fungal infections after lung transplantation

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22 (2008) 89–104www.elsevier.com/locate/trre

Transplantation Reviews

Fungal infections after lung transplantationAmparo Soléa,⁎, Miguel Salavertb

aPulmonary Transplant Unit, Hospital Universitario La Fe, 46009 Valencia, SpainbInfectious Disease Unit, Hospital Universitario La Fe, 460009 Valencia, Spain

Abstract

Lung transplantation (LT) is now considered to be the standard therapeutic intervention in some patients with end-stage pulmonarydisease. Infectious complications after LT are relatively common due to the aggressive immunosuppression used in these receptors and localhost factors derived from this type of transplant. The incidence of fungal infections after LT ranges up to 30%. However, the incidence ofinvasive mycoses has declined over the past decade. These mycoses are associated with high overall mortality rates despite increase of theantifungal armamentarium in the last years. Candida and Aspergillus spp produce most of these infections, but unusual moulds such asScedosporium spp are increasingly recognized as opportunistic pathogens in LT. This review highlights the changing spectrum of invasivefungal infections, risk factors, antifungal prophylaxis, diagnosis, and treatment after LT.© 2008 Elsevier Inc. All rights reserved.

1. Introduction

Infectious complications after lung transplantation (LT)are frequent as a direct consequence of the use of theaggressive immunosuppression employed in these receptors,as well as the presence of impaired mucociliary clearance,ischemic airway injury, altered alveolar macrophage phago-cytic function, and direct communication of the transplantedorgan with the enviroment. Moreover, pulmonary infectionsin LT recipients besides their direct impact on morbidity andmortality have an indirect effect with immunologicalconsequences implicated in the genesis and clinical courseof acute and chronic rejection.

Fungal infections (FIs) are associated with a highmortality rate in lung transplant recipients for severalreasons: the difficulty of establishing an early diagnosis,the lack of effective treatment for infections by somefilamentous fungi, the toxicity and interactions of someantifungal agents with immunosuppressive drugs, the scarcepublished experience about the use of prophylaxis withantifungal drugs in this setting, and finally, the loss ofgrafts as the result of reducing immunosupression to curethese infections.

⁎ Corresponding author. Unidad de Transplante Pulmonar. HospitalUniversitario La Fe. Av. de Campanar. 21, 46009, Valencia, Spain. Tel.: +3496 386 2700x40459; fax: +34 96 197 32 07.

E-mail address: [email protected] (A. Solé).

0955-470X/$ – see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.trre.2007.12.007

Fungal infection occurs in 15% to 35% of patients afterLT, and more than 80% are caused by Candida spp andAspergillus spp, with an overall mortality rate of nearly60% [1-6]. Unusual moulds such as Scedosporium spp areincreasingly recognized as important opportunistic patho-gens in LT; other moulds such as Zygomycetes and speciesof Fusarium have less relevant role in LT, but in all cases,their infection is associated with a high rate of disseminationand poor outcome [7,8]. However, the overall incidence ofinvasive mycoses in LT has declined over the past decade.This may be related to improved surgical techniques,decreases in the length of operations, units of bloodtransfused, more effective prophylactic strategies, andrefinements in immunosuppressive regimens.

This review highlights changing spectrum of invasive FIs(IFIs), risk factors, antifungal prophylaxis, diagnosis, andtreatment after LT.

2. Risk factors for IFIs

In general, risk factors for invasive mycoses in solid organtransplantation (SOT) are concentrated in specific subpopu-lations of transplant recipients. Risk factors for Candidainfection are well known and usually are related with acomplicated postoperative course in the intensive care unitduring the early postoperative period (Candida colonization,central vascular lines, broad-spectrum antibiotics, totalparenteral nutrition, and hospital length of stay), and they

http://dx.doi.org/10.1016/j.trre.2007.12.007

Fig. 1. Bronchopleural fistula due to A fumigatus. A, Before treatment. B,After treatment.

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do not differ in LT recipients with those referred for othertransplant recipients.

A complicated postoperative course, repeated bacterialinfections, concomitant cytomegalovirus (CMV) infection,and renal replacement therapy seem to significantly increasethe risk for early (within the first 3 months after transplanta-tion) invasive Aspergillus infections (AIs). Risk factors forlate-onset FIs (mainly Aspergillus) include advanced age,renal failure, and an increased immunosuppressive state dueto chronic rejection [9-12].

Environmental factors may also increase the risk ofinfection with Aspergillus and other filamentous moulds inlow-risk patients. Such factors include demolition andconstruction in the vicinity of the hospital, and contamina-tion or malfunction of the air-conditioning system nearpatient care areas [13]. It is also possible that hospital watersupplies may be a potential source of Aspergillus spp [14]. Infact, an invasive mycosis in an otherwise low-risk patientshould trigger an investigation into environmental factorsand the use of widespread prophylaxis until the problemis solved.

Patients receiving LT seem to be particularly susceptibleto infection by Aspergillus spp. Risk factors for AI includecolonization before or after transplantation, single lungtransplant, CMV infection, and chronic rejection and the typeof antifungal prophylaxis. With respect to Aspergilluscolonization, it has been demonstrated that prior colonizationdoes not imply the development of invasive pulmonaryaspergillosis (IPA). In fact, in our experience, patients whohave cystic fibrosis (CF) colonized by Aspergillus beforetransplantation do not have a higher incidence of pulmonaryor disseminated disease after transplantation. However, theyare at increased risk of anastomotic infections in the earlyposttransplantation period. Nevertheless, Aspergillus colo-nization before LT has been associated with a higherincidence of invasive infection. Studies report that 6%(range, 3%-20%) of patients with colonization beforetransplantation progress to invasive disease [10]. It hasbeen demonstrated that lung transplant colonized withAspergillus in the first 6 months after transplantation were11 times more likely to develop invasive disease than werenoncolonized patients [12].

Cytomegalovirus disease is another risk factor forinvasive Aspergillus (IA) infection in lung transplantrecipients. In fact, many lung transplants with IA infectionhave concurrent CMV disease [5,6].

In addition, some studies have shown a direct relationbetween the use of some immunosuppressive drugs andinvasive mycoses (cryptococcosis, aspergillosis), mainlywhen they are used as antirejection [15] or posttransplanta-tion lymphoproliferative disorder therapy [16]. In our series,we do not find any association with immunosuppressivetherapy, neither the use of high corticosteroid doses northe use of tacrolimus (p 0.73, no significant ns), beingchronic rejection the only significant association that wehave found [3].

3. Spectrum of FIs in LT

3.1. Aspergillus spp infection in recipients of LT

Aspergillus is a filamentous fungus with a wide environ-mental distribution [17]. Aspergillus infections remainamong the most significant opportunistic infections afterLT. Aspergillus fumigatus, the most pathogenic species,produces the most infections; however, Aspergillus flavus,Aspergillus terreus, and Aspergillus niger have beenincreasingly reported in IFI. Data from the compilation andsynthesis of existing studies give a variable incidence of AIof 6% in the published series (range, 2.2%-30%). These wideranges translate the differences in definition criteria for AI,immunosuppressive therapy, and antifungal prophylaxisexisting in each lung transplant program. It is known thatinfection by Aspergillus may manifest in lung transplantrecipients in 3 different forms: colonization, tracheobron-chitis/anastomotic infections, or invasive pulmonary/disse-minated aspergillosis [18]. Although cases of allergicbronchopulmonary aspergillosis have been reported, this isa rare entity that only occurs in transplant patients with CF[19]. To avoid confusion about AI, the following definitionsare used in this review:

1. Aspergillus airway colonization: patients with Asper-gillus cultured from the airway specimens in theabsence of IA or tracheobronchitis.

2. Tracheobronchial aspergillosis or anastomotic infec-tions: isolation of Aspergillus in culture with histo-pathologic evidence of tissue invasion or necrosis,ulceration, or pseudomembranes on bronchoscopy.

3. Invasive pulmonary aspergillosis: IFI of the lungcaused by Aspergillus spp, with clinical, radiological,and or histological findings of pulmonary tissueinvasion by Aspergillus, together with isolation of thefungus from respiratory samples. Invasive pulmonaryaspergillosis and IA are considered to be disseminatedwhen the infection is documented histopathologicallyat 2 or more noncontiguous organ sites.

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Aspergillus colonization usually occurs up to 30% ofpatients during the first 6 months after transplantation, and itis considered a risk factor to develop IPA. In a single-centerstudy, the isolation of Aspergillus spp from respiratorysamples was reported to precede acute rejection and could bean early marker of graft dysfunction or airway inflammation.

Related to airways lesions, Aspergillus have a propensityfor healing bronchial anastomoses, which leads to endo-bronchial complications such as excessive granulation,bronchial stenosis, dehiscence, necrosis, and bronchoarterialfistula in up to 18% patients (Fig. 1). Isolated tracheobron-chitis and bronchial anastomotic infections are distinctentities from Aspergillus pneumonia. In one study, althoughthe early mortality of patients with bronchial anastomoticAIs did not differ significantly from patients without theseinfections, their long-term survival was reduced [20]. In ourexperience, anastomotic infection was associated with asignificant reduction of survival rate in single lung transplant(4 of 5 cases, 80%). In fact, close monitoring and preemptiveantifungal therapy is recommended for patients withbronchial airway mechanical abnormalities and persistentAspergillus colonization because of their progression toinvasive pulmonary forms.

The incidence of IPA forms is around 5% to 10%,although it depends on several factors but in general occur inseverely immunosuppressed patients. Time of onset differsfor various types of AIs. IPA or disseminated aspergillosisoccurred significantly later than tracheobronchitis. Usually,of the AI occurring within 3 months of transplantation, 75%are tracheobronchitis or bronchial anastomotic infections,18% are invasive pulmonary infections, and 7% aredisseminated invasive infections. Historically, most of theAIs in LT occurred within 90 days of transplantation [21]. Ina previous report, AI occurred at 72% within 6 months of LT,and only 12% were documented after 12 months oftransplantation. Nowadays, characteristics of transplantrecipients developing IA and immunosuppressive regimensare continuing to evolve. Thus, nearly one half of the AI intransplant recipients in the current era are late occurring[22,23]. In fact, in our experience, invasive forms were lateonset (16/19) and the main risk factor was chronic rejection.These data have implications relevant for prophylacticstrategies and guiding clinical management of transplantrecipients presenting with pulmonary infiltrates. In our largesingle-center cohort of lung transplant, the time of onset wasstrongly related to the clinical form of aspergillosis. Alltracheobronchitis or bronchial anastomotic infectionsoccurred within 3 months of transplantation. In contrast,invasive or disseminated aspergillosis was significantly later(33.7 ± 19.6 months posttransplantation). All the earlyinvasive pulmonary forms (25%) were simultaneous withtracheobronchial AI.

With respect to mortality, IA accounts for 9% of deathsin LT recipients [24]. Overall mortality in LT recipientswith AI is between 52% and 80% and varied significantlywith the site of infection (other aspects as type of LT,

time of onset of infection, and antifungal therapy used).Although mortality rate is around 23% for patients withtracheobronchial or bronchial anastomotic infections, it isup to 82% for patients with IPA. Patients with late-onset AIhad significantly higher mortality than those with early-onset infections. However, when only patients with IA wereanalyzed, the mortality rate did not differ for those withlate- vs early-onset AI. In a large series of LTs, AI wasassociated with a reduction in the 5-year survival rate,especially in single lung transplant recipients with bron-chial anastomotic infection and in those with late-onsetinfections and chronic rejection [3].

With regard to the treatment, voriconazole, an extendedspectrum highly lipophilic triazole with 98% oral bioavail-ability, is actually the first choice for initial therapy of IA inLT patients and other immunosuppressed hosts. Otherpotentially effective therapies include lipid formulation ofamphotericin B (AmB) and echinocandins. Combinationtherapy using a triazole and an echinocandin has beenevaluated in SOTwith a significant reduction in mortality inthose patients with renal failure and those infected withA fumigatus [25].

3.2. Candida spp in LT

From a historical point of view, Candida species accountfor the most (43%–80%) FIs in lung transplant recipients[26-29]. Unfortunately, Candida species are commonlyisolated from the respiratory tract of lung transplantrecipients, and distinguishing colonization from invasivedisease is a difficult issue. Pulmonary candidiasis isuncommon in severely immunocompromised patients,except in lung transplants, where they colonize and invadenecrotic tissues and bronchial anastomosis. However, theclinical patterns of candidiasis in LT recipients range frommucocutaneous to invasive disease.

Candida spp appears as a frequent airway colonizer oflung transplant recipients and is likely to be obtained fromdonor airways [30]. Flume et al [31] found that only 10% ofthe 76% of patients colonized with Candida spp developedinvasive disease. Many centers begin preemptive therapywith oral fluconazole for 1 to 4 months when Candida isdetected in the airways after transplant [32], but it is anobsolete strategy in the era of prophylaxis withnew antifungal drugs, which include an adequate coverageof Aspergillus and other moulds infections. Moreover,Candida is now an infrequent pathogen unless concomitantbacterial infection, augmented immunosupression, or multi-system organ failure is present [33]. Candida is frequentlyisolated from the sputum in seriously ill patients onantibiotics, without any clinical relevance. However, isola-tion of Candida from a patient with pulmonary infiltratesafter LT should not be dismissed as benign colonization, anddiagnosis of invasive disease must be ruled out.

Infectious complications due to Candida typicallyinclude fungemia/disseminated disease [34], empyema,


mediastinitis, necrotizing bronchial anastomotic site infec-tions [35], and aortic anastomotic infection after heart-lungtransplantation [36,37]. Candida spp contribute to approxi-mately 10% of bloodstream infections in the first year afterpediatric LT [38]. Bloodstream infection with Candidaspecies is associated with high mortality, with deathoccurring within 30 days of isolation of the organismin 71% of patients in 1 study [6,34]. Immunosuppressedpatients with candidemia have a mortality rate greater than50%, whereas lung transplant recipients with invasiveAspergillus spp disease have a mortality rate of 60% to75% [30,39,40]. Most invasive infections with Candidaspecies occur during the first postoperative month, and mostof them are transmitted via the donor organ. Heavy growth ofCandida species in the donor bronchus is a significantobstacle for accepting the organs for transplantation. Thesequelae are mediastinitis, sepsis, or involvement of the greatvessels leading to mycotic aneurysms and consecutiverupture. In 1 series, 3 of 4 recipients of lung transplantswith heavy growth of Candida species developed mediasti-nitis, which was uniformly fatal [41]. Thus, such donororgans should possibly be discarded. Nevertheless, if theseorgans are used, antifungal treatment with AmB, echinocan-dins, or new azole drugs should be instituted immediately.

Candida albicans is typically sensitive to fluconazole,which can be reliably used for therapy instead of AmB.However, some Candida species (Candida krusei) areinherently resistant to fluconazole, and others such asCandida glabrata and Candida tropicalis may have highminimal inhibitory concentrations to fluconazole as well.These more resistant Candida isolates (and most filamentousfungi) require treatment with products based on AmB, ornew azoles compounds (voriconazole, posaconazole) orequinocandins (caspofungin, micafungin, anidulafungin).

3.3. Emerging fungal pathogens in LT

Invasive FIs have long been recognized as a significantcomplication in organ transplant recipients. Most infectionsin these patients are due to either Candida (35%–80%) orAspergillus species (9%–52%), with other opportunisticfungi accounting for 1% to 2% of the FI [7,42,43]. However,in the last decade, infections due to infrequently encounteredfungi (eg, hyaline molds, dematiaceous filamentous fungi,and Zygomycetes) have become increasingly common inimmunocompromised hosts, most notably, hematopoieticstem cell transplant (HSCT) recipients [44,45]. These trendsare worrisome, given that the opportunistic molds are oftenrefractory to conventional antifungal agents. Innate resistanceor erratic susceptibility to AmB is characteristic of certainfungi (eg, A terreus, Scedosporium apiospermum, and Sce-dosporium prolificans) [46,47]. The advent of novelantifungal agents represents an advance in the managementof invasive mycoses. However, fungi such as S prolificansand the Zygomycetes are also resistant to the currentlyavailable triazoles and echinocandins [48]. Rare moulds,

more than yeasts, have emerged in the last 2 decades aspathogens in SOT recipients, including Zygomycetes, Sce-dosporium, Fusarium, Paecilomyces, Scopulariopsis, Acre-monium, Tricoderma, and others [49,50]. Many of theseorganisms mimic AI in tissue and must be distinguished in aculture. Aspergillus spp is by far the most common mycosiscaused by moulds, although non-Aspergillus mycelial fungi(NAMF) have emerged as significant and increasingly morecommon pathogens. NAMF account for approximately 27%of mould infections and are more likely to be disseminatedand associated with poorer outcome as compared withaspergillosis. Early and accurate diagnosis is essential to starta specific antifungal therapy because the susceptibility ofthese moulds is different enough in occasions from Asper-gillus and Candida. However, the spectrum and overallimpact of these emerging fungal pathogens have not beenfully defined in SOT recipients.

3.4. Zygomicosis

Zygomycosis is the third invasive mycosis in order ofimportance after candidiasis and aspergillosis and is causedby fungi of the class Zygomycetes [51]. Zygomycosis is anopportunistic infection, primarily associated with diabeticketoacidosis, iron chelation with deferoxamine, neutropenia,hematologic malignancies, high-risk newborns, and trauma[52]. It has been principally studied in patients with diabetesmellitus and hematologic malignancies [53]. The speciesinvolved are ubiquitous saprophytic fungi found primarilyin soil and decaying matter. In tissue, they typically appearas broad, thin walled, sparsely septate, ‘ribbon-like’ hyphae,often with right angle branching [54]. The most commongenera include Rhizopus, Rhizomucor, Mucor, and Absidia.Less frequent are Cunninghamella, Saksenaea, and Apo-physomyces [55]. For the clinical use and of colloquial form,the terms zygomicosis and mucormycosis are in the habit ofbeing compared. The incidence of mucormycosis is approxi-mately 1.7 cases per 1000000 inhabitants per year [56].It is a rare complication of SOT associated with augmentedimmunosuppression. In recipients of LT, the availableinformation comes from case reports and series with smallnumber of patients or from studies of this emergent mycosisin more wide and general population of SOT. The incidenceof zygomycosis in a recent and retrospective study based onthe patients' cohort with SOT of the University of PittsburghMedical Center [8] (2 of 1000 patients) was equivalent to theincidence reported previously. Specifically, the incidence inrenal transplant recipients was 0.4 to 0.5; in liver recipients,4 to 16; in heart recipients, 8; in lung recipients, 13.7 to 14 (allper 1000 patients). Zygomycosis has high morbidity andmortality, but disseminated and rhinocerebral forms have theworst prognosis. A high index of suspicion is necessary, andan invasive procedure, such as a biopsy or fine needleaspiration, should be obtained early to diagnose.

In the retrospective study previously mentioned [8], only10 patients with SOT and invasive zygomycosis were

Fig. 2. Disseminated FI by Scedosporium apioespermun in unilateral lungtransplant. A, Pulmonary infection in native lung. B, Leg micetoma.


included, and the cases published previously in the literaturewere reviewed. Of the 116 cases included, only 4 cor-responded to lung transplant recipients.

In lung transplant recipients, there are 2 case reports ofinfections by Absidia corymbifera documented in theliterature [57]. This mould is a rare cause of pulmonarytract infection and predominated in HSCT patients. The firstcase reported was a fatal A corymbifera pulmonary infectionin the early postoperative period of a lung transplant patientreceiving voriconazole prophylaxis (A corymbifera isvoriconazole resistant). The second case was an LT withtransient bronchial colonization by A corymbifera. Theauthors comment that to prevent airborne transmittedinvasive pulmonary mycoses in the first postoperative periodof LT, the patients should be situated in a room ventilated byhigh efficiency particulate arrestance (HEPA)-filtered air.The specific treatment should start very early when firstsuspicion arises.

Fungal infections at the bronchial anastomosis is asso-ciated with a significant risk of morbidity and mortality afterLT, as one has already commented before. Mucormycosis ofthe bronchial anastomosis is a grave, and very rare, compli-cation after LT. Without combination therapy of surgery andantifungal drugs, mortality has been exceedingly high [58].

Neutropenia predisposing to zygomycosis is usuallyabsent in SOT recipients, but all patients are receivingimmunosuppression, and most LT are on steroids. Steroidsare known to suppress the phagocytic activity of macro-phages in experimental mice models. In this line, theincidence of dissemination was significantly higher inpatients who received pulse of steroids for acute rejection amonth before diagnosis of zygomycosis compared withthose on maintenance therapy.

The mortality rate in the Pittsburgh cohort was 50%, all15 patients with disseminated disease and 42 (41.5%) of 101with localized disease died. Among patients with localizeddisease, the highest mortality rate was observed in patientswith rhinocerebral disease (14 of 15, 93.3%), comparable todisseminated disease [8]. Among cases diagnosed premor-tem, discontinuation or reduction of immunosuppressionwas associated with a better survival rate.

Treatment of zygomycosis requires a rapid diagnosis,correction of predisposing factors, surgical resection,debridement, and appropriate antifungal therapy [59].Liposomal AmB is the therapy of choice for this condition.Azoles have traditionally been ineffective against Zygomy-cetes, only posaconazole and ravuconazole have goodactivity in vitro. Optimal treatment involves early institutionof aggressive surgical debridement combined with AmB andwhenever feasible reduction in immunosuppression. Posa-conazole might be used like adjuvant therapy or ascombination treatment, and also as salvage treatment ofrefractory zygomycosis. A case of pulmonary mucormycosisin a lung transplant recipient cured after posaconazoletherapy has been described [60]. Equinocandins has poor invitro activity against the agents responsible for mucormy-

cosis, but an in vitro or in vivo correlation has not been wellestablished. Caspofungin proved to be active in vitro byinhibiting the (1→3)-β-D-glucan synthetase of Rhizopusoryzae, and in an experimental model of disseminatedmucormycosis caused by this microorganism, low-dosecaspofungin improved the survival of mice with mucormy-cosis induced by diabetic ketoacidosis. Some authorsconsider that further studies should be done to determinethe potential role of caspofungin in mucormycosis becausethere may be a synergy between caspofungin and AmBlipid complex (ABLC).

3.5. Scedosporium spp

Scedosporium spp are filamentous fungi that consist of2 clinically important species, S prolificans and S apiosper-mum, the latter being the asexual anamorph of Pseudal-lescheria boydii. S apiospermum, a hyalohyphomycete,accounts for approximately 25% of NAMF infections in


organ transplant recipients [61-67]. S apiospermum isubiquitously present in soil, sewage, and polluted waters,but the natural habitat of S prolificans is less well defined.Both usually enter via the respiratory tract or the skin aftertrauma. Scedosporium spp can colonize the sinuses andairways of lung receptors with underlying pulmonary diseasessuch as bronchiectasis, sarcoidosis, tuberculosis, and CFbefore transplant, and develop invasive disease after LT. Infact, IFI caused by S apiospermum have been reported onlyrarely, in unilateral LT recipients and CF transplant patients[62,66,67] (Fig. 2). Disseminated Scedosporium infectionstypically occur during or immediately after periods ofprolonged neutropenia or increased immunosuppression,which may also explain the higher rate of dissemination.The average time from transplantation to onset of infectionamong different studies has been between 4months (range, 1–18 months). The mortality for Scedosporium infection in SOTrecipients is significantly high in cases with disseminatedinfection or central nervous system (CNS) involvement,fungemia, and renal failure, being close 100%. The radi-ological and histopathologic appearance of S apiospermum isindistinguishable from Aspergillus spp. Thus, early andaccurate diagnosis is essential because these fungi can beconfused with AmB-sensitive molds, especially Aspergillusspp. Colonization by Scedosporium in transplant recipientsshould not be ignored, and prophylaxis or suppressive therapyshould be considered with newer triazoles (eg, voriconazole,posaconazole, ravuconazole) in all cases. Although norandomized controlled studies have been completed todetermine efficacy of voriconazole as antifungal prophylaxis,in vitro and in vivo efficacy justifies its use. Pretransplantcolonization should also be considered as an indication fordouble-lung transplantation in candidates to LT because apotential reservoir of S apiospermum infection in the nativelung can produce a fatal infection posttransplantation.

The general consensus is that S apiospermum is resistantto AmB treatment, including the lipid formulations. Ofthe newer triazoles (voriconazole, posaconazole, and ravu-conazole) have demonstrated in vitro activity againstS apiospermum [68]. S prolificans is resistant to all knownantifungal drugs. An effective therapeutic approach mayinclude combinations of antifungal drugs, surgery, andagents that expedite immune reconstitution.

3.6. Fusarium spp

Fusarium spp is a representative of the hyaline molds andrecently has emerged as an increased cause of disseminatedinfection in immunosuppressed patients. Members of thegenus Fusarium are ubiquitous fungi, are commonly found insoil and organic debris (saprophytes form), and cancause disease on plants (pathogen form). Fusarium solani,Fusarium oxysporum, and Fusarium moniliforme are thespecies that most frequently isolate from clinical specimens.Like Aspergillus species, Fusarium species have a propensityto invade blood vessels and can result in tissue necrosis and

pulmonary cavitation. In contrast, Fusarium continuouslyreleases spores into the bloodstream consisting of phialidesand phialoconidia. The higher rate of positive blood culturesand dissemination associated with Fusarium is caused by theoccurrence of intravascular adventitious sporulation. Fusar-ium species can be isolated from cultures of blood samples in50% to 70% of cases [69]. The prognosis of disseminatedFusarium infection is poor, and recovery has been reportedonly for those patients in whom neutropenia has resolved orimmunodeficiency has recovered.

Fusariosis is a very exceptional clinical syndrome in lungtransplant patients, and the descriptions of this entity arescanty. Because the pathogenesis of FI differs significantlyin HSCT and SOT recipients, we want to delineate theprevalence and outcome of Fusarium infection among SOTrecipients [70], specifically in the LT [71,72]. Amonganecdotal descriptions and case reports, disseminatedF solani infection with endocarditis in a CF lung transplantrecipient has been reported [73]. Previously, other case ofcavitary lung disease caused by F solani in an LT recipienthad been described [71].

It seems that fusariosis may have different manifestationsin SOTand HSCT recipients. In SOT recipients, the infectiontends to be localized, fungemia is uncommon, onset ofinfection occurs during the late posttransplantation period,and mortality is around 33%. In HSCT recipients, infection isdisseminated, fungemia occurs in 20% to 70% of cases, onsetof infection occurs early in the posttransplantation period,and mortality is high (70%–100%). Symptoms in SOTrecipients with Fusarium pneumonia may include productivecough, dyspnea, pleuritic chest pain, and fever. Although thelung examination may be unremarkable, imaging of the lungsmay reveal thin-walled cavities, which are visualized betterwith computed tomographic (CT) scan.

Fusarium species are relatively and usually resistant totreatment with commercially available antifungal agents.Decreased immunosuppression is the most important factorin determining outcome. In vitro studies have indicatedthat AmB at high doses is the most active of the antifungalagents. However, the newer broad-spectrum triazoles (vor-iconazole, posaconazole, and ravuconazole) have variable invitro activity against Fusarium spp, and they have showedgood results and efficacy for the management of fusariosis[72,74]. In view of the inherent resistance of Fusarium spp tomost antifungal agents, AmB-based combination regimenshave also been suggested or used for fusariosis [75]. Giventhat AmB and voriconazole are the most active agents againstFusarium spp, a strategy combining a lipid formulation ofAmB with voriconazole is the antifungal scheme habituallyused at present.

3.7. Cryptococcus spp

Although Cryptococcus does not belong to the group ofemerging NAMF, we are going to make a brief commentaryon its emergent predisposition to cause several infectious


syndromes in transplant recipients [76-79]. Because inci-dence of Cryptococcus neoformans infection in HIV-infectedpatients has declined, organ transplant recipients havebecome the group of immunocompromised patients athighest risk for cryptococcosis. Although it is not consideredan endemic mycosis, the risk of developing cryptococcosismay be influenced by geographic region. The limitedepidemiologic information suggests most cases in SOT arecaused by C neoformans var. grubii (serotype A), andusually, most infections are developing late (N6 months) inthe posttransplantation period.

Unlike patients with HIV infection, among SOT recipients,Cryptococcus infection may cause other forms of clinicalpresentation, such as pneumonia and cutaneous or osteoarti-cular disease; curiously, CNS infections are less common [80].

In a recently review, C neoformans infection was docu-mented in 2.8% of the organ transplant recipients, with anoverall death rate of 42% [76]. Renal failure at admissionwas the only independently significant predictor of death inthese patients.

Current guidelines recommend that immunocompro-mised hosts (including transplant recipients) with non-CNSdisease should be treated in the same fashion as thosewith CNS disease, regardless of the site of involvement.Based on these guidelines, treatment should include anAmB product together with flucytosine for a 2-weekinduction with subsequent switch to fluconazole to completea minimum of 10 weeks of therapy. Assuming resolutionof disease, chronic suppressive doses of fluconazole shouldbe continued for 6 to 12 months. Fluconazole (or otherazole such voriconazole and posaconazole) monotherapyfor mild to moderate pulmonary cryptococcosis in thetransplant recipient has also been used with good response,although the actual clinical data to support this treatmentare limited.

3.8. Other emergent fungi

Other infrequent NAMF (Acremonium, Scopulariopsis,Paecilomyces, Trichoderma, Alternaria, etc), Pneumocystisjirovecii, rare yeast (Trichosporon spp, Blastoschizomycescapitatus, Geotrichum, Hansenula, Pichia, and Rhodotor-ula), and endemic mycoses (Histoplasma, Coccidioides,Blastomyces, Penicillium marneffei, etc) have not beenincluded in this review because of low or null incidence in LT.

4. Diagnosis

The diagnosis of invasive mycoses in immunosup-pressed patients poses significant clinical challenges. Infact neither radiological findings (patchy infiltrates orconsolidation) nor respiratory samples have a highspecificity. Symptoms of invasive mycoses are nonspecific,and initially, about 30% of cases are asymptomatic.Besides, Aspergillus is cultured from sputum in only 8%to 34%, and from bronchoalveolar lavage fluid (BAL) up to

62% of patients with invasive disease. Moreover, post LTairway colonization arises up to 55% (false positive). Infact, data revisions about aspergillosis in LT have demon-strated the paucity sensibility of an airway culture positivefor Aspergillus in evidencing IA [1,2,5].

4.1. Radiology

With regard to radiology, IPA may appear as single ormultiple nodular opacities, cavities, or alveolar consolida-tion. In fact, plain chest x-rays and CT scan are insensitiveand nonspecific in lung transplant patients. The halo sign,considered a highly characteristic radiographic early featurein neutropenic patients, is infrequently encountered andconsiderably less specific in SOT populations [1,2,81-83].Recently, in a retrospective analysis of a large cohort of SOTpatients [84], it has been demonstrated that severalradiological findings and patient characteristics, are inde-pendently associated with a specific etiology of pulmonarynodules (PNs). So, radiological feature of consolidation wasstrongly associated with infectious etiology regardless oforgan transplanted and that Epstein-Barr virus seronegativityand LT (compared with other organ transplant type) werestrongly associated with posttransplantation lymphoproli-ferative disorder. In addition, PNs found early in theposttransplant period (b90 days) were much more likely tobe due to Aspergillus than those that were diagnosed after90 days. Besides, radiographic features (nodule character-istics or size, distribution) were poorly correlated with theultimate PNs etiology. These findings have the potential forassisting in the selection of empiric therapy in the SOTrecipient with PNs, at least until the results of definitivediagnostic studies become available.

Other method as positron-emission tomography with18-fluoro-2-deoxyglucose (18FDG PET) for the diagnosis ofinvasive mycoses has been investigated recently in immu-nocompromised patients with proven IFI. 18FDG PETrevealed increased uptake corresponding to infected areasvisualized by conventional radiographic tools, even dis-closed small lesions unapparent on the CT scan. This studyconcluded that 18FDG PET is useful for the diagnosis andstaging of IFI; but whether 18FDG PET might be useful forassessing duration of IFI therapy should now be assessed ona larger-scale basis [85].

4.2. Non–culture-based methods

Given that diagnosis of IFI and IA can be problematic,recent efforts have focused on non–culture-based methodsand improved blood culture techniques to establish a rapiddiagnosis. In recent years, promising diagnostic assays havebeen developed, and serodiagnosis has become an importanttool in the management of some FI. However, multicenterstudies are needed to establish the diagnostic value ofgalactomannan (GM) in IA in SOT. In addition, studies ofthe sensitivity and specificity of polymerase chain reaction(PCR) assays for FI in SOT patients are required to establish

Table 1Rapid laboratory methods (not stains) for the diagnosis of frequent IFIs inorgan transplant recipients

Fungi Method Detection of (product)

Aspergillus Sandwich ELISA, LA GMQSAS (1→3)-β-D-glucanPCR Fungal DNA

Candida CH-agar Species of CandidaLA Species of CandidaELISA, enzymatic,IFI-IFA

Mannan/Enolase antibodiesAntibodies to Candida albicansgerm tubes

PCR Fungal DNA and rRNAQSAS (1→3)-β-D-glucan

Cryptococcus LA, ELISA Capsular polysaccharide antigenHistoplasma ELISA, EIA, RIA Histoplasma polysaccharide antigen

CF, IDA, RIA AntibodiesPCR Fungal DNA

Nonspecific PCR Fungal DNA

ELISA indicates enzyme-linked immunosorbent assay; LA, latex agglutina-tion test; QSAS, quantified spectrophotometric assay system; IFI, indirectimmunofluorescence test; IFA, indirect immunofluorescence assay; RIA,radio immunosorbent assay; CF, complement fixation; IDA, immunodiffu-sion assay; CH-agar, chromogenic agar.


their diagnostic value. Unfortunately, only some advances indiagnosis of aspergillosis have been achieved. In fact, theadvances in other opportunistic mycoses, including Can-dida, are scarce, only some new test that providesidentification of Candida 24 to 48 hours earlier thantraditional blood culture techniques (Table 1).

4.3. Galactomannan antigen assay (Platelia)

Galactomannan is a polysaccharide cell wall componentthat is released by Aspergillus during fungal growth. Thedetection of GM by sandwich enzyme immunoassay (EIA)has been approved by the US Food and Drug Administrationfor use in HSCT recipients, but there is few data in SOT[86,87]. In a study of 70 LT recipients, the sensitivity ofserum GM for the diagnosis of IA was low [88]. The testdetected only 30% of the cases of IPA and none of the casesof tracheobronchitis (cutoff value ≥0.66). In a meta-analysis[87], its sensitivity and specificity for SOT was 0.41 (range,21–64) and 0.85 (range, 80–89), respectively. Thus, the testhas demonstrated excellent specificity, but a low sensitivityfor the diagnosis of aspergillosis in this patient population.Patients with CF or chronic obstructive pulmonary diseasemay transiently have a positive test in the early posttrans-plant period. Given that alternate specimens such as BALmay prove to be advantageous in this population. Thepresence of GM in the BAL fluid therefore is likely to be abetter diagnostic indicator for hyphal growth than routinemycological culture. The unique study about the role of GMantigen in BAL for the diagnosis of IA has been assessedrecently in LT recipients; this study evaluates the use ofPlatelia Aspergillus EIA in BAL for the early diagnosis of IAin patients with LT [89]. At the index cutoff value of 0.5 or

greater, the sensitivity was 60% and specificity was 95%.Increasing the index cutoff value to 1.0 or greater yielded asensitivity of 60% and a specificity of 98%. So, an index of1.0 or greater in the BAL fluid in a lung transplant recipientwith a compatible clinical illness may be considered assuggestive of IA [89]. However, patients with IA receivingantifungal prophylaxis could have false-negative results(voriconazole, itraconazole). False-positive GM tests havealso been reported in patients receiving piperacillin-tazo-bactam in serum and BAL [89].

A recently introduced diagnostic test for IA is the (1→3)-β-D-glucan assay. (1→3)-β-D-Glucan is a cell wall poly-saccharide found in fungi that may be a marker of IFI.Sensitivities reported in the scientific literature are variableand seem to stem from differences among availablecommercialized assays. Unfortunately, controlled clinicaltrials regarding the use of (1→3)-β-D-glucan detection assaysamong patients at risk for IFI in lung transplant patients areunavailable, but there are some studies that include a fewSOT (majority cancer and allogenic transplant), which show(cutoff ≥80 pg/mL) a sensitivity of 0.71 and specify of 0.86for invasive mycoses diagnosis [90]. So that, detection of(1→3)-β-D-glucan may be useful in diagnosis of IFI but itmust be join to other identity fungal tools.

Finally, the appearance of new molecular techniques laysa new way in the diagnosis of the FI: the nucleic aciddetection. The use of PCR to detect invasive fungalpathogens (Aspergillus and Candida) has been reported,but false-positive results have limited its clinical use. Theubiquitous nature of some fungi in patient samples and in theair has resulted in false-positive results. Thus, furtherevaluation of this molecular assay is needed. A recentmeta-analysis to obtain an overview of the diagnosticaccuracy of PCR techniques (real-time PCR, PCR enzyme-linked immunosorbent assay, and nested PCR) for thediagnosis of IA has been performed in immunosuppressedpatients (mostly with hematologic al disorders). The analysisconcluded that PCR had a sensitivity and specificity of 0.70and 0.90, respectively. But, despite these good results, thepaucity of standardized methods decreases their use becauseof the difficulty to compare the obtained results [91]. Thefundamental disadvantage of these techniques is the highcost, the necessity of specialized personnel, lack ofstandardized commercial tests, and the lack of studiesthat demonstrate what type of sample and procedure isindicated [92].

5. Prophylaxis

Several prophylactic strategies with antifungal drugs havebeen reported to result in a decreased incidence and mortalityof fungal disease in LT recipients [93-95]. However, therehas not been a uniform approach, data are limited, andbesides, there is a considerable variation in antifungalprophylaxis practices among lung transplant centers


throughout the world. Most lung transplant programs areusing universal antifungal prophylaxis in the postoperativeperiod; about 30% use a preemptive approach for patientswith pre- and/or posttransplant fungal airway colonization.The antifungal agent used as the duration of prophylaxisvaries substantially from center to center [94]. It is clear thatthere is considerable uncertainty to which approach(prophylaxis or preemptive therapy) is most appropriate,which agent is the best, and what duration of prophylaxis orpreemptive therapy is needed. Antifungal prophylaxis inlung transplant recipients should be taken into account (theincidence of colonization, anastomoses healing, chronicrejection, and the time of LT), thus providing a rationale forthe duration of therapy.

To prevent IPA, multiple strategies and antifungal drugshave been used, such as oral itraconazole, voriconazole, oraerosolized AmB, used alone or in combination. Aerosolizedmedication regimens are an attractive option, as druginteractions and systemic toxicities are likely to be limited[96]. Several centers have reported on the safety ofaerosolized AmB deoxycholate (AmBd) with a variety ofdosing regimens [97-99], and others with aerosolized AmBlipid formulations [100-103]. Our institution has usedaerosolized AmBd as part of the post lung transplantprotocol since 1994 [98]. Since 3 years ago, we also areusing ABLC, with the same respiratory tolerability andsafety than aerosolized AmBd, but ABLC results morecomfortably for long periods of time (50 mg inhaled/weekly), and patients have better adherence to treatment.With respect to oral prophylaxis, a recent study [24] thatexamined the efficacy and toxicity of a strategy of universalde novo antifungal prophylaxis with voriconazole comparedwith targeted antifungal prophylaxis has been published. Themain finding of this study was that the overall rate of AI at1 year decreased to 1.5% with universal voriconazoleprophylaxis as compared with 23.5% with a targetedprophylaxis strategy. Interestingly, the rate of Candidacolonization, particularly non-albicans species, in thevoriconazole group was significantly higher [24]. In thevoriconazole prophylaxis cohort, 27% of the lung transplantrecipients had normal liver enzymes throughout the course ofthe study. The main handicap of this azole therapy is thestrong interaction with immunosuppressors that obliges tomonitoring calcineurin inhibitors to avoid toxicity orrejection. Other interesting finding was that universalvoriconazole prophylaxis did not increase the rate of non-Aspergillus FIs (specially, zygomycosis).

Newer azoles (voriconazole, posaconazole) with predict-able bioavailability should be preferred over the azole(itraconazole) with erratic bioavailability. Available echino-candins (caspofungin, micafungin, anidulafungin) have animportant role in antifungal prophylaxis because of theirantifungal profile, pharmacokinetics, and security; however,they are expensive and need intravenous administration.Lipid preparations of AmB appear to be ideal for inhalationaladministration; however, there are no rigorous pharmacoki-

netic studies in lung transplant recipients to determine theappropriate dose and schedule of their administration.Monforte et al [99,102,104] have demonstrated that aero-solized AmBd and lipid preparations of AmB are safe andachieve high concentrations in BAL fluid for the first24 hours and 14 days, respectively, after nebulization. Theselipid formulations allow a delayed administration (every 7 to14 days), which is rebounded better accomplished by patient.Although the incidence of FI seems to be reduced withaerosolized AmB prophylaxis, the efficacy of this approachhas not been determined in a large prospective clinical trial.Furthermore, without detectable levels of AmB in thecirculation, extrapulmonary FIs may not be prevented bythis strategy. Besides, it is important to take into considera-tion the type of delivery systems used for inhaled drugs[105,106]. In addition, contamination of the nebulizationsystems used in the prophylaxis with AmB nebulized in LThas been described [107]. The contamination of thenebulizing systems may be the origin of respiratory tractinfections, and it is frequent when no strict cleaning anddisinfection protocol are followed. Patients who did notfollow the standard protocol presented a greater isolation ofpathogenic bacteria in the sputum.

Another question is how long should be prophylaxismaintained. Most centers agree to apply universal prophy-laxis during first period posttransplantation (3 months) afterthis time, each center use a tailored prophylaxis. Besides, it isrecommended to use nebulized antifungal prophylaxis and/or preemptive therapy with antifungal agents (voriconazole)in patients with chronic rejection and respiratory samplespositive for Aspergillus, even without clinical or radiologicalsigns, mainly in single lung transplant patients due to thehigh risk of IA. This preemptive treatment should last for atleast 6 months, the period over which colonization has beenshown to precede disseminated infection [5], and in somecases, for life.

6. Antifungal therapy and management

AmBd has been the gold standard antifungal therapy foropportunistic FI for more than 4 decades. However, it isassociated with undesirable toxicities and is commonlyineffective, predominantly in those patients with advancedimmunosuppression. In addition, outcomes of salvagetherapy after progression of infection or toxicity afterinitiation of AmB are extremely poor. For these reasons,antifungal agents with better tolerability and efficacy havebeen needed without delay. In the last decade, several newagents have been introduced, including the lipid formula-tions of AmB, which significantly reduce the toxicity ofAmB and enhance its therapeutic index; extended-spectrumazoles, with improved activity against moulds; and echino-candins, a new class of antifungal with a mechanism ofaction against the cell wall. Despite increase of the antifungalarmamentarium over the past decade, the mortality rate

Table 2Antifungal agents against opportunistic and systemic mycoses

Agent Class Spectrum and clinicalindications

Mechanism of action Advantages Limitations Preferential toxicity andadverse reactions

Cost

AmBd Polyene Candida, Aspergillus,Zygomycetes, and otheropportunistic mycoses

Destabilizes the fungalcell membrane. Bindsto the sterol ergosterolincorporated in the fungalcell membrane, whichcreates pores in themembrane and leadsto depolarization of themembrane with subsequentcell leakage. In mammaliancells, polyenes bindcholesterol

Broad spectrum of activity,few resistant fungi

Dose-limiting re l andinfusion-related xicity;poor efficacy inimmunosuppres d hosts

Infusion-related and/ornephrotoxic: AmB-CDhaving the greatesttoxicity, and AmB-Lhaving the lowest

$

Lipid formulations ofAmB (AmB-L,ABLC, AmB-CD)

Broad spectrum of activity,similar to parent compound

Less toxicity than AmB Renal, infusion lated andother acute toxic ies (withAmB-CD havin thegreatest toxicity ndAmB-L having e lowest);few primary trea entstudies; expensi

$$$$ (AmB-L)$$$ (ABLC,AmB-CD)

Voriconazole Extendedspectrum azole

Aspergillus and other moulds;Candida, especiallynon-albicans and other yeasts

Interfere with sterolsynthesis via inhibitionof CYP-dependentC-14-α demethylase,a fungal CYP enzymeimportant in convertinglanosterol to ergosterol

Survival advantage vsAmB for IA(recommended primarytherapy for most patients);intravenous and oraldelivery

Extensive drug teractions;visual, liver, ski toxicities;azole cross-resis ncein yeasts. Possib need tomonitor plasmat levelsfor efficacy

Hepatic: $$/$$$

Possible benefit (both) incombination therapy foraspergillosis and othermoulds infections

++ (Oral/IV)

Posaconazole Zygomycetes and otheremerging FIs; salvage therapyand prophylaxis in patientswith leukaemia or HSCT,not in SOT patients

Activity against Zygomycetes;well tolerated in trials

Oral suspension nly;azole cross-resis nce

++ $$$

Caspofungin,micafungin,anidulafungin

Echinocandin Candida spp (candidemia,invasive candidiasis), salvagetherapy for Aspergillus(Aspergillus regulatoryapproval only forcaspofungin)

Inhibition of β-(1,3)glucan synthesis viainhibition of β-(1,3)glucan synthase. Fungalcell wall is mostlypolysaccharides, andglucans are the mostabundant polymers infungal cell walls.Glucan synthasecatalyzes polymerizationof these polysaccharides.Inhibition of this uniqueenzyme ultimately leadsto increased cellwall permeabilityand lysis of the cell

Well tolerated; anidulafunginmore effective vs fluconazolein one study of candidemia;micafungin equal effective vsAmB in one study ofcandidemia but less toxicity;micafungin not inferior to astandard dosage ofcaspofungin for candidemiaand other invasive candidiasis;anecdotal benefit incombination therapyfor aspergillosis; activity onbiofilms of Candidaspp in experimental models

Mould activity t getedto Aspergillus; p tentialcyclosporine int actionfor caspofungin xpensive.Non activity on egenera Cryptoco cus

Infusion-relatedand/or hepatic:

$$$$

+ (Caspofungin)+ $$$+ (Micafungin,

anidulafungin)

98A.Solé,

M.Salavert

/Transplantation

Review

s22

(2008)89–104

nato

sereitg, athtmve

inntaleic

ota

aroer; ethc

Others:Flucytosine Fluorinated

analogue ofcytosine

Treatment of seriousinfections caused bysusceptible strains ofCandida and/orCryptococcus spp.,principally in combinedantifungal treatment withAmB or azoles

Transported intracellularlyby cytosine permease.Converted to fluorouracilvia cytosine deaminase,and subsequently to5-fluorouridinetriphosphate, which isincorporated into fungalRNA and interfereswith protein synthesis.The flucytosineintermediate also inhibitsthymidylate synthase,and interferes withDNA synthesis

In combination, incrementedclearance of Cryptococcusin CSF; historical and recentstudies are favorable forcombination antifungal therapyin cryptococcal meningitis;disposable in oral andintravenous formulations

No commercialized inall the countries;gastrointestinal intolerancevery frequently; ivsolution if oral routecontraindicated; monitorserum creatinine and bloodcounts at regular intervals;precaution in patients withmoderate/severe renalor hepatic dysfunction

Hematologic:+++

$

Terbinafine Allyl-amine Any species of Candida,Cryptococcus, and mycelialfungi (especially Aspergillus,Scedosporium, anddematiaceous moulds); use incombination with azoles incases of multiresistant fungalpathogen in immunosupressedhosts; topical or oral therapyof dermatomycoses

Blockade of ergosterolsyntesis by escualeno-epoxidase inhibition,a fungal enzyme

Good absorption and adequatecorporal distribution withaccumulation in fat tissues;in vitro studies are favorablefor use in combination strategyvs panresistant fungi

Gastrointestinal intoleranceis common; importantinteractions with cyclosporineand rifampicine; precaution inpatients with moderate/severerenal or hepatic dysfunction

Hepatic: $++

Plus signs indicate degree of toxicity: +, mild; ++, moderate; +++, severe. AmB-CD indicates AmB colloidal dispersion; AmB-L, liposomal AmB; $, low cost; $$, intermediate cost; $$$, high cost; $$$$, veryexpensive; CSF, cerebrospinal fluid; IV, intravenous route; ABLC, amphotericin B liquid complex; AmBd, deoxycholate amphotericin B.

99A.Solé,

M.Salavert

/Transplantation

Review

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(2008)89–104


for IFI remains high in severely immunocompromisedpatients. Furthermore, in recent years, difficult-to-treat IFIcaused by emerging and rare moulds and yeasts has emergedin high-risk patients receiving antifungal prophylaxis orempirical treatment.

Three classes of antifungals (polyenes, extended-spec-trum azoles, and echinocandins) are now available fortreating systemic FI. Guidance for the appropriate use of thisexpanded variety of antifungals may come from latestclinical trials. Extended-spectrum azoles have excellent invitro activity against Aspergillus and have been shown toimprove clinical outcomes. For Zygomycetes, along with thelipid formulations of amphotericin, of the new agents, onlyposaconazole has activity. For Candida, the echinocandinsoffer a broad spectrum of activity. These new agents haveless toxicity and offer potentially improved efficacy in thesedifficult infections.

This expanded antifungal armamentarium present theclinician a number of new therapeutic choices but alsoelevate questions of where each new agent fits clinically.Clinicians must understand the advantages and limitations ofeach drug and drug class to optimally use these agents tomanage patients' invasive mycoses. Excellent, comprehen-sive reviews of the pharmacology, microbiology, andmechanisms of action of these antifungal drugs have beenpublished elsewhere, and the reader is referred to thosereports for more information [108-111]. This sectionexposed (Table 2) recent clinical evidence on the efficacyand limitations of these new agents and includes the author'sopinions on interpretation and clinical relevance of the data.

Surgical debridement, excision of localized infections(lung, sinuses, eye, brain, soft tissue, and bone), and removalof infected intravenous catheters is required in patientswith localized infections to delay or stop dissemination.Outcome of the IFI is associated with immune reconstitutionand neutrophil recovery in case of neutropenia associatedto transplantation.

The availability of new antifungal agents with uniquemechanisms of action and improved tolerability has widenedthe possibilities for the use of combination antifungaltherapy for difficult-to-treat opportunistic mycoses [112].Antifungal combinations are increasingly used in clinicalpractice to improve outcomes for refractory mycosesbecause of the suboptimal efficacy of current antifungalagents. However, the use of this therapy is largely governedby empiricism, especially in patients with invasive mouldinfections, for whom there is a tremendous need to improveoutcomes [113]. The benefits of combination antifungaltherapy have been difficult to prove for IFI other thancryptococcal meningitis. The recent introduction of severalnew antifungal agents has rejuvenated interest in studyingthose combinations for difficult-to-treat aspergillosis, asrecent observational studies show promise. Because of thedifficulties associated with the design and conduct of clinicaltrials of combination antifungal therapy for opportunisticmycoses, most studies evaluating antifungal combinations

are still performed in the laboratory or using animal modelsof infection. However, the methods used to assess combinedantifungal effects in vitro and in animals are poorlystandardized, and there is little evidence that data generatedfrom these studies can be translated in treating humanmycotic infections, especially in patients with SOT andHSCT [114,115]. Despite the empiricism of combinationantifungal therapy, certain principles help guide the use andstudy of these regimens [116]. In view of the evolvingepidemiology of IFI, combination antifungal therapy couldbe most valuable in preemptive management of carefullyselected high-risk patients; however, this should be studiedin appropriate trials.

No single randomized study on antifungal combinationtherapy in SOT patients has been performed [117]. Existinginformation does not support the use of combination therapyin invasive candidiasis in SOT patients. Indeed, initialcombination therapy with AmB and 5-flucytosine isrecommended for SOT patients with CNS cryptococcosis,mainly with increased white blood cell counts in thecerebrospinal fluid or with altered mental status. No impacton outcome was observed with combination therapy inScedosporium infections in SOT patients. The combinationof voriconazole and terbinafine may be an attractiveoption for S prolificans infections. A prospective study ofvoriconazole plus caspofungin as initial therapy for IAin SOT patients found that combination therapy wasindependently associated with reduced mortality in patientswith renal failure and in those with A fumigatus infection,even when adjusted for other factors predictive of mortalityin the study population [25]. In summary, combinationtherapy should be considered for severe forms of IFI in SOTpatients; however, multicenter studies of such patients areurgently needed.

7. Immune reconstitution syndrome

Although host immunity is crucial in the eradication ofany infection, immunological recovery can also be detri-mental and may contribute toward worsening diseaseexpression [118]. The concept of immune reconstitutionsyndrome (IRS) and its precise diagnosis in the context ofopportunistic mycoses remain poorly characterized. Immunereconstitution syndrome is best considered as a collection oflocalized and systemic inflammatory reactions of varyingdegrees that have both beneficial and noxious features duringan invasive mycosis.

Iatrogenic immunosuppression in transplant recipients isassociated with a dominant anti-inflammatory response.Reduction or withdrawal of these potent immunosuppressiveagents can rapidly lead to a shift toward a proinflammatoryphenotype, particularly if an invading pathogen is estab-lished in host tissue during immune suppression.

Recognition that IRS is a manifestation of a poorlycontrolled inflammatory response rather than direct treatment


failure of antifungal agents to eradicate or kill the fungus iscrucial to avoid unnecessary modifications in therapy.Reduction of immunosuppression in transplant recipientswith opportunistic infections is a common practice and isintuitively logical. However, concurrent withdrawal ofimmunosuppression and initiation of antifungal therapy havebeen shown to predispose not only to IRS but also allograft loss[119]. There is no proven therapy for IRS, and empiricaltreatment of symptomatic IRS in case reports or case series hasbeen attempted using anti-inflammatory agents [120,121],without precision and consensus established respect to certainaspects as agent, dose, or duration. Immunomodulatorytherapies are potentially promising and necessary as adjunctsin the management of FI and therefore balance in themodulation of the immune response will be essential.

8. Conclusion

This review highlights the risk factors and changingspectrum of IFI after LT. Despite the increasing impact ofviral infections in LT, FIs still have a main role in LT. In fact,they remain a common cause of morbidity and mortality inthe early and late post-transplant periods. Aspergillus sppand Candida spp account for most IFI, but recent epide-miological and clinical studies suggest the emergence ofmycelial fungi other than Aspergillus as well as resistantstrains of Candida in these patients. Because of the difficultyin making a definitive diagnosis, the treatment is sometimesdelayed or is not prescribed (postmortem diagnosis).Serological and molecular detection of Aspergillus antigensor fungal DNA, in blood and/or BAL samples, may improvethe diagnosis of pulmonary aspergillosis, but in SOT/LT, thesensitivity is variable and more studies are needed.

Another pendent issue is antifungal prophylaxis in LTrecipients; it is unknown which is the best agent or the timeduration. Nevertheless, universal aerosolized AmB prophy-laxis is currently used in most lung transplant programs. In theabsence of clinical trials, there are considerable expectationsregarding the efficacy of voriconazole or echinocandins forprophylaxis (preemptive therapy) in high-risk LT recipients(mainly colonized by filamentous fungus, unilateral LT, andchronic rejection). AmBd is poorly tolerated and associatedwith significant toxicity; for this reason, the only indication is,nowadays, nebulized prophylaxis. The last decade has seen thedevelopment of newer agents to treat IFI, which haverevolutionised the care of patients with invasive mycoses.

Treatment combining AmB preparations, newer antifun-gal drugs, early surgical resection of infected tissue, anddiscontinuation or modulation of immunosuppressive treat-ment can to be necessary in selected patients and in certainoccasions, and all of them may improve prognosis of IFI inLT. However, there are 2 main handicaps in the managementof FI in LT: firstly, to establish an early diagnosis; secondly,delays in applying early treatment with antifungal drugs.Development of new early diagnostic tools more precise and

well-designed multicenter evaluations of diagnostic methodsand therapeutic regimens available at present are theimportant work in the next 3 to 5 years.

AS declares no conflicts of interest. MS certifies that allsources of financial and material support for the accomplish-ment of this article/study are declared in the manuscript andthose relations of financial character established in the past 3years with any organization, entity, or company includeconsultancy/advisory board for Pfizer, Wyeth, Schering;honoraria/speaking fees for Pfizer, MSD, Gilead, Wyeth; andgrants from GSK, Wyeth.

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