fungal infections in the recipients of solid organ transplantation

Fungal infections in the recipientsof solid organ transplantation

Nina Singh, MDInfectious Disease Section, Veterans Affairs Medical Center and

University of Pittsburgh, Thomas E. Starzl Transplantation Institute,

University Drive C, Pittsburgh, PA 15240, USA

The advent of effective antibacterial and antiviral prophylactic andtherapeutic strategies has led to the emergence of opportunistic mycoses asa principal cause of infection-related mortality in organ transplant recipients.Candida and Aspergillus species have accounted for most invasive fungalinfections in organ transplant recipients. Epidemiologic trends within the lastdecade, however, are notable for the emergence of mycelial fungi other thanAspergillus as increasingly important pathogens in these patients. This articlereviews the epidemiology, clinical manifestations, pathogenetic basis, diag-nosis, and management of invasive fungal infections after organ transplan-tation in context of emerging trends and new developments in these areas.

Epidemiology and risk factors

The frequency of fungal infections, the predilection toward specific fungalpathogens, and the time of onset of infection differ for various types of solidorgan transplants. Unique risk factors and the degree of net immunosup-pression likely account for the variability in aforementioned epidemiologiccharacteristics. Although Candida infections occur most frequently in liver,pancreas, and small bowel transplant recipients, the impact of invasiveaspergillosis is greatest in context of lung and liver transplantation.

Aspergillus and Candida infections

Liver transplant recipientsInvasive fungal infections have been reported in 5% to 42% of the liver

transplant recipients, with Candida spp accounting for 62% to 83% of the

Infect Dis Clin N Am 17 (2003) 113–134

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fungal infections [1–4]. The incidence of invasive candidiasis after livertransplantation is strongly influenced by surgical factors, including technicalcomplexity of the surgery [2,5–7]. Prolonged operation time, greater trans-fusion requirements, Roux-en-Y biliary anastomosis, retransplantation, andbleeding complications requiring reoperation have been shown to confera higher risk of invasive candidiasis in liver transplant recipients [2,5,7,8].

In the last decade, however, significant technical developments in trans-plantation surgical practices have occurred. Liver transplantation can nowbe performed with transfusion of 10 or fewer units, with up to 30% of theoperations requiring no blood transfusions [9,10]. Biliary anastomoses with-out stents or T tubes have led to a striking reduction in the rate of biliarycomplications [11]. Early endoscopic diagnostic and therapeutic interven-tions have further curtailed the need for repeat abdominal surgeries [9].Finally, corticosteroid-sparing or regimens containing low-dose cortico-steroid increasingly are being used for after organ transplantation.

Temporal trends in invasive fungal infections were assessed in contextof evolution in liver transplantation practices, technical developments, andother risk factors in a recent study [12]. A significant decline in the opera-tion time (P = .03), intraoperative transfusion requirements (P = .0001),cold ischemic time (P < .0001), use of Roux-en-Y biliary anastomosis(P = .0015), rate of biopsy-proved rejection (P < .0001), and retransplan-tation (P = .05) were documented over the last decade. Over the same timeperiod, a decline in the incidence of invasive candidiasis (P = .015) hadoccurred even in the absence of systemic antifungal prophylaxis [12].

In another study in liver transplant recipients [13], the frequency ofinvasive fungal infections declined from 18% between 1983 and 1992, to9% between 1993 and 1997. Renal failure, transfusion requirements, retrans-plantation, Roux-en-Y duct anastomosis, and fungal colonization wereidentified as risk factors for invasive fungal infections. A total of 82% ofpatients before 1992, but only 10% since then, had the aforementioned riskfactors for invasive fungal infections [13].

A worrisome trend, however, largely paralleling the observations innontransplant and hematopoietic stem cell transplant recipients, is the risingincidence of non-albicans Candida spp and azole resistance in Candida inliver transplant recipients [14]. A multicenter, case-controlled study ofinvasive candidiasis in liver transplant recipients documented that one thirdof Candida infections in liver transplant recipients are now caused by non-albicans species and that prior fluconazole use was significantly morefrequent in the cases as compared with the controls [15].

Invasive aspergillosis has been documented in 1% to 8% of the livertransplant recipients [16,17]. Aspergillus infections in liver transplantrecipients are notable for their early occurrence, with most infectionsoccurring within the first month after transplantation. Virtually all livertransplant recipients with invasive aspergillosis have evidence of significanthepatic or renal dysfunction [16]. Fulminant hepatic failure, as an indication

114 N. Singh / Infect Dis Clin N Am 17 (2003) 113–134

for transplantation, was associated with a higher risk of invasive fungalinfections, including aspergillosis after liver transplantation [18]. Approx-imately one fourth of the cases of invasive aspergillosis have occurred afterretransplantation [19].

Renal dysfunction, particularly requirement of dialysis, has been shownto portend a 15- to 21-fold greater risk for invasive fungal infections,including aspergillosis, in liver transplant recipients [19]. In the earlierstudies, use of OKT3 monoclonal antibodies and cytomegalovirus (CMV)infection were reported as significant risk factors for invasive aspergillosisin liver transplant recipients [2,20]. Use of OKT3 has declined substantiallyin the current immunosuppressive era, and effective antiviral prophylacticstrategies have led to a decrease in the rates of CMV infection in livertransplant recipients. Other immunomodulatory viruses (eg, human herpes-virus-6 [HHV-6]) have been noted to emerge as novel risk factors for fungalinfections after liver transplantation [21,22].

Lung transplant recipientsInvasive fungal infections occur in 15% to 35% of the lung transplant

recipients, with Aspergillus spp accounting for nearly one half of these[23–27]. Airway colonization with Aspergillus without invasive disease hasbeen documented in approximately 23% of the lung transplant recipients(Table 1). Up to 4% of the patients may develop tracheobronchitis and 6%to 8% invasive pulmonary or disseminated aspergillosis.

Tracheobronchitis is an entity observed uniquely in lung transplantrecipients [28]. Characterized by endobronchial lesions ranging from mildbronchitis with pseudomembranes to ulcers, tracheobronchitis can progressto locally invasive disease. Lesions in the vicinity of or involving the anas-tomotic site can result in fatal bronchopleural fistulas. Bronchial anasto-motic site because of transient devascularization is uniquely susceptible toischemic injury, necrosis, and potentially infection with Aspergillus.

Although airway colonization with Aspergillus is associated with a lowpositive predictive value for invasive aspergillosis, it portends a higher riskfor subsequent invasive infection. Patients with airway specimen culturespositive for Aspergillus within 6 months of lung transplantation were 11-foldmore likely to develop invasive aspergillosis [27].

The median time to onset of Aspergillus infections in lung transplantrecipients is 120 days; 49% and 68% of the infections have occurred within3 and 6 months of lung transplantation, respectively [6]. Risk factorsfor invasive aspergillosis in lung transplant recipients include CMV infec-tion, obliterative bronchitis, rejection, and augmented immunosuppression[16,29].

Up to 86% of the lung transplant recipients can be colonized withCandida spp Locally invasive mucocutaneous infections, pneumonia, media-stinitis, and less frequently disseminated infection are the predominantmanifestations of Candida infections in these patients [23]. Requirement of

115N. Singh / Infect Dis Clin N Am 17 (2003) 113–134

Table

1

Epidem

iologic

characteristics

of

Asp

erg

illu

sinfectionsin

organtransplantrecipients

Typeofrange

(mean)

Incidence

ofinvasive

aspergillosis,%

Incidence

ofcolonization

with

Asp

erg

illu

s,%

mean

(range)

Tim

eof

onset(d)

Proportionofinfections

causedbydisseminated

aspergillosis(%

)

Mortality,

%rate

Liver

1–8(2)

0.5

17d(6–1197d)

50–60

87

—

Lung

3–14(6)

23

120(4–1410)

15–20

68

Heart

1–15(5.2)

NA

45(12–365)

20–35

78

Kidney

0.9–4(.7)

1.7

82(20–801)

9–36

77

Pancreas

1.1–2.9

(1.3)

NA

NA

NA

100

Smallbowel

0–3.6

(2.2)

NA

NA

NA

100

NA,notavailable.


extracorporeal membrane oxygenation in the period immediately after lungtransplantation has been associated with a higher rate of invasive fungalinfections, including candidiasis [30].

Renal transplant recipientsNinety percent to 95% of the invasive fungal infections in renal

transplant recipients are caused by Candida spp Candidiasis in thesepatients is limited largely to the genitourinary tract with disseminatedinfection occurring in fewer than 5% of the patients. A recent survey of33,420 renal transplant recipients in the United States renal data systemdocumented diabetes, prolonged pretransplant dialysis, rejection, andtacrolimus immunosuppression to be risk factors for fungal infections inthese patients [31]. In the absence of graft failure requiring reinstitution ofhemodialysis or intense immunosuppressive therapy, invasive aspergillosisoccurs infrequently in renal transplant recipients [31].

Pancreas transplant recipientsAlthough invasive aspergillosis occurs infrequently, infections caused

by Candida spp are common in pancreas transplant recipients. Intra-abdominal abscesses, deep wound, and surgical site infections caused byCandida occur in 7% to 14% of the pancreas transplant recipients and havebeen associated with significantly poorer allograft and patient survival[32,33]. Risk factors for Candida infections in these patients include donorage; enteric versus bladder drainage; pancreas after kidney transplantation(as opposed to pancreas transplantation alone); preoperative peritonealdialysis; and pancreatic retransplantation [6].

Heart transplant recipientsMost invasive fungal infections in heart transplant recipients are caused

by Aspergillus spp Invasive aspergillosis is second only to CMV as theforemost cause of pneumonia in heart transplant recipients [34]. Aspergillusinfections occur on an average of 35 days after heart transplantation.

Small bowel transplant recipientsInvasive fungal infections have been reported in 40% to 59% of the small

bowel transplant recipients; most of these are caused by invasive candidiasis[35]. Disruption in the integrity of the gastrointestinal tract, requirement ofrelatively higher immunosuppression, and an unusually high incidence ofCMV infection in these patients may account for a higher incidenceof Candida infections in small bowel transplant recipients.

Mycelial fungi other than Aspergillus

Traditionally, invasive mycelial infections in liver transplant recipientshave been almost exclusively caused by Aspergillus spp A prospective,


multicenter study has documented that fungi other than Aspergillus nowaccount for 37% of all mold infections and for 43% of all deaths in organtransplant recipients with mold infections [36]. Mortality in patients withinfections caused by mycelial fungi other than Aspergillus exceeded thatcaused by invasive aspergillosis [36].

Most non-Aspergillus mycelial fungal infections in organ transplantrecipients are caused by phaeohyphomycoses or dematiaceous fungi (dark-pigmented fungi) and less frequently by hyaline molds (eg, Fusarium,Pseudallescheria boydii, and Scedosporium prolificans). The median time toonset of phaeohyphomycoses in a review was 22 months (range 55 days to 6years) [37]. Sixty-two percent of the cases occurred in retransplantrecipients. Overall mortality in organ transplant recipients with phaeohy-phomycosis was 18%; 57% of the patients with systemic invasive infectionsas compared with 7% of those with cutaneous soft tissue or joint infectionsdied [37]. Although infections caused by Fusarium are the third mostcommon fungal infection in bone marrow transplant recipients, they arerare in organ transplant recipients [38].

Infections caused by zygomycoses occur a median of 2 months post-transplant with 80% of the cases occurring within 6 months of trans-plantation [39]. Most zygomycotic infections are of the rhinocerebral form.Overall, 76% of the organ transplant recipients with zygomycoses had priordiabetes or had received augmented immunosuppression, mainly in theform of corticosteroids for rejection. Eleven percent of the cases haveoccurred after retransplantation. Mortality in organ transplant recipientswith zygomycosis was 56%; the mortality rate was 50% for patients withrhinocerebral disease and 0% for those with pulmonary or cutaneouszygomycosis [39].

Geographically restricted or endemic fungi

In endemic regions, about 0.5% of renal transplant recipients have beenshown to develop overt histoplasmosis [40]. During an outbreak associatedwith construction activity near a hospital in Indianapolis, however, theprevalence of disseminated Histoplasma infection rose to 2.1% [41].Occasional cases of H capsulatum infection have occurred in nonendemicregions or outside the United States. The median time to onset is 6 to 15months after transplantation [40,41]. In endemic areas, primary infection isthought to be the etiology of disease. In contrast, in nonendemic regions,reactivation of latent disease with subsequent hematogenous spread is morelikely. Most patients with histoplasmosis have not had an augmentation inimmunosuppression before the onset of infection.

The frequency of overt Coccidioidomycosis immitis infection in solid-organ transplant recipients in an endemic region (eg, Arizona) is about 3%per year, with an overall prevalence of 4.5% for heart transplant recipientsand 6.9% for renal transplant recipients [42,43]. In liver transplant recip-


ients in Los Angeles, 0.6% developed coccidioidomycosis [44]. The mostlikely time to develop coccidioidomycosis is 2 to 6 months after transplanta-tion. Blastomycosis is observed infrequently in transplant recipients, withfewer than 10 cases having been reported [45]. Cases have occurred outsideof known endemic regions.

Cryptococcus neoformans

Cryptococcus neoformans infections have been reported in 2.8% and up to5.3% of the organ transplant recipients [46–48] (Table 2). The overallincidence is 2.4% in liver, 2% in lung, 3% in heart, and 2.8% in renaltransplant recipients. Cryptococcosis occurs a mean of 1.6 years aftertransplantation; however, cases have been documented as early as 2 daysand as late as 12 years after transplantation. Forty-one percent of theinfections have occurred within the first year of transplantation [48]. Thetime to onset varies significantly for different types of organ transplantrecipients. The median time to onset after transplantation was 35 months forrenal, 25 months for heart, 8.8 months for liver, and 3 months for lungtransplant recipients [48]. Renal transplant recipients are generally lessimmunosuppressed than other organ transplant recipients, which could haveaccounted for the later occurrence of cryptococcosis in these patients ascompared with other organ transplant recipients [48]. Although C neofor-mans is generally not considered geographically restricted fungi, patientsfrom the northeastern United States developed cryptococcosis significantlyearlier after transplantation than other patients [49]. Overall, mortality ratein transplant recipients with cryptococcal infection is 42%. Mortality ratewas 49% in patients with central nervous system (CNS) involvement; 22%in those with pulmonary involvement; and 21% in patients with skin, skinsoft tissue, or osteoarticular involvement [48].

Pathogenesis

Defects in the function or number of the cells of the innate immunesystem (eg, neutrophils and macrophages) have long been recognized as

Table 2

Epidemiologic characteristics of fungi other than Candida and Aspergillus species in organ

transplant recipients

Fungal infection

Incidence %,

mean (range)

Time to onset

mean (range)

Mortality

rate (%)

Cryptococcosis 2.8 (0.3–5.3) 1.6 y (2 d–12 y) 42

Dematiaceous fungi <1 11 mo (55 d–6 y) 18

Zygomycoses <1 60 d (5 d–8 y) 56

Fusariosis <1 9 mo (14 d–5 y) 33

Histoplasmosis <1 16 mo (84 d–14 y) 40

Coccidioidomycosis <1 8 wk (4 wk–78 mo) 50

Data from Refs. [38,39,44,48].


predisposing factors for invasive aspergillosis. More recently, it has beenshown that host defense against Aspergillus may also be mediated, at leastin part, through adaptive immune responses of T lymphocytes [50,51].Whereas T-helper (Th1) responses (eg, tumor necrosis factor-a, interferon-c,and interleukin-12) were shown to confer protection against Aspergillus, Th2responses (eg, interleukin-4 and -10 productions) have been associated withdisease progression [50,51].

Increased propensity to Aspergillus infections in transplant recipients mayresult from defects in innate, adaptive, or both components of the hostdefense. Although corticosteroids have a number of nonspecific anti-inflam-matory effects (eg, inhibition of leukocyte immigration) they also inhibittranscription of several cytokines, and interferon-c–dependent expressionof adherence molecules. Corticosteroids significantly impair macrophagekilling of Aspergillus spores and neutrophil-mononuclear cell killing ofAspergillus hyphae and is a principal component of the immunosuppres-sive regimen predisposing to invasive fungal infections. The primary im-munosuppressive agents, cyclosporine and tacrolimus, exert their majortherapeutic effect by inhibiting T-cell activation and transcription of inter-leukin-2, interleukin-3, and interferon-c; a differential inhibition of T-helperover T-suppressor cells is observed [52,53]. Potential targets for biologicimmunosuppressive agents (eg, antilymphocyte globulins and OKT3 mono-clonal antibodies) include macrophages, CD4+ T-cell subsets, and CD8+

cells. These drugs are highly potent immunosuppressive agents and a greaterrisk for opportunistic mycoses (eg, Aspergillus and Pneumocystis carinii in-fections) with their use has been amply documented [5,54].

The pathogenesis of Candida infections varies for different types of organtransplant recipients. Most cases of candidiasis in liver transplant recipientsarise from endogenous gastrointestinal colonization. Translocation acrossthe gut mucosa, manipulation of the gastrointestinal tract, and impairedhepatic reticuloendothelial function are among the key factors predispos-ing these patients to invasive candidiasis. In pancreas transplant recipients,a high incidence of urinary colonization caused by diabetes and nonacidicenvironment in the bladder created by exocrine pancreatic secretionsfacilitates Candida colonization. Liberation of digestive enzymes into thesurgical fossa that may provoke inflammation and necrosis and an inherentpredisposition of pancreas to ischemia caused by its low vascularity provideideal growth conditions for Candida [33]. Defective granulocyte killing ofCandida in diabetics may further accentuate the susceptibility to candidiasis.Most Candida infections in lung and heart-lung transplant recipients resultfrom endogenous or donor colonization of the trachea [23].

A number of immunomodulatory and immunosuppressive viruses (eg,CMV and the novel herpesvirus HHV-6) have been shown to facilitatesuperinfections with opportunistic fungal infections [21,22,55]. CMV-induced immunosuppression is believed to result from CMV-inducedproduction of suppressive cytokines (eg, transforming growth factor-b),


which may alter lymphocyte and macrophage function. Impaired immunitybecause of CMV infection is not confined to the period in which CMVoccurs, but may persist for several months [56].

The HHV-6 was shown to be an independently significant predictor ofinvasive fungal infections in two studies in liver transplant recipients [21,22].Patients with HHV-6 viremia had eightfold greater risk of developing aninvasive fungal infection than those without it [22]. The propensity ofHHV-6 to predispose to fungal infections is proposed to result from uniquecell tropism and other biologic characteristics of HHV-6, including inhibi-tion of mitogen-driven proliferative response of both CD4+ and CD8+

T lymphocytes. Additionally, HHV-6 is a potent inducer of immuno-modulatory cytokines, and has been associated with functional defects ofphagocytes.

Clinical manifestations

Invasive aspergillosis

Up to 90% of the organ transplant recipients with invasive aspergillosishave pulmonary involvement, with CNS lesions occurring in 10% to 50%[17,19]. CNS aspergillosis presents most frequently as an alteration inmental status, which may be rapidly progressive in onset. Seizures havebeen reported in 41% of the patients [1,17]. Focal neurologic deficit orsymptoms are less common, and were observed in 27% of the patients withCNS aspergillosis in one study and 32% in another [57]. Meningismusoccur rarely; however, leptomeningeal involvement or subarachnoid hemor-rhage secondary to rupture of the mycotic aneurysm may be associatedwith meningismus [17].

Aspergillus brain abscesses occur most commonly in the cerebralhemispheres, but the cerebellum or brainstem may also be involved [57].Frontoparietal cerebral lobes seem to be preferentially involved. Given theangiotropic character of Aspergillus with its propensity to cause vascularinvasion, infarcts or hemorrhagic CNS lesions may also be observed.Pulmonary manifestations include single or multiple pulmonary nodules,which may cavitate; however, lobar infiltrates may also occur.

The predominant site of involvement and the clinical presentation ofCandida infections vary with the type of organ transplantation. Commonpresentations of invasive candidiasis after liver transplantation includeintra-abdominal abscesses, peritonitis, wound infections, or fungemia. Can-didiasis in pancreas transplant recipients usually manifests as surgical siteinfections, and less frequently as bloodstream infections. In lung or heart-lung transplant recipients, the clinical pattern of Candida infections rangesfrom tracheobronchitis to pneumonitis, and rarely systemic invasive dis-ease. Invasive candidiasis in these patients may also result in anastomoticdehiscence, mediastinitis, and mycotic aneurysm.


Other fungi

Unique clinical characteristics of C neoformans in transplant recipientswere reviewed in a recent study [48]. In 55% of the patients, CNS wasthe only site of C neoformans infection; 13% had skin, soft tissue, orosteoarticular infection; and 6% had pulmonary infection only. In 24% ofthe transplant recipients, more than one site of infection was documented;overall any CNS, pulmonary, and cutaneous involvement was present in72%, 25%, and 21% of the patients, respectively [48]. Positive bloodcultures for C neoformans occurred in 38% of the transplant recipients withcryptococcal infection and 91% had a positive serum cryptococcal antigenin titers ranging from 1:2 to 1:8192 (median 1:256).

Of patients with CNS cryptococcosis, 62% had headache, 74% werefebrile, and 48% had confusion or lethargy [48]. Most transplant recipientswith C neoformans infection of the CNS (98%) had meningitis; space-occupying or mass lesions caused by C neoformans were distinctly unusual[48]. Cerebrospinal fluid cultures yielded C neoformans in 93% of thepatients with cryptococcal meningitis, and 86% had a positive serumcryptococcal antigen [48]. Cerebrospinal fluid opening pressure was recor-ded infrequently in organ transplant recipients. All 17 patients in one reportin whom such a measurement was conducted, however, had intracranialpressure greater than or equal to 140 mm H2O [48]. These data highlight theneed for assessing intracranial pressure in all organ transplant recipientswith cryptococcal meningitis. Abnormal mental status, absence of headache,and renal failure at presentation correlated with a poorer outcome intransplant recipients with CNS cryptococcosis [48].

Infections caused by dematiaceous fungi in organ transplant recipientshave two distinct clinical presentations. Seventy-nine percent of the patientshad skin, soft tissue, or joint infections (predominantly caused by Exophialaspecies) and 21% had systemic invasive infections (predominantly brainabscesses) [37]. Dematiaceous fungi belonging to the general Dactylaria,Ochroconis, and Scoledobasidium are noteworthy for their neurotropicpotential and their predilection for causing CNS lesions. CNS lesions causedby dematiaceous fungi may be single or multiple and are ring enhancing.Concomitant cutaneous or pulmonary involvement was present in 20% ofthese cases [37].

Up to 57% of the infections caused by zygomycoses in transplantrecipients have been of the rhinocerebral form [39]. Pulmonary, cutaneous,and disseminated forms have each occurred in 13% of the patients, res-pectively [39].

Unlike bone marrow transplant recipients and patients with hemato-logic malignancies in whom disseminated fusariosis or fungemia occursfrequently, Fusarium infections in organ transplant recipients are generallylocalized and present with soft tissue lesions. Consequently, the outcomeof fusariosis is better in organ transplant recipients. Survival in organ


transplant recipients with Fusarium infection was 60% and none of thedeaths were attributable to fusariosis [38].

A major feature of histoplasmosis in solid-organ transplant recipients isthat disseminated infection occurs in over 75% of those affected [41,58].Persistent fever is the usual presentation, although some patients may havean acute fulminant course. Splenomegaly, hepatomegaly, and mucocutane-ous lesions (all of which are common in disseminated histoplasmosis) arerelatively uncommon in infected organ transplant recipients. Pulmonaryradiographic abnormalities include pleural effusion, miliary infiltrates,diffuse interstitial infiltrate, and pulmonary nodules. It should be noted,however, that chest radiographics may be normal in 40% of transplantrecipients with disseminated histoplasmosis. Intrathoracic adenopathy,which may be a useful clue to the diagnosis of histoplasmosis, is infrequentin transplant recipients.

A subacute presentation occurring several to many months after trans-plantation with anorexia, weight loss, fatigue, and sometimes a fever isthe typical presentation of coccidioidomycosis. Despite lack of pulmonarysymptoms, a cavitary infiltrate may be observed on chest radiographs.Rarely, a sepsis-like syndrome with fulminant pneumonia may occur, par-ticularly in patients with early onset infection. A few cases of coccidio-idomycosis in transplant recipients have been fortuitously diagnosed onliver biopsy [59]. Disseminated disease may present with arthritis, menin-gitis, or skin lesions, but is infrequent.

Diagnosis

Although routine laboratory methods (eg, histologic evaluation bymicroscopy and culture) can effectively detect most fungal infections, failureto diagnose invasive Aspergillus infections in a timely manner has beena major limitation of these conventional diagnostic tests. The finding ofAspergillus in cultures is highly predictive of invasive aspergillosis inliver and heart transplant recipients; however, a significant proportion oftransplant recipients with invasive aspergillosis do not have Aspergilluscultured before death [20,60]. Indeed, Aspergillus has been cultured fromsputum in only 8% to 34% and from bronchoalveolar lavage fluid in 45%to 62% of patients with invasive pulmonary aspergillosis [16]. Initiation oftherapy on culturing Aspergillus from sputum or bronchoalveolar lavagefluid may not be early enough because progression to invasive disease mayalready have occurred.

Although the appearance of pulmonary infiltrates visualized on chestroentgenograms is nonspecific, high-resolution thoracic CT has been shownto detect characteristic signs of invasive aspergillosis and allow earlier diag-nosis of the infection. Systematic CT scanning has proved to be a valuabletool for the early diagnosis of invasive aspergillosis in febrile neutropenic


patients. Unfortunately, although the halo sign is frequently seen in neutro-penic patients, it is neither specific for aspergillosis [16,61] nor is it commonlyseen in solid-organ transplant recipients with aspergillosis [16,61].

Assays for the detection of circulating fungal antigen (eg, Aspergillusgalactomannan) are emerging as potentially useful tests for the early diagnosisof invasive aspergillosis. Most experience exists in Europe using a sandwichenzyme-linked immunosorbent assay for the detection of Aspergillusgalactomannan in patients with hematologic malignancies and bone marrowtransplant recipients. A sensitivity of 50% to 90% and a specificity of 81% to93% for the diagnosis of invasive aspergillosis have been reported with thisassay [62]. Additionally, galactomannan can often be detected in the serumbefore the appearance of clinical and radiographic signs of invasiveaspergillosis [62]. False-positive tests have been documented in subgroups ofpatients (eg, premature infants without invasive disease) [63]. False-negativereactivity was noted in a patient with chronic granulomatous disease. Thesignificant value of transient positivity remains to be ascertained. Ina retrospective study in liver transplant recipients, five of nine patients withinvasive aspergillosis had Aspergillus antigen detected [64]. Data regardingthe use of this test are largely lacking in organ transplant recipients.Furthermore, in lung transplant recipients in whom colonization occursfrequently, it is not known if the test can reliably distinguish colonization frominvasive disease.

Recently, the detection of (1!3)–b-D-glucan has been proposed asa marker of systemic fungal infections caused by a wide array of fungi,including Candida and Aspergillus. Whereas prokaryotes, viruses, and thecells of humans lack this polysaccharide, (1!3)–b-D-glucan is an integralcomponent of the cell wall of fungi, except for Zygomycetes and, to a lesserextent, of cryptococci [65]. Although shown to be diagnostically and prog-nostically useful in a study in liver transplant recipients from Japan, itsprecise role in the clinical setting has yet to be defined [66].

Detection of fungal DNA by polymerase chain reaction has also beenproposed to be useful for the early diagnosis and for monitoring response toantifungal therapy [67]. In an experimental model of invasive aspergillosis,the polymerase chain reaction assay was 19.4 times more sensitive than theculture [68]. Polymerase chain reaction demonstrated a sensitivity of 100%and specificity of 65% for the diagnosis of invasive aspergillosis in bonemarrow transplant recipients [69]. Definitive studies documenting the use ofpolymerase chain reaction–based assays for the diagnosis of Aspergillusinfections, however, are largely lacking at this point.

Diagnosis of C neoformans infection is established by culture of thefungus in blood or clinical specimens. A positive serum cryptococcal antigenhas been documented in 91% of the organ transplant recipients withcryptococcosis and can be used to monitor response to therapy [48]. False-negative tests, however, may occur in patients with isolated pulmonarydisease.


Management

Prophylaxis

Antifungal prophylaxis in organ transplant recipients remains a com-plex and controversial issue. The types of patients to receive prophylaxis,the antifungal agent, route of administration, and the optimal timing ofprophylaxis have not been well defined. Given the high incidence andsignificant mortality, use of prophylaxis for invasive candidiasis in liver andpancreas transplant recipients and for invasive aspergillosis in liver and lungtransplant recipients is justifiable [6].

At least two randomized studies have assessed the efficacy of fluconazoleprophylaxis for invasive fungal infections in liver transplant recipients[70,71]. A randomized trial from Europe compared fluconazole with oralnystatin for 28 days after transplantation as antifungal prophylaxis [70].Although the incidence of colonization with Candida and superficial fungalinfections was lower among fluconazole recipients, a difference in thefrequency of invasive candidiasis was not observed between the two groups.Another study found that fluconazole for 10 weeks was associated witha significant decrease in the incidence of invasive fungal infections [71]. Thestudy reported an unusually high incidence of invasive mycoses (43%),however, most of which were superficial fungal infection. The frequency ofinvasive candidiasis in this fluconazole group was similar to that amongpatients at other centers who received no systemic antifungal prophylaxis.The strategy of universal use of fluconazole prophylaxis should, however,be discouraged. Recent data show that non-albicans Candida spp haveemerged as significant pathogens in liver transplant recipients [72]. In-fections caused by these fungi correlated with prior fluconazole use.Fluconazole prophylaxis should be use selectively. When it is used, pro-phylaxis should be directed only to high-risk patients (as identified inTable 3), and for 4 weeks after transplantation. Fluconazole prophylaxis hasanecdotally been reported to be effective after pancreatic transplantation. Inhigh-risk pancreatic transplant recipients (see Table 3), prophylaxis withfluconazole for 4 weeks may be considered.

Prophylaxis for invasive aspergillosis

The efficacy of prophylaxis for aspergillosis with itraconazole (in capsuleor solution form) and low-dose amphotericin B deoxycholate in dosages of0.1 to 0.5 mg/kg/d is unconvincing in liver transplant recipients [6]. Thecapsule formulation of itraconazole has an absolute bioavailability ofapproximately 55%. An acidic environment and the presence of food inthe stomach increase bioavailability. Although steady-state itraconazoleconcentrations tend to be lower in all immunocompromised individuals,poor availability can be particularly problematic in critically ill liver trans-plant recipients [6]. Reformulation in hydroxypropyl-b-cyclodextrin has


Table

3

Suggestedapproach

toantifungalprophylaxisfororgantransplantrecipients

Typeof

transplant

Fungalpathogen

targeted

High-riskcharacteristics

Antifungalagents

Suggestedduration

ofprophylaxis

Liver

Asp

erg

illu

sPoorallograftfunction,particularlyprimary

nonfunctionoftheallograft;pretransplantation

fulm

inanthepaticfailure;retransplantation;

dialysis

Liposomal

amphotericinB

4wk

Liver

Can

did

aRepeatedoperation;higher

intraoperative

transfusionrequirem

ent;longer

operationtime;

renalfailure

Fluconazole

4wk

Lung

Asp

erg

illu

sAirwayspecim

enculturespositivefor

Asp

erg

illu

s,

particularlyforpatients

withrejection,increased

immunosuppression,cytomegalovirusinfection,

andobliterativebronchiolitis

Itraconazole

�aerosolized

amphotericinB

4–6mo

Pancreas

Can

did

aEntericdrainageprocedure;pancreas

transplantationafter

kidney

transplantation;

preoperativeperitonealdialysis;pancreatitisafter

reperfusion;pancreaticretransplantation

Fluconazole

4wk

Allorgans

Coc

cid

ioid

esim

mit

isHistory

ofcoccidioidalpulm

onary

infectionor

reactivecoccidioidalserologybefore

transplantation

Triazole

antifungal

agents

Prolonged

or

perhaps

indefinitely


significantly improved the oral bioavailability of itraconazole. A random-ized, controlled trial has compared the oral solution of itraconazole withplacebo for prevention of systemic fungal infections in liver transplantrecipients [73]. The study, however, was inadequately powered to dem-onstrate the efficacy of itraconazole against invasive aspergillosis; therewere no documented Aspergillus infections in 33 patients who receiveditraconazole or in 38 controls who received placebo.

The lipid formulations of amphotericin B have several characteristics thatrender them attractive antifungal agents for prophylaxis for high-risk livertransplant recipients. These formulations are less nephrotoxic and are atleast equivalent in efficacy against invasive mycelial infections. In a study inliver transplant recipients, liposomal preparation of amphotericin B ata dosage of 5 mg/kg/d targeted toward high-risk patients (those requiringdialysis) was associated with a significant reduction in invasive fungal in-fections, including aspergillosis [74].

Lipid formulations of amphotericin B, however, are expensive and thedata supporting their efficacy are limited. Although firm recommendationsregarding prophylaxis for infections caused by Aspergillus cannot be madewithout further research, prophylaxis for invasive aspergillosis in livertransplant recipients, if deemed necessary, may be considered using a lipidformulation of amphotericin B at a dosage of at least 3 mg/kg/d, preferably5 mg/kg/d, targeted toward high-risk patients (as identified in Table 3) fora period of 4 weeks after transplantation [6]. The need for continuing pro-phylaxis beyond this period should be assessed individually, on the basis ofthe persistence of risk factors.

In lung transplant recipients, inhaled liposomal amphotericin B isa promising antifungal prophylactic approach [75]. Such a strategy avoidsthe systemic side-effects and drug interactions and has been shown to besage and well tolerated [76].

Treatment

Successful management of invasive mycoses depends on prompt recog-nition of infection, adjustment of the level of immunosuppression, andantifungal therapy in adjunct with surgery when indicated. Amphotericin Bdeoxycholate has long been a mainstay of therapy for Aspergillus infections.Its use in dosages between 1 and 1.5 mg/kg/d, however, is frequently com-plicated by nephrotoxicity in organ transplant recipients receiving cyclo-sporine or tacrolimus. Nephrotoxicity developed in 30% of the solid organtransplant recipients treated with amphotericin B deoxycholate for sus-pected or proved aspergillosis, and 18% required hemodialysis [77].

Despite their higher costs, many investigators believe that the use ofliposomal preparations of amphotericin is justifiable as first-line therapy intransplant recipients with invasive aspergillosis [6,78]. A lower nephrotoxicpotential of these drugs has been amply documented in the literature. These


agents may also be superior in efficacy, however, as suggested by at least twostudies in organ transplant recipients [79,80]. A difference in efficacy be-tween the three currently available liposomal preparations of amphotericinB, however, has not been documented in organ transplant recipients. Therisk of infusion-related toxicity and the cost may be the primary deter-minants of the choice of the liposomal preparation used as therapy.

A role of itraconazole as monotherapy for invasive aspergillosis has notbeen established. Although a successful response was documented in 60%(18 of 30) of the solid-organ transplant recipients in open-label or compas-sionate use trials with itraconazole, many of these patients had receivedprior antifungal therapy or had localized tracheobronchial aspergillosis,which has substantially lower mortality as compared with invasive pulmo-nary or disseminated aspergillosis [81,82]. In a report in heart transplantrecipients, itraconazole had inferior efficacy as compared with amphotericinB for invasive pulmonary aspergillosis [83]. The role of itraconazole islargely as sequential or step-down therapy in patients experiencing an initialresponse with amphotericin B or its liposomal preparations. The potentialfor azoles to increase cyclosporine and tacrolimus concentration should beborne in mind if these drugs are used in the transplant setting; itraconazolecan increase cyclosporine levels up to twofold and tacrolimus levels by up tofivefold.

Suboptimal absorption and poor bioavailability of itraconazole in thecapsule form has been particularly problematic in transplant recipients.Solubilization of itraconazole in naturally occurring cyclic oligosaccharides(eg, cyclodextrin) has led to a significant improvement in its absorption.Data documenting the efficacy of the cyclodextrin preparation for thetherapy of Aspergillus infections in organ transplant recipients, however, arelargely lacking.

Based on a recent study that documented the superiority of voriconazoleover amphotericin B [84], voriconazole is now widely regarded as the drug ofchoice for the treatment of invasive aspergillosis. Only limited experienceexists with the use of voriconazole with transplant recipients, but it is likelyto grow in the foreseeable future. An echinocandin, caspofungin thatinhibits b-(1-3)-D-glucan synthesis has become available. In a study thatincluded transplant recipients, the response with caspofungin when used assalvage therapy for invasive aspergillosis was 41% compared with 16% withstandard therapy [85].

Amphotericin B deoxycholate is considered the drug of choice forinvasive candidiasis. Dosages of amphotericin B deoxycholate (0.5 to 0.7mg/kg/d) used for candidiasis are likely to be tolerated better in transplantrecipients than the higher dosages required for invasive aspergillosis. Forpatients intolerant of amphotericin B deoxycholate or for those with pre-existing renal dysfunction, however, lipid preparations of amphotericin Bmay be used. Use of fluconazole is also reasonable for infections caused byCandida albicans or other susceptible species.


The therapeutic regimens for cryptococcosis have been extrapolatedlargely from studies in the HIV setting. Amphotericin B (0.7 mg/kg/d) withor without 5-flucytosine is widely used for the treatment of cryptococcosis inorgan transplant recipients. Mortality rate in transplant recipients treatedwith amphotericin B (48%) did not differ significantly from that in patientswho received amphotericin B and 5-flucytosine (35%) [48]. An all oralregimen of fluconazole and 5-fucytosine has also been used successfully ina liver transplant recipient with extraneural C neoformans infection.

The triazoles, itraconazole and voriconazole, are regarded as the drug ofchoice for most infections caused by phaeohyphomycoses, particularly thoseassociated with cutaneous and subcutaneous infections (see Table 3).Dematiaceous fungi belonging to the genera Xylohypha, Ochroconis, andDactylaria are noteworthy for their neurotropic potential and the pre-dilection to cause brain abscesses. In one report, two of five organ transplantrecipients with brain abscesses caused by these fungi survived; both hadreceived amphotericin B and flucytosine [37]. Given the potent antifungalactivity of triazole antifungal agents against dematiaceous fungi, however,itraconazole and voriconazole represent promising alternative therapies inthis setting. Management of other less frequently occurring invasive mycoses[38,44,86] in transplant recipients is outlined in Table 3.

Surgery is an integral component of the management of infections causedby zygomycoses and phaeohyphomycoses. In a review, 45% (10 of 22) ofthe organ transplant recipients in whom rhinocerebral zygomycosis wasdiagnosed antemortem and who received amphotericin B were cured; 7 of 10patients cured also underwent surgical debridement [39]. Of five of sixtransplant recipients with pulmonary zygomycosis in whom the infectionwas diagnosed antemortem, were cured [39].

The infections caused by dematiaceous or black-pigmented fungi maybe difficult to eradicate, even with prolonged antifungal therapy. Surgicalresection combined with antifungal therapy is the recommended therapeuticapproach for these fungi. For cutaneous and subcutaneous phaeohypho-mycosis, complete, wide, and deep margin resection should be performed.Surgical resection, when feasible, is also recommended for CNS lesionscaused by phaeohyphomycosis. The role of surgery in the routine man-agement of invasive aspergillosis in solid-organ transplant recipients isless well defined. Surgery, however, is indicated for Aspergillus lesions inclose vicinity of pulmonary vessels because of the risk of erosion. ThoracicCT can help in the early identification of such lesions.

A role for immunomodulatory therapies (eg, interferon-c) and hemato-poietic growth factors as an adjunct to antifungal agents in transplantrecipients has not been clearly delineated. A potential concern with the useof interferon in organ transplant recipients is the augmented risk of allograftrejection.

A number of novel antifungal agents are on the horizon and combinationtherapies are considered potentially promising therapeutic modalities for


fungi (eg, Aspergillus). Newer diagnostic modalities for invasive fungalinfections could further contribute toward early and reliable diagnosis ofthese infections. At the same time, however, the emergence of azole re-sistance in Candida spp is a sobering reminder that effective managementand prophylactic strategies must comprise approaches that not onlyimprove outcome, but also curtail antimicrobial resistance.

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