Published online May 1, 2008
PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1286-e1294 (doi:10.1542/peds.2007-2117)
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ARTICLE

Pediatric Invasive Aspergillosis: A Multicenter Retrospective Analysis of 139 Contemporary Cases

Ana Burgos, MDa, Theoklis E. Zaoutis, MD, MSCEb, Christopher C. Dvorak, MDc, Jill A. Hoffman, MDd, Katherine M. Knapp, MDe, Joseph J. Nania, MDf, Priya Prasad, MPHb and William J. Steinbach, MDa

a Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina
b Division of Pediatric Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
c Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Stanford University, Palo Alto, California
d Division of Pediatric Infectious Diseases, Childrens Hospital Los Angeles, Los Angeles, California
e Division of Pediatric Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee
f Division of Pediatric Infectious Diseases, Vanderbilt University, Nashville, Tennessee


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
OBJECTIVE. Invasive aspergillosis is a major cause of morbidity and mortality in immunocompromised children. Invasive aspergillosis has been well characterized in adults; however, the incidence and analysis of risk factors, diagnostic tools, treatments, and outcomes have not been well described for a large cohort of pediatric patients.

METHODS. We conducted the largest retrospective review of contemporary cases of proven and probable pediatric invasive aspergillosis diagnosed at 6 major medical centers (January 1, 2000, to July 1, 2005).

RESULTS. Aspergillus fumigatus was the species most frequently recovered (52.8%) for the 139 patients analyzed. The majority of the children had a malignancy with or without hematopoietic stem cell transplant. Significant risk factors that impacted survival were immunosuppressive therapies and allogeneic stem cell transplant. The most common clinical site of invasive aspergillosis was the lungs (59%), and the most frequent diagnostic radiologic finding was nodules (34.6%). Only 2.2% of children showed the air crescent sign, 11% demonstrated the halo sign, and cavitation was seen in 24.5% of patients. Before the diagnosis of invasive aspergillosis, 43.1% of patients received fluconazole, and 39.2% received liposomal amphotericin B. After the diagnosis of invasive aspergillosis, 57% were treated with a lipid formulation of amphotericin B; however, 45.8% received ≥3 concomitant antifungal agents. Analysis did not show superiority of any 1 antifungal related to overall mortality. A total of 52.5% (73 of 139) died during treatment for invasive aspergillosis. Of all the interventions implemented, surgery was the only independent predictor of survival.

CONCLUSIONS. Our analyses revealed common findings between adult and pediatric invasive aspergillosis. However, one key difference is diagnostic radiologic findings. Unlike adults, children frequently do not manifest cavitation or the air crescent or halo signs, and this can significantly impact diagnosis. Immune reconstitution, rather than specific antifungal therapy, was found to be the best predictor of survival.

Key Words: Aspergillus • aspergillosis • pediatric

Abbreviations: IA—invasive aspergillosis • HSCT—hematopoietic stem cell transplant • CT—computed tomography • GVHD—graft-versus-host disease

Invasive fungal infections are a major cause of morbidity and mortality in the expanding immunocompromised patient population.1 The incidence of invasive aspergillosis (IA) has increased 357% since 1980,2 and one study demonstrated a 14-fold increase in IA from 1978 through 1992.3 Autopsy data from some tertiary medical centers demonstrate that IA has now surpassed invasive candidiasis as the most frequent invasive fungal infection.3–8 The treatment success rate with IA remains at ~50%, despite newer antifungal agents now available.9

Despite the increasing incidence and continued dismal outcomes, the majority of information surrounding IA epidemiology, diagnosis, treatment, and outcome has been obtained from studies conducted almost solely on adult patients. As a result of this pediatric exclusion, physicians treating children with IA are forced to extrapolate conclusions for their own patients. There have been several previous pediatric IA epidemiology reports,10–12 but those were only single-center studies and were conducted before the availability of many newer antifungal agents and diagnostic strategies. To address these fundamental pediatric IA questions in a contemporary setting, we conducted the largest multicenter retrospective (January 1, 2000, to July 1, 2005) review of IA in children in the setting of newer diagnostic and therapeutic tools.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Sites
Participating medical centers included Duke University Medical Center, Children's Hospital of Philadelphia, Lucile Salter Packard Children's Hospital at Stanford (Palo Alto, CA), Childrens Hospital Los Angeles, St Jude Children's Research Hospital, and Vanderbilt University Medical Center (Nashville, TN). Institutional review board approval was obtained at all of the participating institutions.

Inclusion Criteria and Definitions
Retrospective clinical data were obtained on all cases of IA in children (age 0–18 years) at the 6 tertiary care medical centers during a 5.5-year period from January 1, 2000, to July 1, 2005. Inclusion required cases defined as either proven or probable IA based on the strict classification system of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group for patients with malignancy or who have undergone hematopoietic stem cell transplant (HSCT).13 Proven disease required histopathologic or microbiologic documentation of infection from tissues obtained by biopsy, autopsy, or in culture samples from a normally sterile site. Probable disease required microbiologic and radiologic documentation with compatible signs and symptoms in a child with a recent history of neutropenia, prolonged corticosteroid use, or treatment with immunosuppressive therapies. Microbiologic documentation included detection by direct microscopy, culture of Aspergillus species, or a positive result of Aspergillus galactomannan enzyme immunoassay. Radiologic documentation required the presence of a new infiltrate on chest computed tomography (CT), such as halo sign, air crescent sign, or cavity. Any other type of infiltrate, along with symptoms of lower respiratory tract infection, also met inclusion criteria. These definitions were also applied to those patients who did not have malignancy and had not undergone HSCT. "Day of diagnosis" was defined as the day that the clinical team determined that the patient was infected with IA. For IA diagnosed at autopsy, the date of diagnosis was the date of death. Data regarding death were obtained to determine whether a patient died with active IA as determined by the clinicians caring for the patients. If a patient died with active IA, then the patient was classified as having died because of IA.

Data Collection
A detailed case report form was created and distributed to all of the centers for completion and returned to the coordinating center, Duke University Medical Center. The case report form was designed to capture conditions 30 days before the diagnosis of IA and ≥12 weeks after the diagnosis of IA. Information collected included demographics, host factors (ie, underlying disease, preceding antimicrobial therapy, degree and duration of neutropenia, concomitant infections, and immunosuppressive therapies), diagnostic procedures (culture, galactomannan assay, and radiologic findings), therapy, and outcome. The data were gathered from medical charts and laboratory, radiology, and pathology reports.

Statistical Analysis
Summary statistics were constructed using frequencies and proportions for categoric data elements and means and medians for continuous variables. Univariate analysis on potential risk factors for death was performed. Continuous variables were compared using the Wilcoxon rank-sum test, and categorical variables were compared using the Fisher's exact test. Multivariate analysis was performed using logistic regression to adjust for the presence of confounding. Survey estimation was applied to the logistic regression models, to adjust for clustering among the study sites. All of the variables with a P value < .20 on univariate analysis were considered for inclusion in the multivariate model. The presence of confounding was defined by a difference of >15% in the odds ratio, when adjusting for a covariate. A 2-tailed P value < .05 was considered statistically significant. All of the statistical calculations were performed using the statistical package Stata 8.0 (Stata Corp, College Station, TX).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Patients and Underlying Diseases
We analyzed a total of 139 cases of pediatric IA (Table 1) reported from Lucile Salter Packard Children's Hospital at Stanford (n = 30; 21.6%), Childrens Hospital Los Angeles (n = 29; 20.9%), St Jude Children's Research Hospital (n = 26; 18.7%), Children's Hospital of Philadelphia (n = 23; 16.5%), Duke University Medical Center (n = 22; 15.8%), and Vanderbilt University (n = 9; 6.5%). The ratio of male/female cases of IA was 1.6:1.0. The mean age of patients was 9.9 years (median age: 10.1 years; range: 17 days to 18 years). Half of the patients were white (50.4%), followed by patients of Hispanic/Latino descent (29.4%).


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  		TABLE 1 Patient Characteristics of 139 Contemporary Cases of Pediatric IA

 
The majority of the 139 patients had an underlying malignancy (87 of 139 [62.6%]). An equal number of patients had underlying malignancy not treated with HSCT (n = 53; 38.1%) or an underlying disorder treated with HSCT (n = 53; 38.1%). The underlying conditions for the remainder of the patients were inherited immunodeficiency (n = 16; 11.5%), solid-organ transplant (n = 16; 11.4%), and other (n = 10; 7.1%). Of the 53 patients who underwent HSCT, 96.2% (51 of 53) received allogeneic transplants, 51% of which were from matched, unrelated donors.

Most patients had numerous immunosuppressive risk factors in the 30 days before diagnosis of IA (Table 2). Neutropenia (absolute neutrophil count <500/µL) for ≥3 days was documented in 59% (n = 82) of the 139 patients analyzed. In ~30% of these patients, the neutropenia lasted for ≥30 days (overall mean: 18.9 days). Corticosteroid therapy was administered to 69.1% of all patients, and 90.6% of those received corticosteroid therapy for ≥3 days. Immunosuppressive therapies (ie, cyclosporine, tacrolimus, daclizumab, etc) were given to 43.1% of patients, and in the majority of those (90%), therapy lasted for ≥3 days. Graft-versus-host disease (GVHD) was documented in 16 (30.2%) of the 53 patients who underwent HSCT, and 75% of those had acute GHVD (grade II to IV). Concomitant infections consisted of 124 episodes of bacterial, viral, and other fungal infections among 65.5% (91 of 139) of the patients, of which bacterial infections accounted for approximately half of all the concomitant infections. Overall, 95.7% (133 of 139) of patients had ≥1 of these risk factors. Antifungal agents were administered as prophylaxis or empiric therapy to 73.4% of patients in the 30 days before the diagnosis of IA.


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  		TABLE 2 Findings Before Diagnosis of 139 Cases of Pediatric IA

 
Diagnostic Methods
Of the 139 patients analyzed, 78.4% (109) were diagnosed with proven IA, and the remainder of patients were diagnosed with probable IA (Table 3). Fungal culture isolates were obtained in 125 patients (89.9%), with 2 patients having 2 different isolates, for a total of 127 Aspergillus isolates. Aspergillus fumigatus was the species most frequently recovered by culture (67 isolates [52.8%]) followed by Aspergillus flavus (20 isolates, 15.7%), Aspergillus terreus (6 isolates, 4.7%), and Aspergillus niger (6 isolates, 4.7%). These 127 isolates were recovered from 144 culture specimens (15 patients had positive cultures from ≥2 sites), the most common of which were from deep tissue biopsy (53 of 144 [36.8%]). Histologic examination was performed for 46% (64 of 139) of patients, and the galactomannan assay was used in 9.4% (14 of 139) of patients. The most common clinical site of IA was the lungs (111 patients, 59%), followed by the skin (19 patients, 10%), and the sinuses (18 patients, 9.6%).


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  		TABLE 3 Characteristics of 139 Cases of Pediatric IA

 
A total of 188 pulmonary radiographic findings (Table 4) were seen in 110 of the patients with pulmonary disease, including 61 patients with ≥2 radiologic findings. Nodules were the most frequent finding on chest CT or plain radiograph, seen in 59% (65 of 110) of children with pulmonary findings. Nodules were seen less frequently in the youngest children compared with the older age groups: nodules were seen in 38.7% (12 of 31) of the 0- to 5-year-olds compared with 71.8% (28 of 39) and 62.5% (25 of 40) of the 6- to 12-year-old and ≥13-year-old groups, respectively. However, the relationship between a stratified age variable and pulmonary nodules was not found to be statistically significant. Only 3 (2.2%) of 110 patients showed the air crescent sign, none of whom were in the 0- to 5-year age group. The halo sign was seen in 10.9% (12 of 110) of the patients overall and in 12.9% (4 of 31) of the 0- to 5-year-olds, 12.8% (5 of 39) of the 6- to 12-year-olds, and 7.5% (3 of 40) of those patients ≥13 years of age.


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  		TABLE 4 Radiologic Findings in 125 Cases of Pediatric IA

 
Radiographic findings were also seen in sinus and head imaging. The most frequent findings for the 21 patients with sinonasal disease were mucosal thickening (14 of 21 [67%]) and opacification (10 of 21 [47.6%]). Intraparenchymal brain lesions were seen in 75% (9 of 12) of the patients with head radiologic findings.

Treatment
Before the diagnosis of IA, 102 (73.4%) of 139 patients were receiving treatment with an antifungal agent for ≥3 days (Table 2). Most of those patients received either fluconazole (43.1%) or liposomal amphotericin B (39.2%). After the diagnosis of IA (Table 5), 131 (94.2%) of 139 patients received antifungal agents, whereas 6 patients were diagnosed at autopsy (2 patients did not receive antifungal therapy). A total of 57.3% of patients with IA were treated with a lipid formulation of amphotericin B (mean: 53.6 days). Voriconazole was given to 52.7% of patients for a mean of 184 days, whereas posaconazole had the next longest treatment duration (mean: 146 days) but was only given to 4 patients. A total of 20.6% (27 of 131) of patients received 1 antifungal after the diagnosis of IA, 33.6% (44 of 131) received 2 antifungal agents concurrently, and 45.8% (60 of 131) received ≥3 concurrent antifungal agents for ≥3 days after diagnosis of IA.


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  		TABLE 5 Findings After Diagnosis of IA

 
Other treatments included surgery, granulocyte stimulation factors, interferon, and granulocyte transfusions. Surgical interventions, such as lung lobectomies, excisional biopsies, and debridement, were done in 45.5% (61 of 134) of patients. A total of 58% (38 of 61) of patients who received surgical intervention survived at end of therapy, whereas 32% (23 of 61) died (Table 6). A total of 80 patients (57.6%) received 1 of the stimulation factors, interferon {gamma} or granulocytes.


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  		TABLE 6 Risk Factors for Overall Mortality in 139 Cases of Pediatric IA

 
Patient Outcome
After the diagnosis of IA, clinical conditions related to outcome were again assessed (Table 5). Neutropenia was seen in 51.5% (68 of 132) of the patients, whereas 61.4% (81 of 132) received corticosteroids, and 43.2% (57 of 132) received immunosuppressive therapy after the diagnosis of IA. Approximately 26% (14 of 53) of patients who underwent HSCT were found to have GVHD, and half of these were patients who had not been previously diagnosed with GVHD. The majority of the concomitant infections after diagnosis of IA were again bacterial infections (Table 5).

A total of 52.5% (73 of 139) of patients died during treatment for IA. Analysis of mortality and IA infection showed that allogeneic HSCT was a risk factor for death (Table 6), and 78% (40 of 51; P < .01) of those undergoing allogeneic HSCT died at 12 weeks or at the end of therapy. Of those patients who received immunosuppression, 68% (47 of 69; P < .01) died. Multivariate regression analysis (Table 7) revealed that patients undergoing allogeneic HSCT were 6 times more likely than other patients to die with IA (odds ratio: 6.58; 95% confidence interval: 2.67–16.21). Surgical intervention was an independent predictor of survival; patients who underwent surgery were 70% less likely than other patients to die.


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  		TABLE 7 Multivariate Model for Risk Factors for Overall Mortality in Pediatric IA

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Invasive fungal infections represent an increasingly major cause of morbidity and mortality among immunocompromised patients.1,3,10,14–16 IA is now more commonly seen because of several factors: more intensive immunosuppressive therapies for GVHD and rheumatologic diseases, increased use of unrelated donor transplantations, more intense preparative regimens to avoid rejection or relapse, and an increase in early posttransplantation survival rate because of better control of bacterial and cytomegalovirus infections.17,18 For many clinicians, IA is more worrisome than invasive candidiasis, likely as a result of the better diagnostic tools, prophylaxis, and antifungal therapies now available for Candida infections.

The few published reviews of childhood IA10–12 are limited by single-center sampling and by the treatment modalities used at the time. The improved diagnostic and therapeutic tools available today change the landscape of both the type of patients with IA and the available treatment modalities. In addition, many case series focus on 1 specific patient population, often HSCT recipients or oncology patients receiving conventional chemotherapy. Our study was a multicenter review of all of the pediatric IA cases at each of the large participating pediatric centers conducted over a time period spanning the introduction of newer antifungal agents and diagnostic methods, such as voriconazole or caspofungin and the galactomannan assay, respectively. In addition, we also had the advantage of applying standard definitions of proven and probable IA13 to critically ensure homogeneity of infectious diagnosis.

There have been 3 previous large reviews of pediatric IA, but unfortunately each had their own limitations. The first pediatric IA review was conducted at the Hospital for Sick Children in Toronto (Canada) involving 39 cases of pediatric IA from 1979 to 1988.11 Cutaneous Aspergillus infection was found in 41% (16 of 39) of the patients, and 16 of 39 patients had pulmonary infections. The overall survival rate was 23.1% (9 of 39), much lower than more current series. Our study was similar in that the median age of our subjects was 10.1 years, and the majority of our patients had a hematologic malignancy or underwent HSCT. In contrast, we found that the most common clinical site of IA was the lungs, and the overall survival rate in our study was improved at 47.5% (66 of 139).

The second pediatric IA study was a prospective, 5-year observational study in 346 pediatric patients with cancer receiving intense chemotherapy for newly diagnosed or recurrent malignancy at the University Hospital of Frankfurt.10 During the 5-year period, there were 13 cases of proven or presumptive IA, established per the center's own criteria. All of the cases occurred in patients with hematologic malignancy; the highest rates were seen in patients with acute myeloid leukemia and relapsed acute lymphocytic leukemia. This study only looked at patients with malignancies, but, like ours, found a higher predominance of IA in those patients with leukemia compared with solid tumors. Our study found an almost equal number of IA in acute myeloid leukemia and acute lymphocytic leukemia patients, which may be a result of the fact that our institutions are referral centers and more likely to treat relapsed patients. Additional future analysis may help elucidate this finding. Neutropenia, with an absolute neutrophil count of ≤500 cells per µL in patients with IA, was slightly more prolonged in this study (27.0 days) compared with what we found among our own patients (18.9 days).

The third pediatric study was a review of 66 cases of proven IA from ~9500 children treated from 1962 to 1996 at St Jude Children's Research Hospital.12 The most common site of infection was the lung (46 patients, 70%), followed by skin lesions (13 patients, 20%) and sinus disease (12 patients, 18%). In our series, the clinical site of disease was similar, with lungs accounting for a majority of disease, followed by skin and sinus disease. The St Jude study did include a more diverse population of patients much like our study, but they were not able to examine IA among solid-organ transplant patients or to capture other cases arising out of the general pediatric population. In addition, many of the cases analyzed were from >3 decades ago and may, therefore, be difficult to extrapolate to today's patients.

Overall, compared with the previous studies summarized above, our study is unique in that it captured all of the cases of IA in all of the pediatric patients (0 to 18 years) at multiple tertiary care centers. The patient population included not just oncology and HSCT patients but also patients with inherited immunodeficiencies, acquired immunodeficiency, solid-organ transplant, and other patients who developed IA. Because our sample size was much larger than these previous pediatric studies, we were able to stratify between different age groups and underlying diagnoses.

There are conflicting reports about a potential Aspergillus species difference seen in infected children versus adult patients. The National Institute of Allergy and Infectious Diseases Bacteriology and Mycoses Study Group reviewed 256 isolates of Aspergillus species from adult patients who had IA from 24 medical centers,19 and A fumigatus accounted for 67% (171 of 256) of isolates whereas A flavus was the second most common isolate at 16% (41 of 256). In contrast, the previously described St Jude12 and Toronto11 pediatric reviews revealed that A flavus was the most common species isolated. However, in more recent studies, the pediatric IA epidemiology has paralleled that in adults, with a 2001 French pediatric study demonstrating that the most common isolates were A fumigatus (11 of 23) followed by A flavus (6 of 23).20 Our study mirrored that newer French pediatric study and adult findings,9,19 suggesting that possibly the earlier claims of A flavus predominance in children were a phenomenon of older cases of IA. An additional explanation is the finding of a great number of cases of cutaneous IA in children in the previous reviews, because A flavus has been shown to be involved in cutaneous disease.

As shown by adult studies,21 pulmonary IA is the clinical site most commonly identified, which is expected because of the airborne route of infection. In our series, there were 111 cases of pulmonary IA (111 of 139 [79.9%]), followed by cutaneous IA in 19 patients (19 of 139 [13.7%]). Of the patients with cutaneous disease, 52.6% (10 of 19) were strictly localized to the skin, whereas in the other 47.4%, cutaneous disease was one of the overall clinical manifestations. A fumigatus was the species responsible for 70% (7 of 10) of these strictly cutaneous infections, whereas A flavus and A niger caused 2 of the other infections, and in 1 case the species was not identified. In the Toronto study,11 in 41% (16 of 39) of the patients, the Aspergillus infection was cutaneous, and in the St Jude review,12 20% (13 of 66) of patients had cutaneous infection. However, other pediatric series have not shown such predominance of primary cutaneous infection, as the Frankfurt study only reported 1 such case.10 In a systematic review of nosocomial Aspergillus outbreak reports, 53 outbreaks were found affecting 458 patients. Skin infections were reported in only 5.2% (24 of 458).22 Other studies also show that primary cutaneous aspergillosis is found infrequently in the adult population.23–25 Our study's findings confirm that there is indeed a higher rate of cutaneous infections in children compared with adults, similar to findings from the earlier pediatric-dedicated studies. However, despite this higher rate of cutaneous disease, A fumigatus prevailed as the most common infecting species.

Our study also aimed to identify differences between adults and children with IA that could impact diagnosis and management. Some aspects of IA seem to be similar in adults and children; for example, prolonged neutropenia and dysfunctional neutrophils are recognized as important risk factors for IA in both adults and children.1,26–33 Patients with neutrophil counts >500 cells per µL have been found to have lower case fatality rates.34 Patients receiving high doses of corticosteroid therapy and other immunosuppressive therapies have also been established to be at risk for IA in both patient populations. We found, as have previous pediatric and adult studies, that patients with hematologic malignancies are the most affected group. However, our data revealed that patients with inherited immunodeficiencies and solid-organ transplant recipients were also prominently represented (11.5% each). Among patients with inherited immunodeficiencies, as expected, almost half of the patients had chronic granulomatous disease. Of the solid-organ transplant patients, IA was more common among those receiving lung transplants, with 37.5% (6 of 16) of patients, which is similar to findings in adult series indicating that lung transplant recipients have one of the highest rates of IA in solid-organ transplantation.35,36 In the 53 patients undergoing HSCT, those receiving an allogeneic transplant composed 96% of patients, confirming previous pediatric and adult findings that this subpopulation is at greater risk for IA.1,35–39

The diagnostic features of IA may be different in children.40,41 In adult series of pulmonary aspergillosis, ~50% of patients show cavitation, and 40% have air crescent formation.42 However, in a 10-year review of 27 consecutive pediatric cases (mean: 5-years-old; range: 7 months to 18 years), central cavitation of small nodules was seen in only 25% of children, and there was no evidence of air crescent formation within any area of consolidation on CT.43 Another pediatric series with a higher mean age showed that 43% (6 of 14) of patients had cavitation on CT.44 It may be that air crescent and cavitation are only seen in the older population of children, suggesting an underlying difference in pathophysiology in children. Our study showed similar findings to these older pediatric studies and, unlike the adult series, cavitation was only seen in a fraction of pediatric cases of IA (24.5% in our study). In addition, relying on the finding of air crescent formation to establish the diagnosis of pulmonary IA would be erroneous, because we only had 3 cases with this sign, similar to previous pediatric radiology studies. However, we did not see a trend toward cavitation among the older population of children, and additional studies with a larger population of patients may be necessary to establish such a trend with a true potential diagnostic radiology spectrum related to age.

Despite the devastating complications and high mortality associated with IA, there is still no consensus for a prophylactic agent or treatment of choice for adults and pediatric patients. We found that 79.3% (104 of 131) of the patients received treatment with ≥2 antifungal agents after the diagnosis of IA. Treatment of IA included 57% (75 of 131) of patients who received liposomal amphotericin B, followed by voriconazole use in 53% (69 of 131) of patients. Voriconazole (mean: 184 days) was used for a longer period of time compared with liposomal amphotericin B (mean: 53.6 days), possibly because the oral formulation was easier to administer for outpatient treatment and prophylaxis after infection.

Our multivariate analysis did not show that any 1 antifungal was more effective than another. In fact, our analysis showed that the only predictor of survival was surgical resection of focal disease. However, surgical intervention is not an option for some patients, because disease may not be localized or patients may not be stable for surgery. It is possible that the patients who were able to undergo resection had better immune status or less burden of disease and, therefore, would have done better despite intervention. Further examination of these patients and more detailed analysis of the additional antifungal parameters (ie, voriconazole dosing) among the entire sample may reveal different results.


   CONCLUSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
We found that there are many common findings between adult and pediatric IA, but there also seem to be key diagnostic differences. Cutaneous disease seems more common in children than adults. Diagnostic radiologic findings are also different. Children manifest cavitation, the air crescent sign, or the halo sign with less frequency than adults, and this can impact diagnosis significantly. There are a plethora of antifungal therapies used to treat pediatric IA, many in combination regimens, but no specific antifungal drug or combination regimen was shown to be superior to another with respect to mortality. This highlights the need for early and accurate diagnosis of the disease, as well as a concerted effort to maximize immune reconstitution.


   FOOTNOTES
 
Accepted Nov 2, 2007.

Address correspondence to William J. Steinbach, MD, Division of Pediatric Infectious Diseases, Box 3499, Duke University Medical Center, Durham, NC 27710. E-mail: stein022{at}mc.duke.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

Very little is known about pediatric invasive aspergillosis, and the little work done in pediatrics has all been only single-center work done well before the newer diagnostic and therapeutic tools were available.

 

What This Study Adds

This is the largest pediatric invasive aspergillosis study, the most contemporary study (2000–2005), and the only study done with newer, more relevant antifungal agents.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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