Objectives: Aspergillosis is a common fungal infection among solid-organ transplant recipients. Even after awareness of this infection occurs, there are still gaps in nonculture diagnostic tests, which can delay treatment initiation. Here, we aimed to define the common traits of pulmonary aspergillosis infection among solid-organ transplant recipients, thus shedding light on prevention and early diagnosis.
Materials and Methods: We conducted a database search of patients at Baskent University who had a positive aspergillosis culture between January 2010 and March 2016. Among 20 patients identified, 15 (mean age of 50.93 ± 11.17 y, 2 female and 13 male patients) with solid-organ transplant were included in the study.
Results: Of the 15 study patients, 7 were heart transplant, 6 were kidney transplant, and 2 were liver transplant recipients. Three patients had positive aspergillosis cultures from extrapulmonary specimens (1 brain biopsy and 2 wound swap cultures). Other patients with positive cultures were from bronchoalveolar lavage (6 patients), sputum (4 patients), both bronchoalveolar lavage and sputum (1 patient), and deep tracheal aspiration specimen (1 patient). Aspergillus fumigatus was the most common species. Mean hospitalization duration was 31.53 days (range, 2-135 d). Although all patients had positive culture results, 7 patients (46.7%) had negative galactomannan test results at the time of culture specimen collection. Positive galactomannan test results were statistically higher in 6 heart transplant patients (P = .045). All patients had fever at presentation, and 13 patients had been referred to the pulmonary disease department before positive culture results were obtained.
Conclusions: Risk factors for pulmonary aspergillosis and its clinical presentation in solid-organ transplant recipients are still unclear. Although the expected time for aspergillosis infection in solid-organ transplant recipients is 6 months after transplant, clinicians must remember the nonspecific presentation of infections in these patients and be aware of the reliability of diagnostic tools.
Key words : Heart, Immunity, Infection, Kidney, Liver
Aspergillus is a mold that produces a variety of disease processes and is typically acquired by inhalation of the conidia. Chronic cavitary pulmonary aspergillosis, Aspergillus nodule, single aspergilloma, and allergic bronchopulmonary aspergillosis are forms that can be found in nonimmunocompromised patients with prior or current lung disease. Subacute invasive pulmonary aspergillosis (also known as chronic necrotizing pulmonary aspergillosis) is a more rapidly progressive infection (< 3 mo), which is usually found in moderately immunocompromised patients.1,2
Invasive aspergillosis is the form that threatens patients with prolonged neutropenia or severe immunosuppression. Solid-organ transplant recipients are one of the important groups who are susceptible to invasive aspergillosis. The type of organ transplanted and the level of immunosuppression affect both the timing and development of invasive aspergillosis. In the literature, the highest risk for invasive aspergillosis is known to be in patients who have had small bowel (11.6%) and lung (8.6%) transplants, followed by liver (4.7%), heart (4.0%), pancreas (3.4%), and kidney (1.3%) transplants.3
In this study, clinical, radiologic, and microbiologic features of invasive pulmonary aspergillosis in liver, heart, and kidney transplant patients were evaluated. Even after awareness of Aspergillus infection in transplant recipients occurs and despite the existence of diagnostic criterion standards, there are still gaps in nonculture diagnostic tests and the clinical presentation of invasive aspergillosis in patients with solid-organ transplant remains unclear. Thus, we aimed to define the common traits of pulmonary aspergillosis infection in solid-organ transplant recipients to shed light on prevention and early diagnosis.
Materials and Methods
We conducted a database search of patients at Baskent University who had a positive aspergillosis culture between January 2010 and March 2016. Among 20 patients identified, 15 patients older than 16 years old who had a solid-organ transplant were included in the study.
Diagnosis of invasive aspergillosis and data collection
The European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group have developed a consensus that classifies patients with aspergillosis or other fungal infections.4 It is accepted as proven invasive aspergillosis if the patient has had an “Aspergillus positive histopathologic, cytopathologic or direct microscopic examination of a biopsy material” or “Aspergillus positive sterile material” according to this consensus. If a patient was on immunosuppressive therapy for more than 3 weeks (steroid) or had recent neutropenia and had radiologic evidence on computed tomography scan, that patient was accepted as diagnosed with probable invasive aspergillosis.4
Patient demographics and type of organ transplant were noted. Positive Aspergillus cultures were evaluated according to specimen obtained (tissue, bronchoalveolar lavage fluid, deep tracheal aspirate, wound swap). We also obtained retrospective data on species identification that depended on pure cultures grown on media. Bronchoalveolar lavage fluid and serum galactomannan test results were noted.
Statistical analyses were performed with SPSS software (Statistical Product and Services Solutions, version 20.0, SPSS Inc, Chicago, IL, USA). Continuous variables are expressed as means ± standard deviation. Chi-square test was used to compare the qualitative variables. For investigation of the associations between nonnormally distributed or ordinal variables, correlation coefficients and their significance were calculated with the Spearman test. All P values were 2-sided, and values for P < .05 were considered statistically significant.
Mean age of the 15 study patients was 50.93 ± 11.17 years (2 were females). Demographics of the patients are presented in Table 1. Of the 15 patients, 7 were heart transplant recipients, 6 were kidney transplant recipients, and 2 were liver transplant recipients. Only 2 patients had chronic lung disease before transplant (bronchiectasis and cystic fibrosis). Three of the patients included in the study had positive aspergillosis cultures from extrapulmonary specimens (1 brain biopsy and 2 wound swap culture) but positive thoracic tomography findings at the same time. Other positive cultures for patients were from bronchoalveolar lavage (6 patients), sputum (4 patients), both bronchoalveolar lavage and sputum (1 patient), and deep tracheal aspiration specimens (1 patient). Aspergillus fumigatus was the most common species. Mean hospitalization duration of the patients was 31.53 days (range, 2-135 d).
Although all patients had positive culture results, 7 patients (46.7%) had negative serum galactomannan tests at the time that the culture specimen was taken. Positive galactomannan test results were statistically higher for 6 heart transplant recipients (P = .045). All patients had fever at presentation, and 13 study patients had been referred to a pulmonary disease department before culture results were obtained. Therefore, antifungal therapy was started for all of these patients before positive culture results were obtained. The 2 other patients were given antifungal therapy after culture results were obtained. Thoracic computerized tomography findings of the patients were as follows: dense, well-circumscribed lesions (nodules) in 10 patients, patchy consolidation in 1 patient, cavity lesion in 1 patient, consolidation and atelectasis in 1 patient, consolidation and bronchiectasis in 1 patient, and normal tomography in 1 patient. For this patient, the normal thoracic tomography changed to a patchy consolidation after 1 week (Table 2).
Six patients died after invasive aspergillosis diagnoses, with 5 being heart transplant patients and 1 being a kidney transplant patient. No association was found between death and type of organ transplanted (P > .05).
One kidney transplant recipient and 5 heart transplant recipients had received pulse steroid therapy due to rejection before Aspergillus cultures were obtained. A statistically significant relation was found between death and receiving pulse steroid therapy (P = .036)
Positive Aspergillus cultures for 4 heart transplant patients, 1 kidney transplant patient, and 1 liver transplant patient were obtained at the time of their hospitalization for transplant (timeline shown in Table 3). The other 9 patients had positive Aspergillus cultures during any hospitalization except hospitalization for transplant operation Nine of the patients required intubation in an intensive care unit (7 heart transplant patients, 1 kidney transplant patient, 1 liver transplant patient) within 1 month before they had shown positive Aspergillus cultures, with 6 of these patients remaining hospitalized for transplant.
The risk factors for pulmonary aspergillosis and its clinical presentation among solid-organ transplant recipients remain unclear. For liver transplant recipients, factors associated with invasive aspergillosis are reported as transplant for fulminant hepatic failure, retransplant, renal dysfunction (particularly when renal replacement therapy failure has occurred), cytomegalovirus infection, and prolonged intensive care unit stay.5-8 One liver transplant patient in our group had prolonged intensive care unit stay (22 days); the other risk factors were not found in our 2 patients with liver transplant. However, this might be because of the small number of liver transplant patients in our study. In renal transplant recipients, graft failure requiring hemodialysis and prolonged duration of corticosteroids are determined as risk factors for invasive aspergillosis. Among our 6 renal transplant patients, 1 required hemodialysis and was on pulse steroid therapy due to rejection period; this patient died after invasive aspergillosis diagnosis. The rejection period might be also the reason for mortality in this patient. Because pulmonary infections are known to be associated with mortality in renal transplant recipients,9 invasive aspergillosis should be suspected, especially in clinically unstable transplant patients. In heart transplant recipients, isolation of any Aspergillus species in respiratory tract cultures, reoperation, cytomegalovirus infection, and hemodialysis requirement after transplant are also reported as risk factors for invasive aspergillosis occurrence.10,11 In the 7 heart transplant patients in our study, 4 were hospitalized for transplant operation. All 7 heart transplant recipients were intubated at the time when positive cultures for Aspergillus were obtained from respiratory specimens. The heart recipients in our study group were clinically unstable compared with other organ recipients. Five of the heart transplant patients required hemodialysis and were started on pulse steroid therapy due to rejection, and all died after invasive aspergillosis diagnosis. Reoperation was not performed, and cytomegalovirus infection was not detected in any of the heart transplant recipients. The size of our sample, as a weakness of this study, was a restriction for evaluating the risk factors for invasive aspergillosis and its mortality. However, it is obvious that critically ill transplant patients must be evaluated for possible Aspergillus infection.
In the literature, the risk for invasive aspergillosis is known to be higher in liver transplant (4.7%) than in heart transplant recipients (4.0%).3 In our study, there were more heart transplant patients than liver transplant patients (7 heart vs 2 liver transplant recipients). This also might be due to our small sample size. Our sample size may have been small because of the excluded patients. We included 13 patients with probable and 2 patients with proven invasive aspergillosis patients in this study. However, patients with typical clinical and radiologic patterns for invasive aspergillosis were missed in our study due to lack of a positive culture result.
Bronchoscopy is a useful tool to evaluate patients who have negative sputum or deep tracheal aspiration cultures with typical clinical and radiologic patterns. Diagnosis of proven invasive aspergillosis requires histologic evidence and culture, but these may be time consuming and most of the patients may have unstable conditions. Bronchoscopies or other invasive procedures could not be performed in 8 of our study patients because of the patients’ clinical conditions. Among the patients who did not have bronchoscopies, 2 had negative serum galactomannan results. However, antifungal therapy was started in these 2 patients before culture results according to radiologic findings, and neither patient died or had graft rejection. It is also known that tracheobronchitis of Aspergillus without lung parenchyma involvement may lead to normal radiologic view, where the lesions can be visualized by bronchoscopy. In addition, the “halo” sign (ground glass opacity surrounding a pulmonary nodule and typically seen in angioinvasive aspergillosis) is rarely observed in solid-organ recipients with invasive aspergillosis.12 In addition, 75% of the initial halo signs disappear within 1 week and the “air crescent” sign does not appear until week 3 of the illness, even in nontransplant patients, with its appearance perhaps too delayed to be helpful in the diagnosis of invasive aspergillosis.13 These findings on diagnostic evaluation show the importance of blood galactomannan, which is a molecule found in thecell wall of Aspergillus species. Although the galactomannan test is a widely used assay, sensitivity and specificity in various patient populations are variable. In the literature, it is shown that the performance of the assay, in terms of sensitivity and specificity, decreases in solid-organ transplant patients.14
In our study, all patients had positive culture results, but 7 patients (46.7%) had negative serum galactomannan tests at the time when the culture specimen was taken. Positive galactomannan test results were statistically higher in 6 heart transplant recipients (P = .045). This might be because of the different immunosuppressive regimens in solid-organ transplant recipients. In addition, because the clinical conditions of heart recipients were worse, all of them were on antibiotics. After evaluation of patient data, we also found that all heart transplant recipients had been given piperacillin tazobactam for at least 14 days, which may cause a false positiveness on galactomannan results. Among renal and liver transplant recipients only 2 renal transplant recipients and 1 liver transplant recipient were given piperacillin tazobactam and for these patients, the duration of administration was less than 8 days.
In the literature, it is reported that 55% of Aspergillus infections are diagnosed more than 3 months after transplant.15 However, 6 of our patients (40%) had invasive aspergillosis before the third month of transplant. The early onset of invasive aspergillosis had a significant relation with rejection in this study (P < .05). This may be due to high cortisone treatment against rejection. In transplant recipients, a posttransplant need for hemodialysis is a known risk factor for early onset of invasive aspergillosis.16 In our study group, 5 patients (4 heart transplant recipients, 1 kidney transplant recipient) with early onset of invasive aspergillosis had died, and all 5 of these patients had required hemodialysis. Regardless of any diagnostic test, early administration of antifungal treatment must be kept in mind, especially in critically ill patients who are nonresponsive to antibiotic therapy or in rejection process.
After transplant, clinicians must remember the nonspecific presentation and onset of invasive aspergillosis and be aware of decreased reliability as well as decreased usability of diagnostic tools. New invasive aspergillosis prevention strategies and noninvasive diagnostic tools are critically required for optimal prophylaxis and treatment plans.
Volume : 15
Issue : 1
Pages : 214 - 218
DOI : 10.6002/ect.mesot2016.P91
From the 1Department of Pulmonary Diseases and the 2Department of General Surgery, Baskent University, Ankara, Turkey
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Balam Er Dedekarginoglu, Baskent Hastanesi Gögüs Hst AD, Fevzi Cakmak Cad, 5 sok, No 48, 06490, Bahcelievler, Ankara, Turkey
Phone: +90 533 234 7129
Table 1. Patient Demographics
Table 2. Thoracic Computerized Tomography Findings of Patients at Time of Positive Aspergillus Culture
Table 3. Timeline of Patients With Positive Aspergillus Cultures at Time of Hospitalization for Transplant