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Emergence of Aspergillus calidoustus Infection in the Era of Posttransplantation Azole Prophylaxis

Egli, Adrian1; Fuller, Jeff2; Humar, Atul1; Lien, Dale3; Weinkauf, Justin3; Nador, Roland3; Kapasi, Ali3; Kumar, Deepali1,4

doi: 10.1097/TP.0b013e31825992f0
Clinical and Translational Research

Background Universal antifungal prophylaxis with azoles is commonly used after lung transplantation. We noted an increase in isolates of Aspergillus calidoustus in our transplant population and hypothesized that increasing azole use (universal prophylaxis since 2008) may be promoting this infection.

Methods Clinical and microbiologic data for A. calidoustus cases from 2008 to 2011 were extracted from chart review. For lung transplant patients, a case-control study was performed to determine risk factors, and incidence rates were calculated.

Results From 2008 to 2011, we identified seven organ transplant recipients and one hematopoietic stem-cell transplant patient with positive A. calidoustus culture results in bronchoalveolar lavage at a median of 13 months after transplantation (interquartile range, 4–39 months). Chest computed tomographic scan was consistent with fungal infection in six of eight patients, and the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria classified these as “probable” invasive aspergillosis. In the case-control study, there were no differences in immunosuppression, number of respiratory samples taken, length of intensive care unit stay, or rejection rates. Of controls, 33.3% received third-generation azole prophylaxis compared with 83.3% of cases (P=0.13). However, median duration of exposure was greater in cases than in controls (3 vs. 0 months, P=0.045). Fungal minimum inhibitory concentration for voriconazole was 4 µg/mL or greater for six of eight cases. Incidence rates in lung transplants showed an increase of A. calidoustus (0/1000 vs. 11.3/1000 patient-years in 2006–2007 and 2008–2011, respectively; P=0.018), whereas Aspergillus fumigatus cases decreased (73.9/1000 vs. 49.0/1000 patient-years, P=0.0066).

Conclusions Pulmonary A. calidoustus seems to be an emerging pathogen mainly in lung transplants. We suggest that third-generation azole use reduced the incidence of A. fumigatus, but the incidence of A. calidoustus, an azole-resistant fungus, was increased.

1 Transplant Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada.

2 Medical Microbiology, Provincial Laboratory for Public Health, University of Alberta, Edmonton, Alberta, Canada.

3 Lung Transplant Program, University of Alberta, Edmonton, Alberta, Canada.

4 Address correspondence to: Deepali Kumar, M.D., M.Sc., F.R.C.P.C., Transplant Infectious Diseases, University of Alberta, 6-030 Katz Group – Rexall Centre for Health Research, Edmonton, Alberta, Canada T6G 2E1.

A.E. is supported by the Swiss National Fund Grant PBBSP3-130963. D.K. received speaker honoraria from Pfizer, Astellas, and Merck and research grant for clinical trials from Astellas and Merck. A.H. received educational grant from Pfizer, Astellas, and Merck. J.F. received educational and research grant support from Astellas, Merck, and Pfizer and is a consultant and speaker for Pfizer.


D.K., A.E., and A.H. participated in making the research design and analyzing data. D.K., A.E., J.F., and A.H. participated in writing the article. A.E., J.F., D.L., J.W., R.N., and A.K. participated in performing the research.

Received 21 February 2012. Revision requested 12 March 2012.

Accepted 9 April 2012.

Invasive aspergillosis (IA) remains an important cause of short- and long-term morbidity and mortality after solid organ transplantation (SOT) (1). Aspergillus species is the most common cause of invasive mold infection in SOT recipients (2). The most frequent species isolated from transplant recipients are Aspergillus fumigatus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus nidulans, with IA incidence rates between 1% and 15%, depending on the type of transplant, operative techniques used, environmental exposure, and hospital epidemiology (2–4). IA has been attributed to 9.3% to 16.9% of all deaths within the first year of transplantation, possibly also reflecting the higher amount of immunosuppression during that period (1). Lung transplant recipients are uniquely predisposed to IA because of more potent immunosuppression, direct communication of the allograft with the environment, and the increased likelihood of pretransplantation colonization. Given these risk factors, many transplant centers use universal antifungal prophylaxis from 3 to 12 months after lung transplantation (5–7). The use of antifungal prophylaxis in organ transplant recipients, especially lung transplant patients, may contribute to the emergence of more resistant fungal infections caused by Zygomycetes, Scedosporium species, or more unusual species of Aspergillus (8, 9).

Aspergillus calidoustus belongs to the Aspergillus section “Usti,” a group of hyalohyphomycetes that have been described as emerging causes of IA, mainly in hematopoietic stem-cell transplant (HSCT) recipients and to a lesser extent in SOT recipients (10–15). A. calidoustus exhibits decreased susceptibility to azoles and is phenotypically similar to Aspergillus ustus, differentiated only by the ability of A. calidoustus to grow at 37°C (16). Because these are recently described species that were previously grouped with A. ustus, it is possible that previous human cases of A. ustus were actually caused by A. calidoustus.

We noted an increase in the number of patients with A. calidoustus in our transplant population since 2008, coincident with the time we began using universal voriconazole prophylaxis in our lung transplant population. There are limited reports of A. calidoustus and related species in organ transplant recipients, and we hypothesized that increasing use of third-generation azoles may be selecting for the development of azole-resistant Aspergillus infections. In this study, we examined the clinical and microbiologic characteristics of A. calidoustus infection occurring in transplant recipients at our center over a 5-year period, from 2006 to 2011. We also carried out a case-control study specifically in the lung transplant population to determine factors that may be contributing to the apparent emergence of A. calidoustus.

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Patient Population

We identified eight cases of A. calidoustus infection from 2006 to 2011. The transplant recipients were primarily lung or heart-lung transplant recipients (n=6) but also kidney transplant (n=1) and HSCT (n=1) recipients. Table 1 shows the baseline characteristics of eight identified transplant patients with positive A. calidoustus culture results. Median age was 49 years (interquartile range, 41–59 years). A. calidoustus was detected at a median of 13 months after transplantation (interquartile range, 4–39 months). For all patients, at least one bronchoalveolar lavage sample was positive. A. calidoustus was first isolated in three (37.5%) of eight patients in 2008, two (25%) of eight patients in 2009, one (12.5%) of eight patients in 2010, and two (25%) of eight patients in 2011.



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Underlying Risk Factors

Half of the patients had a diagnosis of chronic lung disease before the A. calidoustus positive culture result including bronchiolitis obliterans syndrome in lung transplant recipients (n=2/6 lung transplant recipients), non–small cell lung cancer in the kidney transplant recipient (n=1), and pulmonary graft-versus-host disease in the HSCT recipient (n=1). The HSCT recipient went on to receive a lung transplant for pulmonary graft-versus-host disease 9 months after diagnosis of A. calidoustus infection. Four patients also received augmentation of immunosuppression in the 6 months before diagnosis including antithymocyte globulin (n=3) and high-dose pulse corticosteroids for acute rejection (n=1). In addition, five (62.5%) of eight patients showed viral, bacterial, or fungal coinfection with the A. calidoustus positive sample (Table 1). There were no prolonged neutropenic episodes (>14 days) in the 3 months before isolation of A. calidoustus.

Interestingly, four patients experienced cytomegalovirus viremia in the 30 days before A. calidoustus diagnosis, with median viral load of 3150 copies per mL (range, 1750–39,000 copies per mL).

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Diagnosis and Antifungal Therapy

According to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, six of eight patients presented with “probable” IA, and two of eight patients were consistent with “possible” IA. According to the International Society for Heart and Lung Transplantation (ISHLT) criteria for fungal infection in thoracic transplant recipients, four of six lung transplant patients met the criteria for probable IA, and two of six patients were classified as “colonization” (17). Serum or bronchoalveolar lavage galactomannan testing was not performed on any of these patients. All patients underwent a chest computed tomographic scan, which showed evidence of nodules or “tree-in-bud” lesions in six of eight patients.

Table 2 summarizes prior azole exposure and therapy of patients along with their outcomes. Before the isolation of A. calidoustus, six (75%) of eight patients had been exposed to voriconazole for varying periods, and all but patients 2 and 7 were receiving voriconazole or posaconazole at the time of diagnosis. Voriconazole therapy was dosed at 200 mg orally twice daily. In these patients, voriconazole was used either for primary prophylaxis after transplantation or for treatment and secondary prophylaxis of a prior A. fumigatus pulmonary infection. Patient 3 was receiving posaconazole at the time of diagnosis of A. calidoustus. In this patient, minimum inhibitory concentration (MIC) to posaconazole was 8 µg/mL, greater than other patient isolates in whom there was no prior posaconazole exposure. Only two patients (one kidney transplant patient and one lung transplant patient) showed no history of voriconazole use (Table 2). The kidney transplant recipient had A. calidoustus isolated at the same time as diagnosis of small cell lung carcinoma. The lung transplant recipient developed A. calidoustus infection only 8 days after transplantation and showed no radiographic abnormalities on computed tomographic scan. The donor fungal culture results for this patient were negative, and the patient was clinically asymptomatic. Compared with patients receiving voriconazole, the voriconazole MIC of his isolate was lower at 2 µg/mL (Table 3). No therapeutic drug monitoring for azoles was performed for the seven organ transplant recipients, but the HSCT patient demonstrated a low serum voriconazole level of 0.39 µg/mL at the time of diagnosis of A. calidoustus and the appearance of new pulmonary nodules.





Because MICs were not available at the time of A. calidoustus isolation, changes in antifungals were up to the treating physician. Therefore, three of eight patients were initiated on combination antifungal therapy. Others were started on voriconazole (n=2), increased dosing of voriconazole (n=1), or kept on the same dose (n=1). In two patients, immunosuppression was reduced. We analyzed patient outcomes at 90 days after infection. Of the six patients with radiologic changes at the onset of infection, four remained stable, one progressed, and one death occurred within 90 days.

Table 3 summarizes the in vitro antifungal susceptibility results. Voriconazole MICs ranged from 2 to 8 µg/mL. Greater variability was observed with caspofungin minimum effective concentrations (range, 0.03–2 µg/mL). Voriconazole MICs were greater in patients with previous exposure to voriconazole (median, 8 vs. 3 µg/mL in those without previous exposure).

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Incidence and Risk Factors in Lung Transplant Recipients

From 2006 to 2007, a total of 74 lung transplant recipients were followed up for a total of 103,821 days, and from 2008 to 2011, a total of 197 patients were followed up for a total of 193,588 days. Incidence rates in lung transplants showed an increase for A. calidoustus (0/1000 vs. 11.3/1000 transplant-years in 2006–2007 and 2008–2011, respectively; P=0.018), whereas A. fumigatus cases decreased (73.9/1000 vs. 49.0/1000 transplant-years, P=0.0066), reflecting a reduction of 53.5%.

In the case-control study of lung transplant recipients, each of the six cases had two controls who were matched for age, gender, baseline lung disease, type of lung transplant (single/double), and follow-up time. When analyzed for other variables that could affect infection, most factors were similar between the two groups, including induction therapy or immunosuppressive regimens, number of respiratory samples taken, length of intensive care unit stay, and rejection rates (Table 4). However, 4 (33.3%) of 12 control patients had received third-generation azole prophylaxis compared with five (83.3%) of six cases (P=0.13). The median duration of exposure to third-generation azoles was greater in cases compared with control patients (3 vs. 0 months, P=0.045).



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Literature Review

Table 5 shows the review of literature on solid organ transplant recipients and HSCT patients with A. ustus–associated IA. A. calidoustus cases have not been described, but in many cases, details of species identification are not described. Therefore, many of the A. ustus cases could have been caused by A. calidoustus. For example, the initial description of A. calidoustus by Varga et al. (16) included the isolates described by Panackal et al. (12), which were eventually noted to be all A. calidoustus. Most cases have been reported in HSCT patients (n=15) with only 6 (28.6%) of 21 previous cases reported in organ transplant recipients. There were 9 cases of cutaneous disease, 17 cases of pulmonary disease, and 6 cases of disseminated disease mainly with cerebral infection. Overall mortality was high with death reported in 13 (65%) of 20 cases with 100% mortality in the 4 cases of cerebral disease. Excluding those with cerebral disease, the eight HSCT patients with fatal outcome received either amphotericin B formulation alone (5/8) or the combination of amphotericin B and caspofungin (3/8).



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We performed a 5-year review of A. calidoustus infection in transplant recipients at our institution. We found eight patients who were predominantly lung transplant recipients, half of whom presented with underlying chronic lung disease and had received either voriconazole or posaconazole before the isolation of the fungus. In our series, A. calidoustus was always isolated from the respiratory tract, in many cases along with copathogens. Four of six lung transplant patients fulfilled ISHLT criteria for probable IA (17). Approximately half had recent augmentation of immunosuppression, either induction therapy with T-cell depleting agents or therapy for acute rejection. In the case-control study, the duration of azole exposure was associated with A. calidoustus infection. In clinical practice, it would be important to identify Aspergillus isolates to the species level. A. calidoustus can be differentiated based on colony and cellular morphology and temperature requirements for growth. Optimal antifungal therapy is not well defined, although isolates tend to be resistant to azoles but sensitive to polyenes and echinocandins.

Our study is the largest series published to date of transplant recipients specifically with the newly described A. calidoustus species. The Transplant-Associated Infection Surveillance Network study showed an 8.6% cumulative 1-year incidence of IA in lung transplant recipients (2). In addition, there are increasing reports of emerging fungal infections after SOT especially in lung transplant recipients. One factor may be the universal use of antifungal prophylaxis. Starting in 2008, our lung transplant program instituted universal voriconazole prophylaxis beginning on the day of transplantation to 3 months after transplantation in all new lung transplants. Before this, voriconazole was only used for preemptive therapy in those with Aspergillus specie colonization or therapy for IA. We did not find A. calidoustus isolates in transplant recipients before 2008. We also document a significant 53% reduction of A. fumigatus cases after the start of prophylaxis.

Observational studies and our own epidemiological analysis indicate that voriconazole prophylaxis may lead to significant reduction of IA associated with A. fumigatus (5–7); however, in our patients, breakthrough infection with A. calidoustus raises concerns about selecting for strains with decreased antifungal susceptibility. A. calidoustus is reported to have higher MICs to azoles (16, 26, 27). In our center, we observed a significant increase of A. calidoustus cases since the introduction of third-generation azole prophylaxis; six of our eight patients had previous third-generation azole exposure. Voriconazole MICs in patients who previously received voriconazole (patients 1, 3, 4, 5, 6, and 8) were elevated compared with those who had not been exposed (patients 2 and 7). In addition, the patient receiving posaconazole (patient 3) showed an elevated MIC to this antifungal.

In addition, some patients had recently had augmentation of immunosuppression. In our case-control study, the cumulative exposure time to azole prophylaxis was the only significant different risk factor (3 vs. 0 months, P=0.045).

Because A. calidoustus is an emerging species, there are no specific case series for this pathogen in transplant patients. Clearly, these cases occur since isolates of A. calidoustus from transplant patients are often included in larger series of Aspergillus susceptibility testing and molecular identification, but these have not been described in detail (16, 26, 27). It is also likely that these infections were previously classified as A. ustus. Therefore, we reviewed data for both pathogens in the setting of transplantation. We noted that this pathogen is more commonly reported in HSCT patients. High mortality was noted in the reports of HSCT recipients, although this may in part be caused by underlying disease. In our series, we only found pulmonary infections, and no disseminated disease was seen. Similar to our cases, reported patients were generally treated with a variety of antifungal combinations. In the reported literature, survival was variable and not related to any particular therapy. However, the organ transplant recipients who survived were mainly on a terbinafine-based combination. Surviving HSCT patients received a combination of voriconazole and caspofungin. However, surgical resection was also used in many cases as an adjunct therapy and may improve outcomes.

Limitations of our study include the retrospective design. However, our case series is the largest to date in the organ transplant population. Although most of our cases are consistent with probable IA, fungal colonization cannot be excluded. Nevertheless, all our patients were immunosuppressed and showed pulmonary nodules or cavities in several cases suggestive of a fungal cause. Finally, an outbreak of A. calidoustus cannot be excluded given that this organism has previously been described in nosocomial water systems (28). However, all the epidemiological factors including time after transplantation, types of transplant, and the location in which patients underwent bronchoscopy varied, making a single source unlikely.

Overall, our case series suggests the emergence of invasive pulmonary A. calidoustus infection in immunosuppressed transplant recipients during azole use. Because prophylaxis is adopted more widely, unusual drug-resistant fungi are more likely to be seen.

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Study Participants

A retrospective review of the clinical microbiology laboratory database was conducted to identify cases of culture positive for A. ustus or A. calidoustus at our institution between January 2006 and January 2011. From this search, we selected to review in detail the clinical information of solid organ transplant or HSCT recipients and determine susceptibility profiles for isolates from these patients.

All transplant patient charts were reviewed for demographics, type of organ transplant (heart, lung, liver, kidney, or combined) or type of stem-cell transplant (allogeneic or autologous), time after transplantation, immunosuppressive regimen, neutropenia, coinfections, cytomegalovirus viremia in the 30 days before diagnosis, acute rejection in the 30 days before diagnosis, imaging studies, pulmonary function testing, antifungal prophylaxis and treatment, and outcome. Descriptive statistics were used for data analysis.

Fungal infections were defined as colonization, probable infection, or proven infection based on the criteria defined by the ISHLT for thoracic transplants only (17). Infections were also categorized using the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria for all patients (29).

Literature review of A. ustus and the newly described species A. calidoustus infection in solid organ transplant and HSCT recipients was conducted using PubMed and search terms Aspergillus calidoustus, Aspergillus ustus, and transplantation.

The study was approved by the institutional research ethics board.

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Identification of A. calidoustus and Determination of MIC

A. calidoustus was identified based on colony and cellular morphology, including columnar conidial heads and echinulate conidia, and by growth (≥30 mm) on Czapek agar after 7 days incubation at 37°C (16). Antifungal susceptibility testing was performed by broth microdilution according to the Clinical and Laboratory Standards Institute M38-A2 standards document (30). These were reported as MICs for azoles and minimum effective concentration for caspofungin.

Susceptibility results were done as part of this study and were not available to the treating physicians at the time of diagnosis.

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Case-Control Study

A case-control study was performed for only the lung transplant recipients. Lung transplant recipients with A. calidoustus infection (n=6 cases) were matched to a historical cohort of lung transplant recipients without infection and underwent transplantation between January 2006 and December 2007 (2:1 ratio, n=12 controls). Controls and cases were matched for age, gender, baseline disease leading to lung transplantation, and single or double lung transplants. Controls were followed up to the time point that A. calidoustus infection was diagnosed in their respective matched cases.

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Statistical Methods

Incidence rates for A. calidoustus and A. fumigatus in the lung transplant population between the periods 2006 to 2007 and 2008 to 2011 were calculated. This was performed using the date of transplantation, date of death, and date of the last follow-up. SPSS version 19.0 (SPSS Inc., Chicago, IL) was used to perform statistical analysis.

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The authors thank Ms. Sandy Shokoples for her technical assistance in susceptibility testing. The authors also thank Ms. Kathy Jackson from the lung transplant program, Mr. Chris Broscheit from pharmacy, and Ms. Leticia Wilson for their assistance in data collection.

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      Immunosuppression; Solid organ transplantation; Hematopoietic stem-cell transplant; Antifungal therapy

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