Infectious Diseases, 2015; Early Online: 1–7
Original article
Invasive fungal infections in pediatric hematopoietic stem cell transplant patients
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Tiffany Simms-Waldrip1, Galit Rosen2, Karin Nielsen-Saines3, Alan Ikeda1, Berkley Brown1 & Theodore moore1 From the 1Department of Pediatrics, Division of Hematology/Oncology, Mattel Children’s Hospital at UCLA, Los Angeles, CA, 2Department of Pediatrics, Division of Hematology/Oncology, Phoenix Children’s Hospital, Phoenix, AZ, and 3Department of Pediatrics, Division of Infectious Disease, Mattel Children’s Hospital at UCLA, Los Angeles, CA, USA
Abstract Background: Pediatric hematopoietic stem cell transplant (HSCT) recipients are at high risk of invasive fungal infections (IFIs). Methods: To characterize IFIs and changes in fungal organisms over time in pediatric HSCT patients, we performed a retrospective cohort study of all HSCTs performed in pediatric patients at UCLA between 1991 and 2006. Results: In all, 318 patients underwent 324 HSCT transplants over the 15-year period and 69 unique fungal infections were identified in 47 transplant patients. The overall incidence of fungal infections in HSCT recipients was 14.5%, with predominant organisms including Candida species (51%) and Aspergillus species (26%), with Candida albicans accounting for 18.8% of all fungal species. The distribution of organisms over time demonstrated a strong trend towards an increase in rare molds in more recent years. The respiratory tract was the main site of infection (52.6%), with urine and blood also noted as significant sites. Of all deaths in the patients with IFIs, fungal-related mortality accounted for 67.6% of deaths. Conclusions: HSCT patients have a much higher risk of fungal infections with rarer organisms becoming more prevalent, a finding likely linked to evolving antifungal practices over time. This emphasizes the need for the development and implementation of improved diagnostic, prophylactic, and therapeutic strategies to improve patient survival.
Keywords: Fungal infections, HSCT, stem cell transplant, pediatric, Candida, Aspergillus
Introduction Immunocompromised patients are at serious risk for invasive fungal infections (IFIs), a major cause of morbidity and mortality in patients undergoing pediatric hematopoietic stem cell transplantation (HSCT) [1–7]. Several risk factors for increased susceptibility to fungal pathogens have been identified in this population, including graft versus host disease (GVHD), prolonged neutropenia, immunosuppressant therapy, delayed immune reconstitution, the use of indwelling catheters, and broad-spectrum antibiotics [1,5, 8–10]. Recipients of allogeneic donor sources are at greater risk of acquisition of IFI compared with their autologous counterparts, secondary to increased incidence of GVHD and longer use of immunosuppressants with delayed immune reconstitution [4,11]. These patients also experience longer periods of neutropenia while awaiting engraftment. Likewise, those
undergoing HSCT with umbilical cord blood are at greater risk for IFI due to prolonged neutropenia and prolonged immune reconstitution [11].The increased use of empiric therapy with broad-spectrum antibiotics is likely also a contributor leading to changes in nosocomial and endogenous flora, and thus rendering patients more susceptible to fungal infections [12–14]. Candida and Aspergillus species have classically been the most common infectious fungal etiologies in hematopoietic stem cell (HSC) recipients [5,6,9], although changes in transplant practices have led to variations in infectious patterns with the emergence of other resistant fungal pathogens [4,15]. The incidence of aspergillosis in transplant patients continues to increase, conferring significant morbidity and mortality. Invasive non-Aspergillus mold infections have also recently become a more frequent cause of
Correspondence: Karin Nielsen-Saines MD MPH, Division of Infectious Diseases, David Geffen UCLA School of Medicine, MDCC 22-442, 10833 LeConte Ave, Los Angeles, CA 90095, USA. Tel: 1 310 206 6640. Fax: 1 310 825 9175. E-mail: [email protected] (Received 16 June 2014; accepted 27 October 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.985709
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infection in HSCT recipients [1,4,15,16]. Current evidence-based guidelines for both pediatric and adult patients recommend prophylaxis with fluconazole following HSCT to prevent invasive yeast infections [17]. Fluconazole provides excellent coverage against many Candida strains and has successfully decreased the incidence of infections by these strains. However, fluconazole lacks reliable activity against Aspergillus as well as many non-Aspergillus species [5,6]. Activity against more resistant Candida species, including C. krusei and C. glabrata, is also lacking. As a result, IFIs induced by fluconazoleresistant fungi have become more prevalent [18], resulting in the development of studies that evaluate the performance of broader spectrum fungal prophylactic agents in HSCT patients. We reviewed all IFIs occurring in pediatric HSCT patients from 1991 to 2006 to identify the trends and characteristics of fungal infections in the pediatric HSCT population in order to understand the magnitude of the problem, a critical step towards future development of prevention and therapeutic strategies.
Materials and methods Patients A retrospective cohort study design was used to evaluate all pediatric patients (aged 0–21 years, mean age 15 years) who underwent either allogeneic or autologous HSCT at the Mattel Children’s Hospital at UCLA from January 1, 1991 until December 31, 2006. The medical records of each patient were individually reviewed. In total, 324 HSCTs were performed in 318 patients during the observed time period. The vast majority of transplants performed in our unit during that time period were allogeneic.
istress, and a gamut of signs and symptoms suggesd tive of a serious invasive infection, as described in prior studies from our institution) [19,20]. Documented and presumed IFI (i.e. with a positive culture in the first case from a sterile site or identification of a fungal organism from a non-sterile site in the presence of constitutional symptoms in the second case) that were subsequently treated with a course of antifungal agents were considered as cases in this study. Fungal colonization was defined as positive cultures obtained from non-sterile sites such as sputum or bronchoalveolar lavage (BAL), particularly in the absence of clinical symptoms. The date and indication for transplant, donor source, date of first positive culture, fungal species isolated, site of infection, and age of patient at time fungal infection were documented, and absolute neutrophil count at time of infection and outcome were obtained for each infectious episode. Neutropenia was defined as an absolute neutrophil count of 500 103/L. Indication for transplantation was categorized as lymphoid leukemia, myeloid leukemia, solid tumors, and others. In a single patient with multiple unique fungal infections, outcome for each individual IFI was considered. Fungal-related death was determined based on the cause of death as stated in the patient’s medical records. The study was approved by the local institutional review board. Statistical analysis The chi-squared test was utilized for associations between variables. Trends were assessed with simple linear regression. All analyses were performed using SAS 9.1. p values of 0.05 were considered statistically significant.
Methods
Results
Microbiology laboratory records of all positive fungal cultures and radiology reports indicating a disease process were compared to the patient’s medical record and our transplant service database to identify those transplant patients with proven or suspected invasive fungal infections. A detailed chart review was performed for each transplant recipient, with findings cross-referenced to microbiology and radiology results. Pathology reports were also assessed when available. An IFI was defined as isolation of fungus from a normally sterile site, or surgical, histologic or radiographic evidence of invasive infection despite negative cultures from sterile sites in the presence of constitutional symptoms (such as prolonged high grade fever, blood pressure instability, respiratory
A total of 69 unique fungal infections were identified in 47 HSCT recipients over the observed time period. The overall incidence of IFIs in HSCT recipients from 1991 to 2006 was 14.5%, with 47 of 318 patients having evidence of infection. Upon further stratification of the cohort by transplantation period, patients undergoing HSCT between 1991 and 1996 had an incidence of IFI of 15.5%, whereas patients receiving HSCT from 1997 to 2001 and 2002 to 2006 had an incidence of 10.7% and 16.2%, respectively (Figure 1). An overall trend in incidence of IFI was not observed. The vast majority of IFIs occurred in allogeneic transplant recipients. A variation in the prevalence of IFI based on indication for transplantation was not noted,
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Invasive fungal infections in pediatric HSCT patients
Figure 1. Incidence of invasive fungal infections (IFIs) in hematopoietic stem cell transplantation (HSCT) patients.
with the exception that autologous transplant recipients did not tend to develop IFI. Candida species caused the majority (51%) of fungal infections in the patient population, with Aspergillus species accounting for 26%. A variety of other fungal species comprised the remainder of infections (Table I). The distribution of organisms over time demonstrated a strong trend towards an increase in Aspergillus species and rare molds in more recent years, although this was not statistically
significant (Figure 2). The overall incidence of candidal infections decreased in linear fashion over the study time period, with a striking decrease in incidence of C. albicans infections. This decrease was offset by a slight increase in fluconazole-resistant strains, C. glabrata and C. krusei. This phenomenon coincides with the widespread implementation of fluconazole prophylaxis for pediatric HSCT recipients at our institution during the third period of observation. In the years 1991–1996 the incidence of Aspergillus infections was 3.9% compared with 9.9% during 2002–2006 (p 0.0425). Likewise, the transplant population has seen an increase in infections with non-Candida and non-Aspergillus species, which totaled 12% of all IFIs between 1991 and 1996 and comprised 24% of all IFIs between 2002 and 2006, although this did not reach statistical significance. This finding is in comparison to a similar study at the same institution, evaluating IFIs of all hospitalized pediatric patients, both immunocompromised and immunocompetent, where Candida species accounted for 91% of the cases [20]. The respiratory tract was the most common site of infection (52.6%), followed by infections in the blood (14%) and urine (11.5%) (Table I). Respiratory cultures included deep sputum, BAL, bronchoscopy, sinus cultures, and lung biopsy specimens.
Table I. Characteristics of cohort over time. Characteristic Age at time of IFI (years) 3 3–12 12 Neutropenia at time of IFI Type of IFI Yeasts C.albicans Non-albicans Molds Aspergillus Non-aspergillus Site of IFI Respiratory tract/sinus Blood Urine CSF/brain GI tract Other Mortality Death from IFI Total BMT Mean BMT day of infection All IFIs
1991–1996 (n 23)
1997–2001 (n 18)
3 12 8 12 (52%)
1 10 7 12 (67%)
2002–2006 (n 28)
1991–2006 (n 69)
p valuea
2 6 20 7 (39%)
6 28 35 31 (45%)
0.0148a
15 7 8 8 5 3
9 2 7 9 2 7
11 4 7 17 11 6
35 13 22 34 18 16
11 3 3 1 3 2
7 3 3 1 3 1
23 5 3 2 1 3
41 11 9 4 7 6
10 10/111 (9%)
25 25/324 (7.7%)
10 5 10/129 (7.8%) 5/84 (6%) 51.17
91.39
NA
68.30
0.0425a
0.033
BMT, bone marrow transplant; CSF, cerebrospinal fluid; GI, gastrointestinal tract; IFI, invasive fungal infection; NA, not available; aChi-squared test; only values 0.05 are listed.
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Figure 2. Distribution of fungal organisms over time.
There was a broad range of fungal organisms associated with respiratory infections, ranging from Candida species to Aspergillus and infections due to rare molds. In 83% of patients with identified Aspergillus species, the infection was localized to the respiratory tract only. Also, 100% of urinary tract infections were caused by Candida species. The diagnosis of infection due to fungal pathogens was made by the clinician at the time of infection. All patients experienced a period of neutropenia post-transplantation. Patients with fungal infections were found to be neutropenic at the time of diagnosis in 45% of all episodes (Table I). We evaluated the data for any difference in IFI in transplants performed with peripheral blood (5%), bone marrow (55%) or umbilical cord (40%). Although umbilical cord blood recipients tend to have a longer period before engraftment, there was no increase in incidence in IFI with cord blood recipients (p 0.76). Of the 318 patients who underwent HSCT during the study period, 142 subsequently died (43.8%), with fungal infections accounting for 7.7% of deaths in this population (Table I). Of the 47 pediatric transplant recipients with a history of fungal infections, 37 ultimately died (80%), with fungal-related mortality accounting for 25 deaths (67.6%) (Figure 3).
[19,20]. In the present HSCT pediatric patient population, where extended periods of neutropenia are expected, the prevalence of this finding at the time of diagnosis of IFI ranged from 39 to 67%. Development of IFI in our patient populations occurred later in the transplant course. It is often difficult to determine the true incidence of fungal infections. A large proportion of HSCT patients develop fever and signs of infection while maintaining negative cultures. The majority of these patients receive prolonged empiric antifungal therapy with successful resolution of their symptoms. A subset of these patients may have had undiagnosed fungal infections due to the poor sensitivity of cultures for IFI [24]. In one study of adult patients with hematologic malignancies, sensitivities of blood cultures for candidiasis and aspergillosis were only 21.3% and 1.1%, respectively, when compared with autopsy-based evidence of IFI [25]. In the present study, there was also a high rate of positive respiratory and urine cultures, likely reflecting
Discussion At our medical center the overall incidence of fungal infections in children undergoing HSCT was 14.5%, which is compatible with prior studies [21–23]. IFIs remain a serious threat to HSCT recipients, both acutely and for years following HSCT. In prior studies we have found that IFIs are significantly associated with the extent and duration of neutropenia
Figure 3. Mortality from invasive fungal infections (IFIs) in patients undergoing hematopoietic stem cell transplantation (HSCT).
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an overestimation of infection. This reiterates the importance of developing and utilizing more sensitive and specific non-invasive diagnostic methods through radiographic and molecular approaches for improved administration of timely and directed antifungal therapy. The patients evaluated in this study were transplanted over a long period of time during which many advances in transplantation were developed, including improved diagnostic methods for infections and the introduction of new antibacterial, antiviral, and antifungal agents [2]. During the first two time periods of our study, antifungal prophylaxis was not routine for pediatric HSCT patients at our institution. During the third observation period, fluconazole prophylaxis became the standard of care for pediatric HSCT patients at our institution. An apparent increase in the incidence of invasive fungal infection may actually be due in part to improved diagnostic capabilities, which may more accurately represent what was previously under-reported. The use of high-resolution CT scanning has greatly improved our ability to diagnose deep-seated fungal infections in the absence of a positive culture [26–29]. Bronchoscopy with BAL has also expanded our diagnostic arsenal. Similarly, a number of serologic assays, including utilization of PCR and ELISA, have been developed and are routinely employed. Galactomannan assays are now in widespread use for detection of invasive aspergillosis infections, but may have limited utility in the younger pediatric population [30]. Our study has limitations in that it was retrospective, used a broad definition of IFI and was subject to temporal variations and changes in medical diagnostic and therapeutic practices over time. Nevertheless, our aim was to report the trends in fungal infections over time in a referral center for pediatric HSCT, to assist us in designing future prospective studies and guiding our choice of antifungal prophylactic agents. Antifungal prophylaxis has been advocated and increasingly used in HSCT patients, particularly in those receiving allografts. Several studies have been performed in the adult transplant population evaluating the effectiveness of different antifungals as prophylactic agents. Initial studies found fluconazole prophylaxis to be effective in preventing IFIs, specifically invasive candidiasis, with improved survival when compared with placebo [31,32]. Current evidence-based guidelines continue to recommend the use of fluconazole daily after HSCT for the prevention of invasive yeast infections [17]. However, fluconazole is best suited for treatment of Candida species and has no activity against Aspergillus or the more recently identified
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non-Aspergillus mold infections. Subsequent studies have compared fluconazole prophylaxis to other antifungal agents, such as new azole drugs and echinocandins, which have a broadened spectrum of activity. Winston et al. reported superiority of itraconazole in prevention of IFI, but found no difference in mortality when compared to fluconazole prophylaxis [7]. Of note, itraconazole was poorly tolerated, with increased incidence of adverse events and laboratory abnormalities, and the numbers of patients were relatively small. More recently, studies have compared fluconazole to voriconazole and posaconazole. Preliminary information released from a randomized trial of 600 patients comparing fluconazole versus voriconazole prophylaxis suggests a non-inferiority between the two agents [33]. There does, however, appear to be an advantage in the use of voriconazole or posaconazole over fluconazole for prophylaxis of invasive Aspergillus infections in high risk patients, such as those with severe GVHD [11,33,34]. It is important to note, however, that these studies were prospective clinical trials, and included very structured assessments and monitored diagnostics, which is not the case in our present retrospective analysis, so findings cannot be easily extrapolated to our setting and to similar centers. Nevertheless, voriconazole has excellent clinical activity in aspergillosis and has been shown to be particularly effective in the prevention of breakthrough fungal infections. It also has excellent activity against many Candida species as well, but lacks activity against zygomycetes, for which posaconazole demonstrates activity. The significant funding and large number of patients needed to conduct additional large randomized non-inferiority trials make it difficult to obtain a definitive answer as to which agent is the best choice for prophylaxis in high risk populations. In summary, fungal infections were relatively frequent (15% incidence) and serious complications of HSCT, accounting for two-thirds of the deaths in our population of 300 HSCT recipients enrolled over a 15-year period. Although Candida organisms continue to be the most prevalent culprits overall, we observed an increase in infections due to less common molds over time. Improved diagnostic methods enabling early detection and identification of fungal infections followed by rapid implementation of broadened antifungal therapeutics are in high demand. This approach would likely reduce adverse morbidity and mortality in our severely immunocompromised HSCT recipients.
Declaration of interest: The authors have nothing to disclose.
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References [1] Bhatti Z, Shaukat A, Almyroudis NG, Segal BH. Review of epidemiology, diagnosis, and treatment of invasive mould infections in allogeneic hematopoietic stem cell transplant recipients. Mycopathologia 2006;162:1–15. [2] Bjorklund A, Aschan J, Labopin M, Remberger M, Ringden O, Winiarski, et al. Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation. Bone Marrow Transplant 2007;40:1055–62. [3] Oshima K, Kanda Y, Asano-Mori Y, Nishimoto N, Arai S, Nagai S, et al. Presumptive treatment strategy for aspergillosis in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother 2007;60:350–5. [4] Pagano L, Caira M, Nosari A, Van Lint MT, Candoni A, Offidani M, et al. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study – Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin Infect Dis 2007;45:1161–70. [5] Robenshtok E, Gafter-Gvili A, Goldberg E, Weinberger M, Yeshurun M, Leibovici L, et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stemcell transplantation: systematic review and meta-analysis. J Clin Oncol 2007;25:5471–89. [6] Trifilio S, Singhal S, Williams S, Frankfurt O, Gordon L, Evens A, et al. Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone Marrow Transplant 2007; 40:451–6. [7] Winston DJ, Maziarz RT, Chandrasekar PH, Lazarua HM, Goldman M, Blumer JL, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 2003;138:705–13. [8] De La Rosa GR, Champlin RE, Kontoyiannis DP. Risk factors for the development of invasive fungal infections in allogeneic blood and marrow transplant recipients. Transpl Infect Dis 2002;4:3–9. [9] Hovi L, Saarinen-Pihkala UM, Vettenranta K, Saxen H. Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years. Bone Marrow Transplant 2000;26:999–1004. [10] Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002;100: 4358–66. [11] Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am 2010;24:257–72. [12] Gözdaşoĝlu S, Ertem M, Büyükkeçeci Z, Yavuzdemir S, Bengisun S, Ozenci H, et al. Fungal colonization and infection in children with acute leukemia and lymphoma during induction therapy. Med Pediatr Oncol 1999;32:344–8. [13] Maertens J, Vrebos M, Boogaerts M. Assessing risk factors for systemic fungal infections. Eur J Cancer Care (Engl) 2001;10:56–62. [14] Krcmery V Jr, Oravcova E, Spanik S, Mrazova-Studena M, Trupl J, Kunova A, et al. Nosocomial breakthrough fungaemia during antifungal prophylaxis or empirical antifungal therapy in 41 cancer patients receiving antineoplastic chemotherapy: analysis of aetiology risk factors and outcome. J Antimicrob Chemother 1998;41:373–80. [15] Dvorak CC, Steinbach WJ, Brown JM, Agarwal R. Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2005;36:621–9.
[16] Chou LS, Lewis RE, Ippoliti C, Champlin RE, Kontoyiannis DP. Caspofungin as primary antifungal prophylaxis in stem cell transplant recipients. Pharmacotherapy 2007;27:1644–50. [17] Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15: 1143–238. [18] Bodey GP, Mardani M, Hanna HA, Boktour M, Abbas J, Girgawy E, et al. The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer. Am J Med 2002;112:380–5. [19] Rosen GP, Nielsen K, Glenn S, Abelson J, Deville J, Moore TB. Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution. J Pediatr Hematol Oncol 2005;27:135–40. [20] Abelson JA, Moore T, Bruckner D, Deville J, Nielsen K. Frequency of fungemia in hospitalized pediatric inpatients over 11 years at a tertiary care institution. Pediatrics 2005; 116:61–7. [21] Groll AH, Shah PM, Mentzel C, Schneider M, JustNuebling G, Huebner K. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996;33:23–32. [22] Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002;34:909–17. [23] Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175:1459–66. [24] Kontoyiannis DP, Reddy BT, Torres HA, Luna M, Lewis RE, Tarrand J, et al. Pulmonary candidiasis in patients with cancer: an autopsy study. Clin Infect Dis 2002;34: 400–3. [25] Kami M, Machida U, Okuzumi K, Matsumura T, Mori Si S, Hori A, et al. Effect of fluconazole prophylaxis on fungal blood cultures: an autopsy-based study involving 720 patients with haematological malignancy. Br J Haematol 2002; 117:40–6. [26] Denning DW, Evans EG, Kibbler CC, Richardson MD, Roberts MM, Rogers TR, et al. Guidelines for the investigation of invasive fungal infections in haematological malignancy and solid organ transplantation. British Society for Medical Mycology. Eur J Clin Microbiol Infect Dis 1997; 16:424–36. [27] Heussel CP, Kauczor HU, Heussel G, Fischer B, Mildenberger P, Thelen M. Early detection of pneumonia in febrile neutropenic patients: use of thin-section CT. AJR Am J Roentgenol 1997;169:1347–53. [28] Kami M, Kishi Y, Hamaki T, Kawabata M, Kashima T, Masumoto T, et al. The value of the chest computed tomography halo sign in the diagnosis of invasive pulmonary aspergillosis. An autopsy-based retrospective study of 48 patients. Mycoses 2002;45:287–94. [29] Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001;19:253–9. [30] Thornton CR. Detection of invasive aspergillosis. Adv Appl Microbiol 2010;70:187–216. [31] Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, et al. Efficacy and safety of
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fluconazole prophylaxis for fungal infections after marrow transplantation – a prospective, randomized, double-blind study. J Infect Dis 1995;171:1545–52. [32] Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, Flowers ME, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 2000;96:2055–61.
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[33] Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 2010;116:5111–18. [34] Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335–47.
Original article
Invasive fungal infections in pediatric hematopoietic stem cell transplant patients
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Tiffany Simms-Waldrip1, Galit Rosen2, Karin Nielsen-Saines3, Alan Ikeda1, Berkley Brown1 & Theodore moore1 From the 1Department of Pediatrics, Division of Hematology/Oncology, Mattel Children’s Hospital at UCLA, Los Angeles, CA, 2Department of Pediatrics, Division of Hematology/Oncology, Phoenix Children’s Hospital, Phoenix, AZ, and 3Department of Pediatrics, Division of Infectious Disease, Mattel Children’s Hospital at UCLA, Los Angeles, CA, USA
Abstract Background: Pediatric hematopoietic stem cell transplant (HSCT) recipients are at high risk of invasive fungal infections (IFIs). Methods: To characterize IFIs and changes in fungal organisms over time in pediatric HSCT patients, we performed a retrospective cohort study of all HSCTs performed in pediatric patients at UCLA between 1991 and 2006. Results: In all, 318 patients underwent 324 HSCT transplants over the 15-year period and 69 unique fungal infections were identified in 47 transplant patients. The overall incidence of fungal infections in HSCT recipients was 14.5%, with predominant organisms including Candida species (51%) and Aspergillus species (26%), with Candida albicans accounting for 18.8% of all fungal species. The distribution of organisms over time demonstrated a strong trend towards an increase in rare molds in more recent years. The respiratory tract was the main site of infection (52.6%), with urine and blood also noted as significant sites. Of all deaths in the patients with IFIs, fungal-related mortality accounted for 67.6% of deaths. Conclusions: HSCT patients have a much higher risk of fungal infections with rarer organisms becoming more prevalent, a finding likely linked to evolving antifungal practices over time. This emphasizes the need for the development and implementation of improved diagnostic, prophylactic, and therapeutic strategies to improve patient survival.
Keywords: Fungal infections, HSCT, stem cell transplant, pediatric, Candida, Aspergillus
Introduction Immunocompromised patients are at serious risk for invasive fungal infections (IFIs), a major cause of morbidity and mortality in patients undergoing pediatric hematopoietic stem cell transplantation (HSCT) [1–7]. Several risk factors for increased susceptibility to fungal pathogens have been identified in this population, including graft versus host disease (GVHD), prolonged neutropenia, immunosuppressant therapy, delayed immune reconstitution, the use of indwelling catheters, and broad-spectrum antibiotics [1,5, 8–10]. Recipients of allogeneic donor sources are at greater risk of acquisition of IFI compared with their autologous counterparts, secondary to increased incidence of GVHD and longer use of immunosuppressants with delayed immune reconstitution [4,11]. These patients also experience longer periods of neutropenia while awaiting engraftment. Likewise, those
undergoing HSCT with umbilical cord blood are at greater risk for IFI due to prolonged neutropenia and prolonged immune reconstitution [11].The increased use of empiric therapy with broad-spectrum antibiotics is likely also a contributor leading to changes in nosocomial and endogenous flora, and thus rendering patients more susceptible to fungal infections [12–14]. Candida and Aspergillus species have classically been the most common infectious fungal etiologies in hematopoietic stem cell (HSC) recipients [5,6,9], although changes in transplant practices have led to variations in infectious patterns with the emergence of other resistant fungal pathogens [4,15]. The incidence of aspergillosis in transplant patients continues to increase, conferring significant morbidity and mortality. Invasive non-Aspergillus mold infections have also recently become a more frequent cause of
Correspondence: Karin Nielsen-Saines MD MPH, Division of Infectious Diseases, David Geffen UCLA School of Medicine, MDCC 22-442, 10833 LeConte Ave, Los Angeles, CA 90095, USA. Tel: 1 310 206 6640. Fax: 1 310 825 9175. E-mail: [email protected] (Received 16 June 2014; accepted 27 October 2014) ISSN 0036-5548 print/ISSN 1651-1980 online © 2015 Informa Healthcare DOI: 10.3109/00365548.2014.985709
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infection in HSCT recipients [1,4,15,16]. Current evidence-based guidelines for both pediatric and adult patients recommend prophylaxis with fluconazole following HSCT to prevent invasive yeast infections [17]. Fluconazole provides excellent coverage against many Candida strains and has successfully decreased the incidence of infections by these strains. However, fluconazole lacks reliable activity against Aspergillus as well as many non-Aspergillus species [5,6]. Activity against more resistant Candida species, including C. krusei and C. glabrata, is also lacking. As a result, IFIs induced by fluconazoleresistant fungi have become more prevalent [18], resulting in the development of studies that evaluate the performance of broader spectrum fungal prophylactic agents in HSCT patients. We reviewed all IFIs occurring in pediatric HSCT patients from 1991 to 2006 to identify the trends and characteristics of fungal infections in the pediatric HSCT population in order to understand the magnitude of the problem, a critical step towards future development of prevention and therapeutic strategies.
Materials and methods Patients A retrospective cohort study design was used to evaluate all pediatric patients (aged 0–21 years, mean age 15 years) who underwent either allogeneic or autologous HSCT at the Mattel Children’s Hospital at UCLA from January 1, 1991 until December 31, 2006. The medical records of each patient were individually reviewed. In total, 324 HSCTs were performed in 318 patients during the observed time period. The vast majority of transplants performed in our unit during that time period were allogeneic.
istress, and a gamut of signs and symptoms suggesd tive of a serious invasive infection, as described in prior studies from our institution) [19,20]. Documented and presumed IFI (i.e. with a positive culture in the first case from a sterile site or identification of a fungal organism from a non-sterile site in the presence of constitutional symptoms in the second case) that were subsequently treated with a course of antifungal agents were considered as cases in this study. Fungal colonization was defined as positive cultures obtained from non-sterile sites such as sputum or bronchoalveolar lavage (BAL), particularly in the absence of clinical symptoms. The date and indication for transplant, donor source, date of first positive culture, fungal species isolated, site of infection, and age of patient at time fungal infection were documented, and absolute neutrophil count at time of infection and outcome were obtained for each infectious episode. Neutropenia was defined as an absolute neutrophil count of 500 103/L. Indication for transplantation was categorized as lymphoid leukemia, myeloid leukemia, solid tumors, and others. In a single patient with multiple unique fungal infections, outcome for each individual IFI was considered. Fungal-related death was determined based on the cause of death as stated in the patient’s medical records. The study was approved by the local institutional review board. Statistical analysis The chi-squared test was utilized for associations between variables. Trends were assessed with simple linear regression. All analyses were performed using SAS 9.1. p values of 0.05 were considered statistically significant.
Methods
Results
Microbiology laboratory records of all positive fungal cultures and radiology reports indicating a disease process were compared to the patient’s medical record and our transplant service database to identify those transplant patients with proven or suspected invasive fungal infections. A detailed chart review was performed for each transplant recipient, with findings cross-referenced to microbiology and radiology results. Pathology reports were also assessed when available. An IFI was defined as isolation of fungus from a normally sterile site, or surgical, histologic or radiographic evidence of invasive infection despite negative cultures from sterile sites in the presence of constitutional symptoms (such as prolonged high grade fever, blood pressure instability, respiratory
A total of 69 unique fungal infections were identified in 47 HSCT recipients over the observed time period. The overall incidence of IFIs in HSCT recipients from 1991 to 2006 was 14.5%, with 47 of 318 patients having evidence of infection. Upon further stratification of the cohort by transplantation period, patients undergoing HSCT between 1991 and 1996 had an incidence of IFI of 15.5%, whereas patients receiving HSCT from 1997 to 2001 and 2002 to 2006 had an incidence of 10.7% and 16.2%, respectively (Figure 1). An overall trend in incidence of IFI was not observed. The vast majority of IFIs occurred in allogeneic transplant recipients. A variation in the prevalence of IFI based on indication for transplantation was not noted,
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Invasive fungal infections in pediatric HSCT patients
Figure 1. Incidence of invasive fungal infections (IFIs) in hematopoietic stem cell transplantation (HSCT) patients.
with the exception that autologous transplant recipients did not tend to develop IFI. Candida species caused the majority (51%) of fungal infections in the patient population, with Aspergillus species accounting for 26%. A variety of other fungal species comprised the remainder of infections (Table I). The distribution of organisms over time demonstrated a strong trend towards an increase in Aspergillus species and rare molds in more recent years, although this was not statistically
significant (Figure 2). The overall incidence of candidal infections decreased in linear fashion over the study time period, with a striking decrease in incidence of C. albicans infections. This decrease was offset by a slight increase in fluconazole-resistant strains, C. glabrata and C. krusei. This phenomenon coincides with the widespread implementation of fluconazole prophylaxis for pediatric HSCT recipients at our institution during the third period of observation. In the years 1991–1996 the incidence of Aspergillus infections was 3.9% compared with 9.9% during 2002–2006 (p 0.0425). Likewise, the transplant population has seen an increase in infections with non-Candida and non-Aspergillus species, which totaled 12% of all IFIs between 1991 and 1996 and comprised 24% of all IFIs between 2002 and 2006, although this did not reach statistical significance. This finding is in comparison to a similar study at the same institution, evaluating IFIs of all hospitalized pediatric patients, both immunocompromised and immunocompetent, where Candida species accounted for 91% of the cases [20]. The respiratory tract was the most common site of infection (52.6%), followed by infections in the blood (14%) and urine (11.5%) (Table I). Respiratory cultures included deep sputum, BAL, bronchoscopy, sinus cultures, and lung biopsy specimens.
Table I. Characteristics of cohort over time. Characteristic Age at time of IFI (years) 3 3–12 12 Neutropenia at time of IFI Type of IFI Yeasts C.albicans Non-albicans Molds Aspergillus Non-aspergillus Site of IFI Respiratory tract/sinus Blood Urine CSF/brain GI tract Other Mortality Death from IFI Total BMT Mean BMT day of infection All IFIs
1991–1996 (n 23)
1997–2001 (n 18)
3 12 8 12 (52%)
1 10 7 12 (67%)
2002–2006 (n 28)
1991–2006 (n 69)
p valuea
2 6 20 7 (39%)
6 28 35 31 (45%)
0.0148a
15 7 8 8 5 3
9 2 7 9 2 7
11 4 7 17 11 6
35 13 22 34 18 16
11 3 3 1 3 2
7 3 3 1 3 1
23 5 3 2 1 3
41 11 9 4 7 6
10 10/111 (9%)
25 25/324 (7.7%)
10 5 10/129 (7.8%) 5/84 (6%) 51.17
91.39
NA
68.30
0.0425a
0.033
BMT, bone marrow transplant; CSF, cerebrospinal fluid; GI, gastrointestinal tract; IFI, invasive fungal infection; NA, not available; aChi-squared test; only values 0.05 are listed.
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Figure 2. Distribution of fungal organisms over time.
There was a broad range of fungal organisms associated with respiratory infections, ranging from Candida species to Aspergillus and infections due to rare molds. In 83% of patients with identified Aspergillus species, the infection was localized to the respiratory tract only. Also, 100% of urinary tract infections were caused by Candida species. The diagnosis of infection due to fungal pathogens was made by the clinician at the time of infection. All patients experienced a period of neutropenia post-transplantation. Patients with fungal infections were found to be neutropenic at the time of diagnosis in 45% of all episodes (Table I). We evaluated the data for any difference in IFI in transplants performed with peripheral blood (5%), bone marrow (55%) or umbilical cord (40%). Although umbilical cord blood recipients tend to have a longer period before engraftment, there was no increase in incidence in IFI with cord blood recipients (p 0.76). Of the 318 patients who underwent HSCT during the study period, 142 subsequently died (43.8%), with fungal infections accounting for 7.7% of deaths in this population (Table I). Of the 47 pediatric transplant recipients with a history of fungal infections, 37 ultimately died (80%), with fungal-related mortality accounting for 25 deaths (67.6%) (Figure 3).
[19,20]. In the present HSCT pediatric patient population, where extended periods of neutropenia are expected, the prevalence of this finding at the time of diagnosis of IFI ranged from 39 to 67%. Development of IFI in our patient populations occurred later in the transplant course. It is often difficult to determine the true incidence of fungal infections. A large proportion of HSCT patients develop fever and signs of infection while maintaining negative cultures. The majority of these patients receive prolonged empiric antifungal therapy with successful resolution of their symptoms. A subset of these patients may have had undiagnosed fungal infections due to the poor sensitivity of cultures for IFI [24]. In one study of adult patients with hematologic malignancies, sensitivities of blood cultures for candidiasis and aspergillosis were only 21.3% and 1.1%, respectively, when compared with autopsy-based evidence of IFI [25]. In the present study, there was also a high rate of positive respiratory and urine cultures, likely reflecting
Discussion At our medical center the overall incidence of fungal infections in children undergoing HSCT was 14.5%, which is compatible with prior studies [21–23]. IFIs remain a serious threat to HSCT recipients, both acutely and for years following HSCT. In prior studies we have found that IFIs are significantly associated with the extent and duration of neutropenia
Figure 3. Mortality from invasive fungal infections (IFIs) in patients undergoing hematopoietic stem cell transplantation (HSCT).
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an overestimation of infection. This reiterates the importance of developing and utilizing more sensitive and specific non-invasive diagnostic methods through radiographic and molecular approaches for improved administration of timely and directed antifungal therapy. The patients evaluated in this study were transplanted over a long period of time during which many advances in transplantation were developed, including improved diagnostic methods for infections and the introduction of new antibacterial, antiviral, and antifungal agents [2]. During the first two time periods of our study, antifungal prophylaxis was not routine for pediatric HSCT patients at our institution. During the third observation period, fluconazole prophylaxis became the standard of care for pediatric HSCT patients at our institution. An apparent increase in the incidence of invasive fungal infection may actually be due in part to improved diagnostic capabilities, which may more accurately represent what was previously under-reported. The use of high-resolution CT scanning has greatly improved our ability to diagnose deep-seated fungal infections in the absence of a positive culture [26–29]. Bronchoscopy with BAL has also expanded our diagnostic arsenal. Similarly, a number of serologic assays, including utilization of PCR and ELISA, have been developed and are routinely employed. Galactomannan assays are now in widespread use for detection of invasive aspergillosis infections, but may have limited utility in the younger pediatric population [30]. Our study has limitations in that it was retrospective, used a broad definition of IFI and was subject to temporal variations and changes in medical diagnostic and therapeutic practices over time. Nevertheless, our aim was to report the trends in fungal infections over time in a referral center for pediatric HSCT, to assist us in designing future prospective studies and guiding our choice of antifungal prophylactic agents. Antifungal prophylaxis has been advocated and increasingly used in HSCT patients, particularly in those receiving allografts. Several studies have been performed in the adult transplant population evaluating the effectiveness of different antifungals as prophylactic agents. Initial studies found fluconazole prophylaxis to be effective in preventing IFIs, specifically invasive candidiasis, with improved survival when compared with placebo [31,32]. Current evidence-based guidelines continue to recommend the use of fluconazole daily after HSCT for the prevention of invasive yeast infections [17]. However, fluconazole is best suited for treatment of Candida species and has no activity against Aspergillus or the more recently identified
Invasive fungal infections in pediatric HSCT patients
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non-Aspergillus mold infections. Subsequent studies have compared fluconazole prophylaxis to other antifungal agents, such as new azole drugs and echinocandins, which have a broadened spectrum of activity. Winston et al. reported superiority of itraconazole in prevention of IFI, but found no difference in mortality when compared to fluconazole prophylaxis [7]. Of note, itraconazole was poorly tolerated, with increased incidence of adverse events and laboratory abnormalities, and the numbers of patients were relatively small. More recently, studies have compared fluconazole to voriconazole and posaconazole. Preliminary information released from a randomized trial of 600 patients comparing fluconazole versus voriconazole prophylaxis suggests a non-inferiority between the two agents [33]. There does, however, appear to be an advantage in the use of voriconazole or posaconazole over fluconazole for prophylaxis of invasive Aspergillus infections in high risk patients, such as those with severe GVHD [11,33,34]. It is important to note, however, that these studies were prospective clinical trials, and included very structured assessments and monitored diagnostics, which is not the case in our present retrospective analysis, so findings cannot be easily extrapolated to our setting and to similar centers. Nevertheless, voriconazole has excellent clinical activity in aspergillosis and has been shown to be particularly effective in the prevention of breakthrough fungal infections. It also has excellent activity against many Candida species as well, but lacks activity against zygomycetes, for which posaconazole demonstrates activity. The significant funding and large number of patients needed to conduct additional large randomized non-inferiority trials make it difficult to obtain a definitive answer as to which agent is the best choice for prophylaxis in high risk populations. In summary, fungal infections were relatively frequent (15% incidence) and serious complications of HSCT, accounting for two-thirds of the deaths in our population of 300 HSCT recipients enrolled over a 15-year period. Although Candida organisms continue to be the most prevalent culprits overall, we observed an increase in infections due to less common molds over time. Improved diagnostic methods enabling early detection and identification of fungal infections followed by rapid implementation of broadened antifungal therapeutics are in high demand. This approach would likely reduce adverse morbidity and mortality in our severely immunocompromised HSCT recipients.
Declaration of interest: The authors have nothing to disclose.
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