There is little specific information on the fundamental epidemiology of pediatric IA. In one large study of 621 patients with IA done in the greater Paris area, the mean age was 40.3 years (range 6 days – 89.7 years) and there were no specific pediatric data (Cornet et al, 2002).
Another study examined risk factors for mould infection in 230 bone marrow transplant patients and enrolled patients from age 4 months – 54 years but the mean age was approximately 29 years and there was no specific pediatric analysis (Yuen et al, 1997). One study examined 409 patients for early infections after HSCT and enrolled patients from ages 6 months – 65 years (mean age 32 years), but again there was no pediatric analysis (Kruger et al, 1999). Another study of 173 allogeneic HSCT patients after non-myeloablative conditioning analyzed patients with a mean age of 53 years (range 0-72 years) and did not comment on pediatric disease (Fukuda et al, 2003). One study of 327 patients with IA from 1985-1999 did stratify patients into three age groups (Marr et al, 2002). A total of 13% of patients were < 19 years old, with 34% between 19-40 years old and 53% of patients > 40 years. The number of transplants performed in that youngest age group was not reported so a true incidence of pediatric disease cannot be calculated. The true incidence of IA in children
Even large-scale studies of infections in pediatric HSCT patients do not answer the fundamental questions. In a study of 148 pediatric HSCT patients from 1986-1996 with 8 proven IA
Autopsy data from Japan for IA patients from years 1989, 1993, and 1997 analyzed the patients based on age into single decade blocks (Kume et al, 2003). From a total of 412 IA patient autopsies there were 14 IA cases in children aged 0-9 years, and 24 in those aged 10-19 years. By comparison, there were 92 cases from age 50-59 years and 102 cases from ages 60-69 years. The study did not report the total number of children in each range who underwent autopsy so it is again impossible to calculate an incidence of pediatric IA.
In an excellent review of IA case fatality rates pooled from 1,941 patients from clinical trials, cohort or case-control studies, and case series of ³ 10 patients with definite or probable IA from 1995-1999, there was some stratification of case fatality rate by
There have been two published reviews of childhood cases and both suffer from the limitations of time because diagnostic and therapeutic tools available to today's pediatric clinician have improved substantially. In 1993 the Hospital for Sick Children in Toronto reviewed 39 cases of pediatric IA from 1979-1988 (Walmsley et al, 1993). Of those 39 cases, 24 were proven IA and 15 were probable IA. The median age of the cases was 10 years (range 22 days – 18 years), and 74% had a hematologic malignancy or were a bone marrow transplant recipient. Thirty-one of 36 patients had an absolute neutrophil count (ANC) less than 500 cells/
In 41% (16/39) of the total patients, the Aspergillus infection was
The second pediatric IA study was a review of 66 cases of proven IA from approximately 9,500 children treated from 1962-1996 at St. Jude's Children's Hospital in Memphis (Abbasi et al, 1999). The median age was 11.2 years (range 1.3 – 21.6 years). The ANC for these patients was < 500 cells/
The species distribution of Aspergillus isolates for pediatric and adult patients is different in some studies. A large National Institute of Allergy and Infectious Diseases Bacteriology and Mycoses Study Group study reviewed 256 isolates of Aspergillus species from patients with IA from 24 medical centers (Perfect et al, 2001) and A.
However, in two more recent
There has not been a dedicated, prospective, large-scale investigation into
In a retrospective French study of 46 pediatric patients treated with
An analysis of the compassionate
The second largest series of pediatric aspergillosis patients who received voriconazole is seven patients with a mean age of 5 years (range 2-13 years), all with hematologic malignancies. They underwent liposomal AmB therapy for a mean of 6 weeks (range 2-18 weeks) before switching to voriconazole (Cesaro et al, 2003). There was a complete response in 2 patients, a partial response in 2 patients, stability in one patient, and failure in two patients. Complete or partial response coincided with recovery from neutropenia and hematologic remission of underlying diseases. This yielded an overall response rate of 57% and a 100-day survival rate of 42%.
Pharmacokinetics of antifungal drugs in children
Fundamental to treating aspergillosis is an understanding of the pediatric pharmacokinetics and pharmacodynamics of new antifungal drugs in children. Complete reviews of the newer antifungals and immunomodulatory strategies for IA in adults have already been published, (Steinbach et al, 2003, Steinbach, Stevens & Denning, 2003) but there are important differences in children. Voriconazole metabolism is non-linear in adults with an approximately 3-fold increase in the area under the concentration-time curve (AUC) following a 33% increase in dosage. Elimination of voriconazole is linear in children following doses of 3 and 4 mg/kg every 12 hours. This linearity was based on a eleven patient, single dose, open, two-center study in the United Kingdom of children ages 2-11 years (mean age 5.9 years) and a 28 patient multiple-dose, open, multicenter study in two age cohorts (ages 2-6, 6-12 years) (mean age 6.4 years) from eight centers (Walsh et al, 2004).
Drug exposures based on mean AUC at 4 mg/kg every 12 hours in children were similar to doses of 3 mg/kg every 12 hours in adults, suggesting that pediatric patients have a higher capacity for elimination on a weight basis than do adult healthy volunteers. Based on extrapolated plasma pharmacokinetics for the pediatric population at dosages of 5 – 12 mg/kg every 12 hours compared with adult data at 4 mg/kg every 12 hours, the pediatric dosage of approximately 11 mg/kg every 12 hours is equivalent to the adult dosage of 4 mg/kg every 12 hours in terms of AUC and mean plasma concentration. This statement is valid only when the linear pharmacokinetics of voriconazole were maintained throughout the dosage range (Walsh et al, 2004). The correct pediatric dosage is unknown but is likely much higher than that for adult patients. A new pharmacokinetic study that will
Caspofungin therapy in adults begins with a single daily loading dose of 70 mg followed by a 50 mg dose once daily. Pharmacokinetics in healthy men revealed linear pharmacokinetics and dose-proportional AUC concentration data, but pharmacokinetics appeared slightly different in children. The initial pediatric pharmacokinetic study enrolled 39 patients (ages 2-17) and data were obtained using both a weight-based (1mg/kg/d) and body surface area (70 mg/m 2 /day or 50 mg/m 2 /day) approach (Walsh et al, 2002). The weight-based approach resulted in sub-optimal plasma concentrations in all children relative to adults. The 50 mg/m 2 /day regimen yielded similar plasma concentrations and increased AUC to adult patients (50mg/d). Caspofungin had a beta half-life reduced 32-43% in children, with pharmacokinetic projections suggesting that dosing at 50 mg/m 2 /day appears to be more appropriate in children than using 1 mg/kg/day.
Division of Pediatric Infectious Diseases
Duke University Medical Center
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