are the usual bacteria (e.g., Staphylococcus aureus, a variety of streptococci, E. coli and other Gram-negative bacilli) and viruses (e.g., influenza, respiratory syncytial virus, and hepatitis B and C) of concern, but more unusual pathogens must be considered. These unusual pathogens include fungi, not only the traditional organisms such as Candida albicans but also opportunistic species such as Aspergillus and Cryptococcus. In addition, there is an increasing problem with what has been termed the “new and emerging” organisms (such fungi as Scedosporium, Fusarium, and the zygomycetes). Uncommon bacterial (Nocardia, Mycobacterial, and pathogenic corynebacterial) and viral infections (e.g., SARS and West Nile virus) add significantly to the management challenges faced by the clinician. On the one hand, the impact of traditional pathogens is greater in this patient population; on the other hand, the effects of newly introduced pathogens will be particularly threatening in transplant patients and other immunosuppressed hosts. They are truly “sentinels” for excess trafficking in potential pathogens in the environment.7 4. There is a direct link between early diagnosis and effective therapy. Indeed, the patient would be well served by considering diagnosis and therapy together as part of an infection management program, one that includes not only antimicrobial therapy but also diagnostics that inform the use of these drugs. Although culture techniques remain the cornerstone of disease management, new approaches such as antigen detection, polymerase chain reaction (PCR) detection of microbial nucleic acids, and newer radiologic 473
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient procedures hold great promise for early diagnosis and the deployment of effective therapy. In contrast, serologic diagnosis (the testing for specific antibodies in the serum), which is measuring the immunologic response to a particular antigen, is far less sensitive and is usually not part of the diagnostic evaluation in immunocompromised patients with active infection. The major application of serologic techniques is prior to transplant when these measurements can help assess the risk of particular infections. The key concept here is to forge the link between early diagnosis and the preventive and therapeutic use of antimicrobials.1,2
Risk of fungal infection in the organ transplant recipient The risk of fungal infection in the organ transplant recipient is determined by the interaction of four factors.
Net state of immunosuppression The net state of immunosuppression is a complex function that is made up of a number of factors; the level of immunosuppressive therapy being administered is the primary determinant but, in addition, other entities contribute to this function: neutropenia, protein calorie malnutrition (and, probably, other metabolic disturbances such as uremia and hyperglycemia); systemic infection with one or more of the immunomodulating viruses (cytomegalovirus (CMV), Epstein–Barr virus, human herpesvirus-6; hepatitis viruses B and C, and the human immunodeficiency virus); and other factors such as immune response genes. The importance of these additional contributors to the net state of immunosuppression is underlined by the following observations: transplant patients with a serum albumin level of <2.5 gm/dl have a 10-fold increase in the incidence of life-threatening infection; 90% of opportunistic infection occurs in the setting of viral infection. For those patients without viral infection, there is a high probability of an excessive environmental hazard being present to account for the invasive infection; that is,viral infection increases the net state of immunosuppression such that the individual is susceptible to invasive infection.1,2,4
Environmental exposures Excessive environmental exposures can occur within the community or in the hospital. In the community, aerosols can be created and inhaled during the course of construction, gardening or farm work. Hospital exposures of importance that can result in invasive fungal infection can be divided into two general categories: domiciliary and non-domiciliary. Domiciliary refers to the acquisition of infection on the ward where the patient is housed, with outbreaks of this type being marked by clustering of cases in time and space. Non-domiciliary exposures occur as a patient travels in the hospital for essential procedures. Exposures of this sort can occur in the halls of the hospital, the operating room, the radiology or bronchoscopy suites and elsewhere. Non-domiciliary outbreaks are not uncommon, with the clue of a possible hazard coming from the diagnosis of infection at a point in time when the net state of immunosuppression 474
should not have been great enough by itself for such infection to occur. Excessive amounts of infectious particles in the potable water and/or the air that is inhaled can produce invasive disease, particularly in the transplant situation in which the cellmediated response to fungal tissue invasion is most affected by the immunosuppressive therapy being administered.5-7 In recent years a growing problem has been the person-toperson spread of azole-resistant Candida infection (both resistant C. albicans and non-albicans ������� Candida strains being spread in this fashion), on the unwashed hands of medical personnel.1,5,7,10,11 The dimorphic fungi (Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum) grow in the soil as a mould composed of a mesh of septate hyphae bearing conidia (the infectious particles) that can be aerosolized when the ground bearing these organs is manipulated during urban renewal projects, “clean-up” efforts, and explorations of sites where the soil is “enriched” with bird and animal droppings (e.g., bat caves, chicken roosts, and beaver habitats). Inhalation of aerosolized conidia will initiate clinical infection in the lungs, with the tissue invasive form being yeast.1,2,8,9,12,13 The clinical consequences of tissue invasion by these organisms can be quite diverse. Primary infection occurs in the first month after exposure. This may be asymptomatic or be associated with a flu-like syndrome. In addition, hypersensitivity manifestations such as erythema multiforme, erythema nodosum, and reactive arthritis are common manifestations of primary infection and the development of immunity in a normal host. In transplant patients, such immune effects are uncommon, whereas progressive primary pneumonia and postprimary dissemination via the bloodstream are common. These dimorphic fungi have a similar epidemiology and pathogenesis: a pulmonary portal of entry after inhalation of the infectious aerosol; an initial host defense response of polymorphonuclear leukocytes and alveolar macrophages as a consequence of the pulmonary invasion; followed by the development of a specific humoral and cell-mediated immune response.1,9,12,13,15,16
Technical or anatomic abnormalities The presence of technical or anatomic abnormalities that lead to undrained fluid collections (blood, urine or bile, and/or lymph), devitalized tissues, and the need for the placement of drainage catheters and other foreign bodies that compromise mucocutaneous surfaces can contribute significantly to the risk of infection. Surgical misadventures, vascular access devices, and the need for prolonged respiratory support can all play a role here. Surgery in a transplant patient is the most unforgiving form of surgery that is encountered, with a surgical misadventure being highly associated with secondary invasive infection.1,2,5-7
Darwinian factors Darwinian factors are now being recognized as important contributors to the pathogenesis of certain infections. The most common example of this phenomenon is when broadspectrum antibacterial therapy has been given in the setting if an anatomic problem that has not been corrected. Candida superinfection is a common result, requiring surgical correction as well as systemic antifungal therapy. Another version of Darwinian influences is when excessive amounts of growth
Clinical timetable for the occurrence of fungal infection in transplant patients
factors are present, thus favoring microbial overgrowth. Thus, excessive amounts of iron can result in zygomycosis, listeriosis, and other life-threatening infections, as well as an increase in the microbial burden in the case of a local staphylococcal wound infection.1,2,6,10,11
infection will be influenced by prophylactic antimicrobial therapy. A not uncommon result when this effort fails is to prolong the incubation period without affecting the incidence. As a general rule, the incubation period may be extended 2–6 months.1,2,4,6
Summary
First month after transplant
Environmental exposures can occur within the community or in the hospital. In the community aerosols can be created and inhaled during the course of construction, gardening or farm work. Moulds such as Aspergillus can cause invasive disease following such exposures. In addition to such opportunistic infections, the endemic mycoses (B. dermatitidis, C. immitis, and H. capsulatum) can have a significant impact on the health of the transplant patient. These dimorphic fungi have a similar epidemiology and pathogenesis. They each are geographically restricted, growing in nature as a mould composed of a mesh of septate hyphae bearing conidia (the infectious particles) that are aerosolized during urban renewal projects, “clean-up” efforts, and explorations of sites where the soil is “enriched” with bird and animal droppings. Inhalation of aerosolized conidia will initiate clinical infection, with the tissue invasive form being yeast. The critical host defense is the cell-mediated response to tissue invasion, just that aspect of host defense most affected by the immunosuppressive drugs required for successful transplantation.9,12,16 Epidemiologic patterns of infection that occur are: primary infection, often with bloodstream dissemination; reactivation infection with the potential for secondary dissemination; and reinfection, again with the possibility of dissemination. Transplant patients are particularly vulnerable to reinfection, due to attenuation of previous immunity by the chronic immunosuppressive therapy.1,2,4 The net state of immunosuppression is a complex function that is made up of a number of factors. For those patients without viral infection, there is a high probability of an excessive environmental hazard that should be identified and corrected as quickly as possible, in order to prevent additional cases.1,2,4,6
There are three major causes of infection in this time period.
Clinical timetable for the occurrence of fungal infection in transplant patients There is an important temporal component to the infections that occur post transplant; that is, different infections occur at a particular time after the transplant procedure and initiation of immunosuppression. Ultimately, the net state of immunosuppression (and the development of infection) is related to sustained therapy, the area under the curve, rather than the daily doses. The point to be emphasized is not that pneumonia can only occur at a specific time but rather that the restricted time period applies to the etiology. The timetable can be useful in the following ways: in helping to generate a differential diagnosis in a patient who presents with a clinical illness that could be a manifestation of invasive infection; as a tool of infection control – exceptions to the timetable demand an explanation; and as the foundation of a variety of preventive strategies. The three time periods that have been defined do not include the impact of prophylaxis. Both CMV and fungal
1. Infection in the recipient that was not eradicated prior to the transplant operation, and may be further exacerbated by surgery and post transplant immunosuppression. Although every patient should be carefully screened for active infection prior to the procedure, particular attention should be paid to those individuals already receiving immunosuppression prior to transplantation. Thus, we have seen patients with conditions such as Crohn’s disease, primary biliary cirrhosis or a cardiomyopathy, in a desperate attempt to avoid transplantation, come to transplant receiving chronic corticosteroids, and with infection due to Pneumocystis or Cryptococcus already present. These infections can be a major problem in the early post transplant period. 2. Infection of donor origin, with bloodstream infection seeding the allograft prior to surgery. Parenchymal infection may contribute to infections such as histoplasmosis and the other endemic fungi in the recipient. 3. The most common infections in this time period are the same wound, pulmonary, vascular access or drainage catheter infections seen in normal hosts undergoing comparable surgery. The prime determinant is the technical skill with which the surgery and perioperative care are carried out. Notable by their absence during this time period are infections with opportunistic fungal pathogens such as Aspergillus. Indeed, when such infection occurs, this should trigger a search for excessive environmental dangers.1,2,4,6
One to six months after transplant In this time period the net state of immunosuppression is particularly high, because of the sustained immunosuppression and the effects of the immunomodulating viruses. As a result, infections such as those due to Aspergillus species can occur in the absence of an unusually intense exposure. The most common cause of febrile syndromes during this period are the herpes group viruses, particularly CMV and human herpesvirus-6. Since these predispose to opportunistic infections such as those caused by fungi, Listeria, and Nocardia, a careful assessment for dual or sequential infection should always be a part of the clinical review once CMV is diagnosed.1,2,4,6
More than six months after transplant In this period the patients may be regarded as fitting into one of two general categories in terms of fungal infection. Approximately 80% of organ transplant patients will have had a good result from their transplant: good allograft function, maintenance immunosuppression, and freedom from viral infection. This group is at minimal risk for invasive fungal infection unless 475
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient an excessive environmental exposure has occurred. Mucocutaneous candidal infection and, uncommonly, asymptomatic pulmonary nodules due primarily to Cryptococcus neoformans are the major fungal concerns. The remaining patients have had a poorer outcome from transplantation: less satisfactory allograft function, too much acute and chronic immunosuppression, and, often, chronic or recurrent viral infection. This group is often characterized as “chronic ne’er do wells.” They are at the greatest risk of any transplant patient for disseminated cryptococcal infection, invasive aspergillosis, and, if the epidemiologic history is appropriate, systemic infection with one of the endemic mycoses.
Fungal infections of particular importance for the organ transplant recipient The endemic mycoses As previously discussed, transplant patients are particularly vulnerable to the endemic mycoses if an exposure has occurred. The salient epidemiologic and clinical characteristics of the different infections in this group of patients are very similar: the organisms are dimorphic, growing in the soil over a limited geographic area as a mould with the infectious particles, the conidia, liberated from the mould in an aerosol following a variety of manipulations of the infected soil. Inhalation of the conidia is the key step in initiating the infection, with a pulmonary portal of entry being characteristic of these organisms. Tissue invasion is accomplished by yeast forms. There is an initial polymorphonuclear leukocyte and alveolar macrophage response to these events, with a subsequent humoral and cell-mediated response. The key host defense is a specific cytotoxic T cell response. The combination of the initial nonspecific inflammatory response with the specific response will limit the extent of the pulmonary infection, as well as access to the bloodstream and systemic infection. In transplant patients the attenuation of the specific immune response engendered by immunosuppressive therapy leads to an increased incidence and severity of progressive pulmonary and disseminated infection, as well as metastatic spread to sites such as the skin, the CNS, bones, and joints.8,9,12-17
Blastomycosis Blastomyces dermatitidis grows as a mould on decaying wood. The geographic distribution of these organisms is similar to that of H. capsulatum (the midwest and southeastern United States). Human infection results following the inhalation of a conidia-laden aerosols. Clinically, pulmonary symptoms (cough, sputum production, chest pain, and dyspnea) predominate. Radiologic findings include non-specific infiltrates and hilar adenopathy. Disseminated infection not uncommonly results in metastatic skin involvement, with large nodular skin lesions that undergo necrosis and fibrosis. Genitourinary and skeletal infection are the other common sites of metastatic spread. Blastomycosis is the least common of the systemic mycoses to infect the transplant recipient. Diagnosis usually requires biopsy for pathologic and cultural examination. Initial treatment usually requires an amphotericin preparation 476
a dministered intravenously, followed by oral itraconazole. The role of newer antifungals is still being defined.
Coccidioidomycosis Coccidioides immitis is a dimorphic fungus which grows as a mesh of septate hyphae bearing the arthoconidia that initiate clinical disease following inhalation of an aerosol laden with these infectious arthroconidia. Within the mammalian host maturation of the arthroconidia into spherules, the definitive tissue pathogen, takes place. The natural habitat of C. immitis is the desert soil of the Lower Sonoran life zone, an area whose climate features hot, dry summers and mild winters with moderate rainfall. Geographic areas that fit this description include the San Joaquin Valley of California, the southwestern United States, northern Mexico, and various sites in Central and South America. The arthroconidia can be so efficient at transmitting the infection that clinically important disease can occur many miles from an endemic area, due to wind or dust storm conditions, or exposure to dust on packages or clothing sent from the endemic sites. Major risk factors for serious clinical disease include the following: intensive immunosuppressive therapy, pregnancy, and non-Caucasian racial status. For example, on moving into an endemic area there is a 5% risk of developing primary infection during the first year of residence, with an additional annual infection rate of 2–3% per year. Dissemination, with a predominance of CNS infection, was noted in 75% of these individuals, with around two-thirds of these dying from this infection.6,8,16-20 A variety of clinical syndromes are associated with C. immitis infection. As previously discussed, primary infection in a nonimmunosuppressed individual will probably cause hypersensitivity reactions; in contrast, in a transplant patient receiving immunosuppressive therapy, the hypersensitivity reactions are uncommon, and progressive pneumonia and/or bloodstream infection due to invasive disease are the rule. The most important manifestation of infection in transplant patients is meningitis. Typically, a diffuse granulomatous meningitis encases the base of the brain, resulting in hydrocephalus and cranial nerve palsies. Headaches and an impaired state of consciousness are common. Vasculitis can occur, resulting in focal neurologic findings, including aphasia, hemianopia, and hemiparesis, aneurysms and subarachnoid hemorrhage. CNS disease caused by this organism can be the first or only evidence of coccidioidomycosis, and vice versa. Other sites of metastatic infection include the skin, the skeleton, and the genitourinary tract. The diagnosis of coccidioidomycosis can be difficult and should be regarded as being in a state of flux. Traditionally, KOH preparations of sputum, scrapings of skin or visceral tissues, or biopsies have yielded the diagnosis under the microscope. Cultures can be performed, but this approach is potentially dangerous if the diagnostic laboratory is inexperienced and/or appropriate protective biohazard equipment is not in place and utilized. Skin tests in immunosuppressed patients may be difficult to interpret. In contrast, rising titers of antibody, especially complement fixing antibody directed against C. immitis, are quite suggestive (although the possibility of cross-reacting antibodies can be seen with blastomycosis and histoplasmosis). Cerebrospinal fluid (CSF) in patients with meningitis usually reveals a lymphocytic pleocytosis, an elevated protein level and a low sugar (hypoglycorrhachia), and
Fungal infections of particular importance for the organ transplant recipient
increased intracranial pressure. Complement fixing antibodies in the CSF are of great diagnostic value. It is quite likely that in the next few years quantitative measurements of specific antigens and/or PCR detection of C. immitis nucleic acids will become the cornerstone of the diagnostic effort. Antifungal chemotherapy for coccidioidomycosis is also in evolution. High-dose amphotericin therapy has been, and continues to be the standard of care. However, because cure is unlikely and relapse to be expected, we advocate a different approach: gain control with amphotericin and then switch to high-dose azole therapy. For this purpose, itraconazole has been used successfully. We prefer fluconazole for this longterm maintenance therapy, because of the greater reliability of absorption, pharmacokinetics, and lesser amounts of interaction with cyclosporine and tacrolimus. Ideally, preemptive fluconazole therapy should be prescribed for transplant patients with a past history of coccidioidomycosis or when the transplant care is being given in an endemic region. Once initiated, the fluconazole should be maintained for an indefinite period.8,16-20
Histoplasmosis Histoplasma capsulatum, the dimorphic fungus, grows well in soil enriched by the droppings of chickens, starlings, and bats. In the United States the center of activity is found in the Ohio and Mississippi river valleys, extending eastward into Virginia and Maryland. The inhalation of aerosolized organisms results in a patchy bronchopneumonia with a neutrophilic inflammatory response. This is followed by the development of specific cell-mediated immunity and, finally, by the development of epithelioid granuloma with Langhans’ type giant cells, easily recognized on microscopic examination of the lung. Because of the impaired cell-mediated immune responses in transplant patients, systemic dissemination and/or progressive primary pneumonia are common, with infected mononuclear cells being efficient carriers of the infection to distant sites. Sites of extensive involvement are those organs with large numbers of reticuloendothelial cells: liver, spleen, lymph nodes, bone marrow, gut, and adrenal glands. In addition to these sites, mucocutaneous and CNS infection are not uncommon.5,6,8,9 Data presented by Wheat and his colleagues in Indianapolis, which is in the heart of the histoplasmosis belt, have shown that clinical disease occurs in 2–4% of renal transplant recipients, with a high percentage of these patients having disseminated disease. During an urban epidemic, this rate can exceed 10–15%. Although reactivation disease with secondary dissemination can occur, most such cases appear to be due to new exposures. Most clinical cases occur more than 6 months after transplant, particularly in those patients who have required greater than normal immunosuppression. Dissemination is the rule, with CNS infection, both parenchymal and meningeal, occurring in as many as one-quarter of cases. The clinical presentation of histoplasmosis is essentially identical to that of coccidioidomycosis: subacute onset of fever, respiratory complaints, metastatic infection, headache, and altered consciousness.8,9,12,14
Opportunistic fungal infection Aspergillosis Of the more than 200 species of Aspergillus, 95% of the clinical disease is caused by three species (A. fumigatus, A. flavus, and A. niger, with an occasional human case caused by
A. nidulans, A.terreus, A. oryzae, and A. versicolor). These organisms are ubiquitous in the environment and are particularly likely to cause infection in transplant patients in nosocomial or community settings in which construction activities result in the creation of an aerosol laden with Aspergillus conidia. There are several distinct clinical syndromes that can be produced following inhalation of the infectious aerosol.1,2,4 1. Hypersensitivity syndromes, including both asthma and extrinsic allergic alveolitis. 2. Colonization syndromes, in which the formation of fungal balls or mycetomas occurs in previously injured sinuses and, more commonly, in pulmonary cavities or sites of bronchiectasis. These fungal balls tend to cause irritation and inflammation. Life-threatening hemorrhage from the sites of the fungal balls can also occur. 3. Allergic bronchopulmonary aspergillosis is a clinical entity that combines aspects of both the hypersensitivity and colonization syndromes. Colonization of the tracheobronchial tree, an irritative cough, the appearance of “brown bits” in the sputum, and fleeting pulmonary infiltrates have been well described, including an 80% response to corticosteroids. 4. Invasive aspergillosis is the key response to this problem. Invasive aspergillosis is potentiated by steroids and/or neutropenia, and occurs only in patients who are significantly immunocompromised and/or exposed to a major environmental hazard. The consequences of invasive aspergillosis in this patient population are related to the vascular invasion that occurs: hemorrhage, infarction, and metastases. In a transplant patient, colonization with Aspergillus significantly increases the risk of subsequent invasion. 5. Semiinvasive aspergillosis is an uncommon entity in which true immunocompromised is not present but subtle findings of hyperglycemia, liver disease, influenza, etc. are present and are thought to be associated with the slow progression of this necrotizing process. Vascular invasion is a minor part of this syndrome. Surgical ablation under cover with an azole drug appears to be the treatment of choice. Other associations that merit comment include the presence of Aspergillus in marijuana, which can lead to invasive disease. Direct inoculation of damaged skin (e.g., vascular access sites, burns, and sites of inoculation) can likewise require treatment. In lung transplant recipients two additional forms of Aspergillus infection have been noted: infection of the suture line, with subsequent necrosis and disruption, and tracheobronchial disease. Invasive aspergillosis, then, primarily occurs in situations of poor leukocyte function or sustained exposure to steroids. However, even patients whose net state of immunosuppression is minimal can develop invasive aspergillosis if the environmental exposure is great enough. An important corollary to this observation is that a single case of invasive aspergillosis occurring in the first month post transplant (a “golden period” during which opportunistic infection only occurs under conditions of unusually intense environmental exposure) should trigger a search for environmental hazards before more cases occur.1,2,4-6 Whatever the portal of entry, blood vessel invasion is the hallmark of invasive aspergillosis, resulting in the three 477
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient characteristics of this entity: tissue infarction, hemorrhage, and metastatic spread through the cardiovascular system. Of all the Aspergillus species, A. fumigatus, A. flavus, and A. niger account for virtually all cases, with A. fumigatus causing the majority of these.1,2,4-6 Clinically, invasive aspergillosis of the lungs, the most common presentation of invasive disease, can occur as the primary event or as a superinfection after pulmonary injury due to virus or bacteria, or pulmonary infarction. In as many as 50% of cases, metastatic spread has already occurred by the time of diagnosis, and a site of metastasis may be the first presentation of invasive disease. The typical radiologic finding of invasive aspergillosis of the lungs is focal lung disease, with either a nodule or a consolidation being present, often with cavitation. Unlike the patient with leukemia and aspergillosis, halo signs and air crescent signs are uncommon in organ transplant patients. Specific diagnosis requires a biopsy procedure. Other diagnostic approaches such as the galactomannan assay appear to be quite promising. If the early promise is confirmed, then early preemptive therapy will become an important part of patient management.1,2,4-6 The traditional view of Aspergillus syndromes is that there is little overlap; that is, a colonization syndrome never turns invasive or allergic bronchopulmonary disease does not turn invasive. It is now clear that on occasion there is “overlap” “or crossover.” The availability of voriconazole now makes it possible to treat any evidence of invasive disease and, in many patients, avoid surgery. Combining voriconazole with surgery is also a useful strategy, preventing complications of surgical manipulation.1,2,4 The standard of care for invasive disease due to aspergillosis has long been a prolonged course of intravenous therapy. Sustained therapy of this sort was rendered difficult by the toxicities of this regimen: an acute infusion toxicity, with cytokine release, fever, rigors and malaise, chronic, progressive renal toxicity. Fortunately, there has been a major advance in the availability of alternative antifungal drugs.21-31 Lipid-associated amphotericin B products There are now three approved lipid-associated amphotericin products, whose use is approved by the Food and Drug Administration. The use of these drugs is clearly associated with a striking decrease in toxicity and a greatly increased cost. Issues such as optimal dose and duration and relative effectiveness are still being assessed. At present, a common strategy is to initiate therapy with conventional amphotericin and then switch to a lipid compound when the toxicity becomes evident, but is easily reversible. Amphotericin B, a polyene antifungal, acts by binding to fungal membrane sterols (most notably ergosterol) and causing a significant increase in fungal cell permeability, resulting in leakage of intracellular contents and cell death. Flucytosine Flucytosine is mentioned here because it can only be used in conjunction with amphotericin. It has synergistic antifungal activity against yeast in the presence of an amphotericin preparation. Flucytosine can be administered orally and has a very useful pharmacokinetic profile (including the ability to penetrate the CNS, eye, and urinary tract). Single-step mutation to resistance is common and is the reason for using amphotericin to protect the flucytosine. Flucytosine has therapeutic effects related to its effects on nucleic 478
acid synthesis. Toxicities include the bone marrow and liver. Its primary therapeutic use is in the treatment of serious cryptococcal and candidal infection. Therapeutic azoles These agents comprise the most important class of new therapeutic, antifungal drugs in the last two decades. Cytochrome P450-dependent 14-α-demethylase is the target of the azoles, causing a fungistatic effect on ergosterol synthesis. The first of the new fungal agents to gain FDA approval, ketoconazole was the first of these drugs to reach the marketplace. It is available only in an oral preparation. The spectrum of activity is attractive; unfortunately, the pharmacokinetic profile is difficult (requires an acid pH in the stomach for absorption). Penetration of the CNS, eye, and urinary tract is unreliable. Hepatic toxicity is common, and it is primarily a drug of historic interest whose major use these days is as a third-line agent for prostate cancer. Itraconazole requires gastric acidity for absorption and penetrates the CNS and urinary tract poorly. Formulation is an important aspect of the drug. Itraconazole in solution with β-hydroxydextrin is absorbed more reliably and completely than the parent drug. A dextrin formulation for parenteral use is now available. Itraconazole is reliably broad spectrum (including aspergillosis, “wrap-up” therapy for yeast and mould infection). Precise delineations of dose and duration are still being determined. Fluconazole is the “best behaved” of the azoles, limited primarily by a spectrum of activity that includes Candida spp. and Cryptococcus neoformans. In addition, it has been shown to be useful as “wrap-up” therapy in the management of C. immitis infection, particularly that involving the CNS. The volume of distribution is quite good, including the CNS, eye, and urinary tract. Fluconazole has excellent bioavailabiliy, with the same dose utilized orally and intravenously. Toxicity is less than with other antifungal drugs, consisting primarily of hepatic dysfunction and skin rashes. Fluconazole’s effect is primarily fungistatic. Therapy with an amphoterocin preparation to gain control, followed by a prolonged course of oral fluconazole, is a commonly used strategy. Voriconazole is a broad-spectrum azole, with useful activity against fluconazole-resistant Candida, Aspergillus, Fusarium, and Pseudallescheria. It is available both orally and parenterally, and should be considered the most effective drug currently available for aspergillosis. In addition to its utility against invasive aspergillosis, it can be useful against colonization syndromes as well, thus extending its range of clinical usefulness. There is also emerging evidence that combination therapy with other classes of anti-Aspergillus drugs may have value. Liver toxicity is more common than with fluconazole and needs to be carefully monitored. Particularly in patients being treated with high-dose intravenous therapy, a variety of transient visual complaints can occur, usually lasting a short period of time. These symptoms do not persist once the drug is discontinued and are thought to represent retinal dysfunction. In most respects this entity resembles the visual disturbances observed in some patients with digitalis toxicity. Posaconazole resembles voriconazole in activity, efficacy, and toxicity, with one additional quality. It appears to be useful, particularly in combination with surgical resection, in the management of zygomycosis. Since there is some
Conclusion
e vidence that zygomycosis is selected for by voriconazole, this property of posaconazole may be quite useful clinically. The full range of clinical uses for this drug is still being defined, as is the relative value of other azoles that are being studied. Echinocandins Echinocandins are potent inhibitors of fungal cell wall synthesis, by means of their effects on β1,3-glucan synthase. These agents bind rapidly to the fungal enzyme, causing rapid cell death of the fungus. The first of these, caspofungin, has been approved and appears to have useful activity against Aspergillus, Candida, some of the endemic fungi, and even Pneumocystis. Cryptococcal infection is not affected by the echinocandins. Whereas the other antifungal drugs exert their effects primarily through effects on ergosterol synthesis and function, thus affecting the fungal cell membrane, the echinocandins inhibit cell wall synthesis. Analogy has been made to the cell wall effects of penicillin in many bacteria. The hypothesis has been put forward that echinocandins are the “penicillins” of the antifungal world, and combination therapy with azoles and/or amphotericin formulations should increase penetration of the azoles and polyenes, and improve further antifungal efficacy. This hypothesis is currently being tested.21,22
drugs to be considered are the those utilized for the other fungal species.
Candidiasis
1. Primary infection of the skin at a site traumatized by an extravasated, intravenous event or pressure dressings contaminated by Rhizopus sporangioconidia. 2. Primary pulmonary infections following inhalation of sporangiospores. 3. Rhinocerebral zygomycosis in which the fungal aerosol establishes disease in the nasal sinuses, with progressive extension into intracranial structures.
Candidiasis is the most common form of fungal infection affecting the transplant recipient. The range of species and consequences of candidal replication are quite broad, ranging from mucocutaneous overgrowth to bloodstream infection and metastatic infection. There are three stages in the pathogenesis of candidal infection. 1. An increase in the Candida load in the gastrointestinal tract, mucocutaneous surfaces, and the female urogenital tract. The driving force is the level of glucose and glycogen at the site. This occurs in the face of broad-spectrum antibacterial therapy and in the setting of diabetes out of control, with the increased level of glucose functioning as an important growth factor. 2. A break in the mucocutaneous integrity at sites of glucose increase will promote bloodstream invasion. 3. Once penetration occurs, the key host defenses against candidal infection are adequate numbers of normally functioning polymorphonuclear leukocytes and intact cell-mediated immunity. Candida albicans and tropicalis are the most likely species to cause clinical disease. However, in the face of person-toperson spread on the hands of medical personnel or exposures to fluconazole without correction of the anatomic abnormality associated with the occurrence of the infection, reinfection with C. glabrata, C. krusei, and other resistant strains causing disease is common. Mucocutaneous infection, urinary tract infection, infection related to drains and catheters (including peritoneal dialysis catheters), and infection related to surgical procedures should be considered for anticandidal preemptive therapy, particularly when surgical manipulation is planned. Preemptive anti-candidal therapy should be considered when surgery is to be carried out in the presence of Candida. Similarly, vascular access devices, drainage catheters, and sites of a heavy microbial burden should also receive antifungal therapy. The
Cryptococcosis Cryptococcus is a ubiquitous organism that has a pulmonary portal of entry. Pulmonary disease, usually minimally symptomatic, is common and usually quite responsive to therapy. The lung findings vary from asymptomatic nodules to pneumonia. Postprimary dissemination via the bloodstream is common, with metastatic seeding of the meninges and/or the brain parenchyma (as well as sites such as the skin and skeletal system). CNS infection is the most important form of cryptococcal infection. Cryptococcal cellulitis may be the first evidence of disseminated infection. Most cases occur more than 6 months post transplant, particularly in patients who have been overimmunosuppressed, the chronic “ne’er do wells.” Therapy is given with an amphotericin preparation plus flucytosine, and then completed with fluconazole.
Zygomycosis (syn. mucormycosis) This is a rapidly progressive fungal infection that causes tissue infarction. This necrotizing infection is observed in the following situations.
The clinical hallmark of zygomycosis is rapidly progressive, necrotizing infection, often with eschar formation in the skin and mucosa overlying involved tissues. Risk factors include acidosis, particularly diabetic ketoacidosis, steroids, overimmunosuppression, and devitalized tissues that can be secondarily infected. Therapy is with posaconazole +/- ablative surgery.
Conclusion The invasive fungal infections remain a major problem for transplant recipients, causing pneumonia and bloodstream infection at a considerable cost and with greater consequences if early diagnosis and aggressive therapy have not been accomplished. There has been a major improvement in the treatment of fungal infection, with there being three separate classes of drugs (lipid-associated amphotericin drugs, antifungal azoles, and echinocandins) that can be utilized. Particularly appealing is the possibility that combination therapy, bringing together different mechanisms of action, will result in even better and more effective therapy. Early diagnosis, as with the galactomannan assay or a PCR-based technique, will improve the therapeutic results. Better diagnostics will also help. High-definition chest CT is proving to have a role in early diagnosis which is an example of utilizing existing technology in an innovative fashion. One word of caution: false-positive galactomannan assays are seen with piperacillin/tazobactam and amoxicillin/ clavulanate up to a week after discontinuing the antibiotics. 479
S E C T I O N T H R E E CLINICAL SYNDROMES AND ORGAN SYSTEMS Fungal infection in the organ transplant recipient
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