Invasive pulmonary Aspergillosis in organtransplants – Focus on lung transplants
Christian Geltnera,n, Cornelia Lass-Florlb
aDepartment of Pulmonology, Academic Hospital Klinikum Klagenfurt am Wörthersee, Feschnigstr. 11,A-9020 Klagenfurt, AustriabDivision of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
The number of patients with acquired immunodeficiency dueto transplantations, antitumor chemotherapies, antirheumaticdrugs, and various lymphocytotoxic monoclonal antibodies isincreasing. The results of solid organ transplantations for end-stage disease are promising, and the overall incidence of theseprocedures is increasing worldwide. In the United States, thetotal number of organ transplantations performed has reached28,000 per year. In 2013, more than 3800 lung and 4200 hearttransplantations were performed worldwide [1,2].
The overall 5-year survival rates range from 70% for lungtransplantations to 490% in heart and kidney transplanta-tions. This survival benefit and the favorable outcome mainlyresult from improvements in immunosuppression, anti-infective treatment, and surveillance strategies. Among awide range of adverse effects and complications after solidorgan transplantations, infections are very common andpotentially life threatening. The most problematic infectiousagents are viral and fungal pathogens.
Unlike in North and South America, where endemic fungalinfections such as cryptococcosis and blastomycosis occur with ahigh incidence, in Europe and Eastern Asia pulmonary fungalinfections are common in immunosuppressed patients withacquired or iatrogenic immunosuppression. Invasive pulmonaryaspergillosis (IA) is almost exclusively a disease of compromisedimmunity typically occurring in transplant recipients andpatients with acquired immunodeficiency syndrome; however,it is also increasingly seen in chronic steroid therapy, anti-tumornecrosis factor therapy, prolonged critical illness, severe chronicobstructive pulmonary disease (COPD), and after cardiothoracicand vascular surgery [3].
2. Incidence and frequency of filamentousfungal infections in solid organ and stem celltransplantations
In an incidence study on aspergillosis, Morgan et al. [4]presented results for invasive fungal disease. Lung transplant
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(cumulative incidence [CI], 3.5%/year) followed by allogeneic(CI, 2.3%/year) and autologous stem cell transplant (CI, 0.8%/year) and other organ transplant recipients were the mostcommon patients affected by fungal infections. The mortalityrate of invasive pulmonary mycosis was 53% and 76% inautologous and allogeneic hematopoietic stem cell transplan-tation (HSCT), respectively, whereas the mortality rate insolid organ transplant (SOT) patients ranged from 20% to66%. A prospective 2-year nationwide Austrian Aspergillosisregistry study [5] gives an insight into the local epidemiology,which depends very much on the respective transplant unit,and the local endemic situation and prevalence. This studyalso showed that patients with acute myeloid leukemia(AML), non-Hodgkin lymphoma, acute lymphatic leukemia,and various organ transplants are also prevalently affected.All patients had lung involvement; a third of the patients hadproven, probable, or possible aspergillosis of the lung accord-ing to the international EORTC/MSG (European Organizationfor Research and Treatment of Cancer/Invasive Fungal Infec-tions Cooperative Group and the National Institute of Allergyand Infectious Diseases Mycoses Study Group) classification[6,7]. The risk factors for the development of invasive fungaldisease were neutrophil count o500 cells/mm3, immunosup-pressive therapy, and corticosteroid therapy. Of the patients,43% received antifungal prophylaxis for Z7 days, of whom30% (24 patients) had a breakthrough fungal infection [2].Most of the detected fungal pathogens were Aspergillus spp.(67%), followed by mucormycetes (28%) and others (4%).Mortality depends on comorbidity. Among SOT patients,hepatic insufficiency, malnutrition, and central nervous sys-tem disease were poor prognostic indicators [8].
3. Aspergillosis and filamentous fungi afterlung transplantation
An overall increase of fungal infections is observed in lungtransplant recipients. In 2003, Singh [9] described a preva-lence of 6.5% of invasive fungal infections with a mortalityrate of 52%, the common sites of infection being the bronchial
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anastomoses. Invasive and disseminated fungal diseases
occurred in 34% and 22%, respectively.The local epidemiology is crucial: the largest German lung
transplantation program in Hannover describes fungal colo-nization in 28% of patients and invasive fungal infection in
5.6%; this fact led to a comprehensive oral prophylaxis withitraconazole or voriconazole [10]. Other centers describe areduction of incidence from 25% to 5% by means of achemotherapeutic prevention. The Austrian registry mainly
included lung-transplanted patients from Innsbruck with avery high incidence of Aspergillus terreus as well as anincreasing number of non-Aspergillus fumigatus fungal infec-
tions. The occurrence of infections after lung transplantation(analogous to other SOT) can be assigned to time. There is afrequency distribution in the occurrence of infectionsdepending on the time of transplantation (Fig. 1), and the
risk of IA in organ transplant recipients correlates with theintensity of immunosuppression [11]. Cytomegalovirus (CMV)infection and renal dysfunction are immunomodulatory con-ditions known to heighten the immunosuppressive state [12].
Infection with filamentous fungi is an independent riskfactor for the development of obliterative bronchiolitis(bronchiolitis obliterans syndrome, BOS) and correlates withprogressive organ failure [13]. The authors hypothesized that
colonization with small Aspergillus conidia is associated witha greater risk of BOS, based on an increased likelihood ofdeposition in small airways [14]. The lung itself is an open
system connected to environmental air and microbes. Itserves as an immunologically active organ; hence, a highimmune suppression is usually necessary to control acuteand chronic rejection. This explains the high incidence of
infectious complications compared with other organ trans-plant recipients. The use of antifungal prophylaxis (mostlywith itraconazole, voriconazole, and inhaled amphoterin B)
Fig. 1 – Timeline of infectious complications after solid organtransplantations (especially lung transplantations). The riskfor bacterial pneumonia is greatest in the first 4 weeks anddecreases after 3 months, whereas the risk forcytomegalovirus infection peaks after the discontinuation ofantiviral prophylaxis similar to pneumocystis. Molds,yeasts, and parasites mainly occur in the first 3–12 months.CMV, cytomegalovirus; HSV, herpes simplex virus; EBV,Epstein–Barr virus; PTLD, post transplantlymphoproliferative disease; PCP, pneumocystis cariniipneumonia. Modified from Ref. [35].
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compared with preemptive antifungal therapy showed a clearbenefit concerning the reduction of colonization rates [15].
4. Appearance of fungal infection in the lung
In immunocompetent patients, saprophytic aspergillosis maybe present in preformed pulmonary cavities (aspergilloma) oras small nodules. Allergic bronchopulmonary aspergillosis isa hypersensitivity lung disease that is associated with inflam-matory destruction of airways in response to Aspergillusspecies. It typically occurs in immunocompetent patientsassociated with IgE elevation, allergic asthma, and bronch-iectasis. Compared with immunocompetent patients, theclinical manifestation of fungal infection can vary in casesof immunosuppression.
Lung involvement is present in all SOT recipients, stemcell transplant (SCT) recipients, and other immunocompro-mised hosts. Systemic disease, fungal sepsis, and multiorganfailure can be a fatal complication. Aspergillus infections inthe lungs and other pulmonary mycoses have differentappearances.
4.1. Airway colonization
The significance of fungal colonization especially in trans-plant recipients is unclear. However, at any time, coloniza-tion may progress to IA. In immunocompromised patients,treatment recommendations are based on the presence ofrisk factors.
4.2. Invasive pulmonary aspergillosis
� Proven IA (biopsy proven, demonstration of fungal ele-ments in infected tissue).
� Probable IA (host factorþclinical factorþmicrobiologicalculture).
� Possible IA (host factorþclinical factor).
The criteria for host and clinical factors mentioned in theguidelines for the diagnosis of IA lead to the secure manage-ment of these patients.
4.3. Tracheobronchial aspergillosis and anastomositis
This manifestation of a semi-invasive and potentially inva-sive form of Aspergillus infection in lung transplant recipientscovers plaques, lawn fungus, ulcerations, pseudo-mem-branes, and granulation tissue within the bronchial system.This manifestation form of aspergillosis is typical for lungtransplant recipients.
As frequent laboratory monitoring and bronchoscopies areroutinely performed in lung transplantations, 80% could beclassified as “proven IA.” The features of invasive fungaldisease are shown in Fig. 2.
Bronchoscopic examination is the gold standard in diagnos-ing bronchial aspergillosis and fungal invasion. The anastomoticregion is the predominant site of infection. Fig. 3 shows typicalendoscopic views of different anastomotic diseases after lung
Fig. 2 – Features of Aspergillus infections in the lung. Typical radiological and endoscopic signs of invasive aspergillosis andnecrotizing anastomositis resp. tracheobronchitis after lung transplantation.
Fig. 3 – Endoscopic images of (1) necrosis and invasive bronchial infection, (2) fungal anastomositis at 6 weeks posttransplantation, and (3) normal anastomosis at 3 weeks post transplantation.
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transplantation. A “normal” anastomosis with tissue necrosisand some granulation is often present in the first months aftertransplantation (Fig. 3-3). This has to be distinguished from therare surgical complication of anastomosis dehiscence wherefistulae to the mediastinum sometimes become visible. Moldinfection, colonization with Aspergillus, or other invasive patho-gens are shown in Fig. 3-2. The worst scenario is a deepnecrotizing bronchitis with bacterial and fungal superinfectionand destroyed bronchial mucosa, and sometimes necrosis of theentire bronchial wall (Fig. 3-1).
Singh et al. showed that clinical outcomes were better inlung transplant recipients with nodular than nonnodularpresentations of IA. The mortality rate ranged from 25% to64%, respectively. Usually, cases of IA in lung transplantrecipients appear as pulmonary disease; disseminated asper-gillosis occurs infrequently. Indeed, the rates of disseminateddisease are generally lower in lung transplant recipients thanin other organ transplant recipients [16].
Recently, immunoreconstitution syndrome (IRS) wasdescribed as a new pathomechanism of lung disease. After
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the reduction of immunosuppression in case of the occurrenceof invasive fungal disease, an enhancement of symptoms andinfiltrates has been demonstrated [17]. Host defense againstAspergillus and other molds is mediated through T-helper cells.Th1 (CD4þ) cells (protection and enhancement of the antifungalactivity of polymorphonuclear cells against Aspergillus) and Th2cells (CD8þ) (facilitation of disease progression by inhibition ofphagocyte-mediated hyphal damage, oxidative burst, and Th1neutralization) are necessary for a sufficient antifungal defenseof the immune system [18,19]. The typical manifestations of IRSin lung transplants include the new onset or progression ofpulmonary infiltrates, consolidation, pleural effusions, cavita-tion, or respiratory failure.
5. Diagnostic measures in invasive pulmonaryaspergillosis
Radiologic examination supports the diagnosis of suspectedaspergillosis (possible or probable IA), and computed tomography
Fig. 4 – Forty-nine-year-old female patient (case 2) with bilateral lung transplantation for chronic obstructive pulmonarydisease and emphysema. Invasive aspergillosis (Aspergillus fumigatus) after therapy for steroid refractory acute rejection.
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(CT) scans help in the diagnosis of IA. In CT, typical signs ofinvasiveness are known as the perilesional halo sign and the air-crescent sign. In CT-angiography, invasivity can be suspected.The different patterns of mold infections are shown in Fig. 2 andhave been described above.
The gold standard of diagnosis consists of mycologicalculture and microscopic examination of the infected tissue.This can be achieved by means of CT-guided perthoracic needlebiopsy of solid infiltrations or coin lesions. In lung transplantrecipients, a bronchoalveolar lavage (BAL) and/or transbronchiallung biopsy is helpful in proving a diagnosis; culture positivitycan be achieved in only 50–70% of all cases, and resistancetesting is possible only when culture is available.
The value of serum galactomannan and PCR is limited inSOT patients; negative PCR results do not exclude invasivefungal infections, and panfungal PCR tests are available forthe detection of non-Aspergillus molds [20].
The use of galactomannan test in BAL (BAL-GM) fluid hasbeen evaluated previously and was reported to have reason-able results of higher than 90% sensitivity and specificity [21].The recently published largest study evaluating the accuracyof BAL-GM in hematologic patients undergoing bronchoscopyshowed a limited value and a very modest accuracy for thediagnosis of invasive fungal disease [22]. The definitive use ofBAL-GM for confirming the diagnosis of invasive pulmonarymycosis remains unclear. However, in combination withserum galactomannan and β-D-glucan, it can be a useful tool.
The diagnostic use of PCR in BAL is similar to that ofgalactomannan. The combination of both tests reaches a highnegative predictive value (95%), but only a moderate positivepredictive value [23].
6. Different cases of invasive mycosis in lungtransplant recipients
6.1. Case 1
A 54-year-old male patient was treated with unilateral lungtransplantation (left) for α-1-antitrypsin-deficiency (phenotypeZZ). The immunosuppressive regimen consisted of daclizumabinduction, tacrolimus, mycophenolate mofetil, and taperedsteroids. Four months after the transplantation, he developedpost transplant lymphoproliferative disease (PTLD) and there-fore received antitumor chemotherapy (R-CHOP) and
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alemtuzumab. As complication of the augmented immunosup-pressive therapy an infection with an invasive mold occurred.The disease started with a coin lesion. Later disseminatepulmonary infiltrates developed. Final diagnosis and cause ofmortality was invasive pulmonary mycosis due to Penicilliumchrysogenum [24].
6.2. Case 2
A 49-year-old female patient underwent bilateral lung trans-plantation for end-stage COPD and emphysema. Two yearsafter the transplantation, she had an episode of acute rejection(A2–3). Despite two steroid bolus therapy courses, she developedrecurrent and steroid refractory lung rejection 6 weeks later. Shewas treated with alemtuzumab after the third episode ofallograft rejection. Two months later, signs of pulmonary fungaldisease occurred, and she was treated successfully with vor-iconazole and caspofungin. The CT scan was suspicious for IA(probable IA). Infection was proven by the bronchio-alveolarlavage and transbronchial lung biopsy results. The culturerevealed A. fumigatus to be the invasive pathogen (Fig. 4).
6.3. Case 3
Fig. 4 depicts an endoscopic image of necrotizing bronchitis(invasive bronchial anastomosis) in a patient after bilaterallung transplantation. The site of the anastomosis is the targetsite in fungal tracheobronchitis. Complications occurred 14days after the transplantation in the presence of amphoter-icin B inhalation, which was given as routine antifungalprophylaxis. Bronchial biopsy revealed A. terreus as theinvasive pathogen, and a therapy with voriconazole andcaspofungin was started. Several weeks later, the centralbronchial system and the anastomoses appeared withoutany sign of Aspergillus infection. Early treatment of theselesions allows complete restitution ad integrum and preventsthe development of invasive pulmonary mycosis.
6.4. Case 4
Case 4 demonstrates a 52-year-old female patient who under-went bilateral lung transplantation in 2006 for COPD andemphysema. Three years after the transplantation and rou-tine immunosuppression with daclizumab, tacrolimus,mycophenolate, and steroids, PTLD (Epstein–Barr virusþ,
Fig. 5 – Chest radiograph (left) and computed tomography scan (right) of invasive pulmonary mycosis due to Absidiacorymbifera in a 52-year-old woman after treatment of post transplant lymphoproliferative disease with rituximab.
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CD20þ non-Hodgkin lymphoma) occurred. Treatment withrituximab caused a high level of immunosuppression and
was probably the basis for the development of invasive fungaldisease despite antifungal prophylaxis with posaconazole(200 mg tid). Bronchoscopic examination revealed invasive
mold infection due to Absidia corymbifera (Fig. 5).
7. Mycological spectrum and emergence ofnon-Aspergillus species
The most common filamentous fungi are A. fumigatus fol-lowed by Aspergillus niger, A. terreus, and A. flavus. Theoccurrence of non-A. fumigatus species is crucial, and knowl-
edge about these species is important for therapeutic deci-sions and outcome, especially in case of fungal invasion. A.
terreus is genuinely resistant to amphotericin B. In the lastyears, a shift to non-Aspergillus fungi has often been demon-strated in several studies. A retrospective analysis of 2898
SOT recipients by Stelzmüller at al. showed 12 patients with anon-Aspergillus infection in 2008 [25]. Rare species such asmucormycetes, Mucor sp., Pseudallescheria sp., and Alternaria
sp. occurred. Treatment with antithymocyte and antilym-phocytic monoclonal antibodies for PTLD was found to be tobe the main risk factor. Concomitant diseases and host
factors such as graft-versus-host disease (GvHD), diabetes,and chronic renal failure complicated the postoperative
course and led to higher levels of immunosuppression. Inlung transplant recipients, a similar trend was seen: 24% of atotal of 25 patients with invasive pulmonary mycosis showed
infection with mucormycetes and Penicillium species [26]. Inthese patients, a temporarily increased immunosuppressionoccurred because of refractory acute rejection or post trans-
plant lymphomas. Of the 25 patients with proven invasivepulmonary mycosis, 14 had classic fungal disease with A.
fumigatus, 5 with other Aspergillus species (A. terreus and A.
niger), and 6 presented with non-Aspergillus molds (Absidiasp., Scedosporium sp., Penicillium sp., and Mucor sp.). The
Hannover lung transplant group described an emergence ofmucormycetes as colonizers in 65 of 580 patients after lungtransplantation. Several of these colonized patients devel-
oped invasive diseases [27]. The treatment of fungal diseases
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in the presence of primary or secondary resistant pathogensin patients without host defense is challenging.
In 1995, cases of mucormycosis were described in a kidneytransplant recipient for the first time. A shift to lung transplantsoccurred later, and was published recently [28]. These molds arenaturally resistant to voriconazole and echinocandins. Thefrequent use of these new antifungals for prophylaxis and/ortreatment and high levels of immunosuppression are probablyresponsible for the widespread occurrence of azole-resistantfilamentous fungi in immunosuppressed patients [29].
8. Prophylaxis in HSCT
In all HSCT patients, prophylaxis with posaconazole (200 mgtid orally) or fluconazole (400 mg daily) is usually recom-mended [30]. Posaconazole is the drug of choice for theprophylactic treatment in allogenic SCT with GvHD and forAML. Fluconazole alone can be given for allogenic SCTrecipients without signs of GvHD. There is an IIB recommen-dation for inhaled amphotericin B in neutropenic patients.
Breakthrough infections after or during prophylaxis withposaconazole occur in up to 17% of patients. As seen in otherimmunocompromised patients, a shift to infections withnon-Aspergillus molds such as mucormycetes, e.g., Mucor orPenicillium spp., is observed [31].
9. Prophylaxis in SOTs
Usually, inhaled prophylaxis with amphotericin B or liposomalamphotericin is given in centers performing lung transplanta-tions. The duration of treatment is at least 3 months and/oruntil the complete healing of the anastomoses (see Fig. 3). Somecenters have changed to oral prophylaxis with voriconazole orposaconazole in the first month up to 1 year. Prophylaxis is
recommended in case of augmented immunosuppression dur-ing treatment of rejection, concurrent viral infection, especiallyCMV reactivation, administration of monoclonal antibodies(anti-CD54 or anti-CD20), or antilymphocytic substances. Sur-veillance and frequent bronchoscopies facilitate an earlydiagnosis.
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Husain et al. showed that voriconazole prophylaxis is anoption for the prevention of IA in lung transplant recipients.The use of voriconazole prophylaxis was associated with anincrease of liver enzymes in a significant percentage ofpatients [15]. However, recently published meta-analysis didnot show any benefit for antifungal prophylaxis; in lungtransplantations, the overall incidence of IA was equal inthe presence or absence of universal antifungal prophylaxis[32]. In general, an intensive monitoring with routine bronch-oscopies, radiological evaluations (chest radiography, CTscan), and clinical surveillance is recommended to reducethe risk of fungal infections.
10. Therapeutic considerations
The strategies for prophylaxis and for preemptive therapydepend on the local epidemiology and the risk of infection.The Infectious Diseases Society of America guidelines for thetreatment of invasive pulmonary mycosis provide recommen-dations for the diagnosis and treatment in these cases [33].Knowledge of the endemic situation and the resistance profileof pathogens involved in infections are essential for earlyintervention. Pathogen specification is usually not available atthe time of radiological or clinical suspicion of invasive disease.The occurrence of amphoterin B-resistant molds such as A.terreus, or the emergence of secondary resistance to voricona-zole or posaconazole, challenges the choice of antifungal drugsapplied as first-line treatment. In lung transplant recipients, theearly commencement of a sufficient antifungal pharmacother-apy is essential. Several epidemiologically based studies displaya high rate of primarily resistant molds responsible for fungalinfections (25%), e.g., mucormycetes or A. terreus. At ourinstitution, the rate of non-Aspergillus molds is 25%, and therate of A. terreus (primarily resistant to amphoterin B) is up to20%. Therapeutic algorithms have to be adapted bearing theseregional influences in mind (Fig. 6). The primary drug approachhas to be set depending on the probability of fungal invasivity
Fig. 6 – Therapeutic algorithm for the early treatment ofinvasive fungal disease in lung transplant recipients. Thechoice of the primary pharmacotherapy is dependent onlocal epidemiology and the individual risk of the patient. CT,computed tomography; BAL, bronchoalveolar lavage; BL,bilateral lung; TBB, transbronchial biopsy; IA, invasiveaspergillosis.
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and the individual risk situation of the patient. The first-line use
of echinocandins is recommended if Candida is more likely than
Aspergillus. Voriconazole is recommended in the case of prob-
able or possible IA. In case of countable risk of infections with
non-Aspergillus fungi, an upfront combination therapy can be
discussed unless typing and resistance profile is done. De-
escalation and modification of therapy starts after the final
diagnosis of the underlying pathogen, and with the availability
of resistance profiles.
11. Innate drug resistance of non-A. fumigatusspecies and therapeutic implications
Several of the molds mentioned have innate resistance to
various antifungal drugs. Aspergillus spp. other than A. fumigatus
are resistant to amphotericin B (especially A. terreus). The
antimycotic drugs of choice are therefore voriconazole, posaco-
nazole, or echinocandins. Mucormycetes are resistant against
voriconazole and have low sensitivity to echinocandins. Accord-
ing to ECIL-3 (Third European Conference on Infections in
Leukemia) guidelines, the options for the first-line chemother-
apy of mucormycosis include liposomal amphotericin B and
amphotericin B lipid complex. Posaconazole and a combination
therapy of liposomal amphotericin B or amphotericin B lipid
complex with caspofungin are options for second-line treat-
ment. Surgery is recommended for rhinocerebral and skin and
soft tissue diseases [34]. Penicillium spp. are mostly sensitive to
voriconazole and posaconazole but do not respond to ampho-
tericin or amphotericin lipid complex.The first-line therapy is difficult, and combination thera-
pies can be useful. As the exact typing of these molds is
usually not available at the time chemotherapies should be
started, the choice of drugs has to be influenced by local
epidemiology. The combination of two new drugs is recom-
mended until susceptibility testing is available.
12. Summary
Invasive pulmonary fungal infections are common in immu-
nosuppressed patients (SCT and lung transplant recipients).
Depending on the local epidemiology, an increase of non-
Aspergillus infections with mucormycetes, Alternaria sp., and
Penicillium sp. are on the rise. These pathogens are difficult to
treat; hence, early diagnosis is required. Prophylaxis is
recommended in specific cases.
Conflict of interest
Christian Geltner received honoraria for lecturing and travel
fees from Eli Lilly, Böhringer Ingelheim, Menarini, Novartis;
Cornelia Lass-Flörl was funded by Pfizer, Gilead Sciences,
Merck Sharp and Dohme, Astellas and Schering Plough and
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