Approach to multidrug resistant infections in pediatric transplant recipients.

Introduction: There is increasing recognition of infections due to multidrug-resistant Gram negative (MDRGN) bacterial infections among children undergoing solid organ and hematopoietic cell transplantation, which may be associated with morbidity and mortality. Methods: We present two vignettes that highlight the clinical challenges of evaluation, management, and prevention of MDRGN bacterial infections in children prior to and after transplantation. The goal of this discussion is to provide a framework to help develop an approach to evaluation and management of these infections. Results: Source control remains the utmost priority in management of MDR infections and is paired with antibiotic selection guided by in vitro susceptibilities, adverse effect profiles, and clinical response. Identification and confirmation of resistance can be challenging and often requires additional testing for recognition of complex mechanisms. Current antimicrobial approaches to MDRGN infections include use of novel agents, prolonged infusion, and/or combination therapy. We also discuss preventative efforts including infection control, antimicrobial stewardship, targeted pre-emptive or prophylactic treatment, and decolonization. Discussion: The impact of MDRGN infections on patient and graft survival highlights the need to optimize treatment and prevention strategies.

Adjunctive Diagnostic Studies Completed Following Detection of Candidemia in Children: Secondary Analysis of Observed Practice From a Multicenter Cohort Study Conducted by the Pediatric Fungal Network.

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown. METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed-effects logistic regression. RESULTS: In 662 pediatric candidemia episodes, 490 (74%) underwent AbdImg, 450 (68%) OE, 426 (64%) echocardiogram, 160 (24%) neuroimaging, and 76 (11%) LP; performance of each aDS per episode varied across sites up to 16-fold. Longer durations of candidemia were associated with undergoing OE, AbdImg, and echocardiogram. Immunocompromised status (58% of episodes) was associated with undergoing AbdImg (adjusted odds ratio [aOR] 2.38; 95% confidence intervals [95% CI] 1.51-3.74). Intensive care at candidemia onset (30% of episodes) was associated with undergoing echocardiogram (aOR 2.42; 95% CI 1.51-3.88). Among evaluated episodes, positive OE was reported in 15 (3%), AbdImg in 30 (6%), echocardiogram in 14 (3%), neuroimaging in 9 (6%), and LP in 3 (4%). CONCLUSIONS: Our findings show heterogeneity in practice, with some clinicians performing aDS selectively, potentially influenced by clinical factors. The low frequency of positive results suggests that targeted application of aDS is warranted.

Body surface area compared to body weight dosing of valganciclovir is associated with increased toxicity in pediatric solid organ transplantation recipients.

Optimal dosing of valganciclovir (VGCV) for cytomegalovirus (CMV) prevention in pediatric solid organ transplantation recipients (SOTR) is controversial. Dosing calculated based on body surface area (BSA) and creatinine clearance is recommended but simplified body weight (BW) dosing is often prescribed. We conducted a retrospective 6-center study to compare safety and efficacy of these strategies in the first-year posttransplant There were 100 (24.2%) pediatric SOTR treated with BSA and 312 (75.7%) with BW dosing. CMV DNAemia was documented in 31.0% vs 23.4% (P = .1) at any time during the first year and breakthrough DNAemia in 16% vs 12.2% (P = .3) of pediatric SOTR receiving BSA vs BW dosing, respectively. However, neutropenia (50% vs 29.3%, P <.001), lymphopenia (51% vs 15.0%, P <.001), and acute kidney injury causing treatment modification (8.0% vs 1.8%, P <.001) were documented more frequently during prophylaxis in pediatric SOTR receiving BSA vs BW dosing. The adjusted odds ratio of VGCV-attributed toxicities comparing BSA and BW dosing was 2.3 (95% confidence interval [CI], 1.4-3.7] for neutropenia, 7.0 (95% CI, 3.9-12.4) for lymphopenia, and 4.6 (95% CI, 2.2-9.3) for premature discontinuation or dose reduction of VGCV, respectively. Results demonstrate that BW dosing is associated with significantly less toxicity without any increase in CMV DNAemia.

Monoclonal Antibody Use for Coronavirus Disease 2019 in Pediatric Patients: A Multicenter Retrospective Study.

Monoclonal antibodies for COVID-19 are authorized in high-risk patients aged ≥12 years, but evidence in pediatric patients is limited. In our cohort of 142 patients treated at seven pediatric hospitals between 12/1/20 and 7/31/21, 9% developed adverse events, 6% were admitted for COVID-19 within 30 days, and none received ventilatory support or died.

Comorbidities Associated with Hospitalization and Progression Among Adolescents with Symptomatic Coronavirus Disease 2019.

OBJECTIVE: To identify subgroups likely to benefit from monoclonal antibody and antiviral therapy by evaluating the relationship between comorbidities and hospitalization among US adolescents with symptomatic coronavirus disease 2019 (COVID-19). STUDY DESIGN: We analyzed the relationship between presence of comorbidities and need for hospitalization within 28 days of COVID-19 diagnosis for adolescents aged 12-17 years listed in the Pediatric COVID-19 US registry, a multicenter retrospective cohort of US pediatric patients with COVID-19. Comorbidities assessed included obesity, chronic kidney disease (CKD), diabetes, immunosuppressive disease or treatment, sickle cell disease (SCD), heart disease, neurologic disease/neurodevelopmental disorders, and pulmonary disease (excluding patients with mild asthma). We used multivariable logistic regression to determine race/ethnicity-adjusted associations between comorbidities and hospitalization. RESULTS: A total of 1877 patients met our inclusion criteria, of whom 284 (15%) were hospitalized within 28 days of their COVID-19 diagnosis. In a race/ethnicity-adjusted model, the following comorbidities were independently associated with increased odds of hospitalization: SCD (aOR, 6.9; 95% CI, 3.0-15.9), immunocompromising condition (aOR, 6.4; 95% CI, 3.8-10.8), obesity (aOR, 3.2; 95% CI, 2.1-4.9), diabetes (aOR, 3.0; 95% CI, 1.4-6.2), neurologic disease (aOR, 2.8; 95% CI, 1.8-4.3), and pulmonary disease (excluding mild asthma) (aOR, 1.9; 95% CI, 1.2-3.1). Heart disease and CKD were not independently associated with hospitalization. CONCLUSIONS: SCD, immunocompromising conditions, obesity, diabetes, neurologic disease, and pulmonary disease (excluding mild asthma) were associated with hospitalization for symptomatic COVID-19. Adolescents with acute COVID-19 and these comorbidities should be prioritized for consideration of therapy to avert hospitalization.

Epidemiology and outcomes of invasive aspergillosis among pediatric immunocompromised patients: A 12-year single-center experience.

Invasive aspergillosis (IA) remains a common cause of mortality in pediatric immunocompromised populations. Much of our knowledge of IA stems from adult literature. We conducted a retrospective evaluation of cases of proven or probable IA, defined according to the 2019 EORTC/MSG criteria, in patients with underlying immunocompromising conditions at Boston Children's Hospital from January 1, 2007 to January 1, 2019. We estimated survival curves over 12 weeks using the Kaplan-Meier method for all-cause mortality, and we used univariate Cox proportional hazards modeling to evaluate for mortality risk factors. We identified 59 cases, 29% with proven and 71% with probable IA. Pulmonary IA was the most common presentation (78%). The median age at diagnosis was 11 years (range, 0.5-28). Hematopoietic cell transplantation (HCT) was the most frequent predisposing underlying condition (41%). Among affected patients, 44.8% were neutropenic and 59.3% were lymphopenic at diagnosis. The 12-week all-cause mortality rate was 25.4%; HCT recipients comprised the majority of deaths (9/15) with a hazard ratio of 2.47 [95% CI, 0.87-6.95]. No patients with congenital immunodeficiencies (n = 8) died within 12 weeks of IA diagnosis. Other risk factors that were significantly associated with mortality included mechanical ventilation at diagnosis, intensive care unit stay, and lymphopenia; treatment with an Aspergillus-active azole was associated with decreased mortality.In conclusion, our study found that in pediatric immunocompromised hosts, IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the HCT population. LAY ABSTRACT: This study explores the epidemiology, outcomes and predictors of mortality of invasive aspergillosis (IA) at a high-volume pediatric center for immunocompromised hosts. Much of our understanding of pediatric IA is extrapolated from the adult literature. Our study found that IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the hematopoietic cell transplantation study cohort.

Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022.

The COVID-19 pandemic continues to generate challenges for pediatric solid organ transplant (SOT) recipients and their families. As rates of COVID-19 fluctuate, new SARS-CoV-2 variants emerge, and adherence to and implementation of mitigation strategies vary from community to community, questions remain about the best and safest practices to prevent COVID-19 in vulnerable patients. Notably, decisions about returning to school remain difficult. We assembled a team of specialists in pediatric infectious diseases, transplant infectious diseases, public health, transplant psychology, and infection prevention and control to re-address concerns about school re-entry, as well as COVID-19 vaccines, for pediatric SOT recipients in the United States in 2021. Based on available literature and guidance from national organizations, we generated expert statements specific to pediatric SOT recipients focused on school attendance in 2021.

Return to School for Pediatric Solid Organ Transplant Recipients in the United States During the Coronavirus Disease 2019 Pandemic: Expert Opinion on Key Considerations and Best Practices.

The coronavirus disease 2019 (COVID-19) pandemic has created many challenges for pediatric solid organ transplant (SOT) recipients and their families. As the pandemic persists, patients and their families struggle to identify the best and safest practices for resuming activities as areas reopen. Notably, decisions about returning to school remain difficult. We assembled a team of pediatric infectious diseases (ID), transplant ID, public health, transplant psychology, and infection prevention and control specialists to address the primary concerns about school reentry for pediatric SOT recipients in the United States. Based on available literature and guidance from national organizations, we generated consensus statements pertaining to school reentry specific to pediatric SOT recipients. Although data are limited and the COVID-19 pandemic is highly dynamic, our goal was to create a framework from which providers and caregivers can identify the most important considerations for each pediatric SOT recipient to promote a safe return to school.

Mitochondrial Dysfunction and Insulin Resistance in Pubertal Youth Living with Perinatally Acquired HIV.

Mitochondrial dysfunction (MD) is linked to cardiometabolic complications, such as obesity and insulin resistance (IR), the frequencies of which are higher in adults living with HIV infection and receiving combination antiretroviral therapies (ARV). ARV-treated youth living with perinatally acquired HIV infection (YLPHIV) may be especially susceptible to IR due to long-term exposure to both factors. Medical histories, fasting blood chemistry panels, and mitochondrial function in banked peripheral blood mononuclear cells (PBMCs) were assessed in eligible YLPHIV from the Pediatric HIV/AIDS Cohort Study (PHACS)/Adolescent Master Protocol (AMP) Mitochondrial Determinants Component cohort, stratified by Homeostatic Model Assessment of IR (HOMA-IR) score: case (score ≥4, n = 39) or control (score <4, n = 105). PBMCs were sources for mitochondrial (mt) DNA copies/cell; mtRNA transcript levels of oxidative phosphorylation (OXPHOS) subunits NADH dehydrogenases 1 and 6, and cytochrome B; and enzymatic activities of OXPHOS Complexes I (CI) and IV (CIV). Logistic regression models were fit to estimate the odds of IR case diagnosis, adjusted for sex, race/ethnicity, body mass index (BMI) z-score, and Tanner stage. IR cases were similar to controls by age, sex, and race/ethnicity. Cases had higher median levels of peak HIV viral load, lactate, pyruvate, triglycerides, and BMI z-scores. OXPHOS CI enzymatic activity was lower in cases (log10 1.62 vs. 1.70) and inversely correlated with HOMA-IR score (r = -0.157, p = .061), but did not associate with IR in adjusted models. Fully adjusted models indicated associations of nadir CD4% [odds ratio (OR) = 0.95, 95% confidence intervals (CIs) = 0.90-1.00] or peak HIV load (OR = 3.48, 95% CIs = 1.70-10.79) with IR. IR in YLPHIV was strongly associated with morphometrics, but early virologic and immunologic factors may also influence MD.

Assessment of the Clinical Utility of Plasma Metagenomic Next-Generation Sequencing in a Pediatric Hospital Population.

Metagenomic next-generation sequencing (mNGS) of plasma cell-free DNA (cfDNA) is commercially available, but its role in the workup of infectious diseases is unclear. To understand the clinical utility of plasma mNGS, we retrospectively reviewed patients tested at a pediatric institution over 2 years to evaluate the clinical relevance of the organism(s) identified and the impact on antimicrobial management. We also investigated the effect of pretest antimicrobials and interpretation of molecules of microbial cfDNA per microliter (MPM) of plasma. Twenty-nine of 59 (49%) mNGS tests detected organism(s), and 28/51 (55%) organisms detected were clinically relevant. The median MPM of clinically relevant organisms was 1,533, versus 221 for irrelevant organisms (P = 0.01). mNGS test positive and negative percent agreements were 53% and 79%, respectively, and 50% of negative mNGS tests were true negatives. Fourteen percent of tests impacted clinical management by changing antimicrobial therapy. Immunocompromised status was the only patient characteristic that trended toward a significant clinical impact (P = 0.056). No patients with culture-negative endocarditis had organisms identified by mNGS. There were no significant differences in antimicrobial duration retest between tests with clinically relevant organism(s) and those that returned negative, nor were the MPMs different between pretreated and untreated organisms, suggesting that 10 days of antimicrobial therapy as observed in this cohort did not sterilize testing; however, no pretreated organisms identified resulted in a new diagnosis impacting clinical management. Plasma mNGS demonstrated higher utility for immunocompromised patients, but given the detection of many clinically irrelevant organisms (45%), cautious interpretation and infectious diseases consultation are prudent.

Progressive multifocal leukoencephalopathy presenting with acute sensorineural hearing loss in an intestinal transplant recipient.

A 20-year-old male presented 3.5 years after intestinal transplantation with rapidly progressive sensorineural hearing loss. Initial brain imaging was consistent with inflammation and/or demyelination. Lumbar puncture was initially non-diagnostic and a broad infectious workup was unrevealing. Three months after presentation, a repeat LP detected JC virus for which tests had not earlier been conducted. He continued to deteriorate despite withdrawal of prior immunosuppression and addition of mirtazapine, maraviroc, and steroids. He died of progressive neurologic decompensation 5 months after his initial presentation. This case highlights progressive multifocal leukoencephalopathy (PML) as a rare complication after solid organ transplantation and acute sensorineural hearing loss as an unusual first presenting symptom of PML. JC virus should be considered in the differential diagnosis of acute sensorineural hearing loss in any immunocompromised patient.

Impact of standardized protocols for cytomegalovirus disease prevention in pediatric solid organ transplant recipients.

End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre- and post-implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention. The pre- and post-intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (P < .01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P < .001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.

Human T-cell lymphotrophic virus in solid-organ transplant recipients: Guidelines from the American society of transplantation infectious diseases community of practice.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Human T-cell lymphotrophic virus 1 (HTLV)-1 in the pre- and post-transplant period. HTLV-1 is an oncogenic human retrovirus rare in North America but endemic in the Caribbean and parts of Africa, South America, Asia, and Oceania. While most infected persons do not develop disease, <5% will develop adult T-cell leukemia/lymphoma or neurological disease. No proven antiviral treatment for established HTLV-1 infection is available. The effect of immunosuppression on the development of HTLV-1-associated disease in asymptomatically infected recipients is not well characterized, and HTLV-1-infected individuals should be counseled that immunosuppression may increase the risk of developing HTLV-1-associated disease and they should be monitored post-transplant for HTLV-1-associated disease. Currently approved screening assays do not distinguish between HTLV-1 and HTLV-2, and routine screening of deceased donors without risk factors in low seroprevalence areas is likely to result in significant organ wastage and is not recommended. Targeted screening of donors with risk factors for HTLV-1 infection and of living donors (as time is available to perform confirmatory tests) is reasonable.

Pediatric post-transplant hepatic kaposi sarcoma due to donor-derived human herpesvirus 8.

In areas of the world where human herpesvirus 8 (HHV-8) is endemic, Kaposi sarcoma (KS) is a common SOT-associated cancer. In the United States, where the virus is not prevalent, PTKS is rare, and there is little literature on pediatric PTKS. We present a North American female who underwent deceased donor, left lateral segment liver transplant for biliary atresia at age 11 months. The donor was a male with no known history of KS, originally from an HHV-8-endemic country. Three months after transplantation, the patient developed liver nodules and portal vein thrombosis. Analysis of needle biopsy established the diagnosis of KS and confirmed that the transformed cells were donor-derived. HHV-8 viremia was detected, and ganciclovir dosing (which had been started prophylactically) was increased. Immunosuppression was changed from tacrolimus to sirolimus. After further disease progression, 8 cycles of paclitaxel were administered. Under this treatment, her nodules regressed, HHV-8 viremia resolved, and she had marked clinic improvement. Notably, the adult recipient of the right liver lobe from the same donor also developed PTKS. This is one of few pediatric PTKS cases described in the literature. It contributes to the mechanistic understanding of PTKS development, illustrating the risk posed by donors from HHV-8-endemic countries, as well as the potential for strong PTKS correlation between multiple recipients of organs from a single shared donor.

Clinical Vignettes: Donor-Derived Infections.

Patients undergoing solid organ transplantation (SOT) may acquire infections from the transplanted organ. Routine screening for common infections are an established part of the pretransplant evaluation of donors and recipients. Likewise, strategies exist for prophylaxis and surveillance for common donorassociated infections including hepatitis B, CMV and EBV. However, despite advances in diagnostic testing to evaluate the infectious risk of donors, unanticipated transmission of pathogens occurs, particularly when donors are asymptomatic or have subtle or unusual manifestations of a transmissible Infection. Infectious diseases (ID) providers play an integral role in donor and recipient risk assessment and can advise transplant centers on organ utilization and guide evaluation and management of the SOT recipient. Consideration of the donor cause of death and preceding clinical syndromes are important for characterizing the potential risk for recipient infection. This allows a more accurate analysis of the risk: benefit of accepting a life-saving organ and risk of infection. ID providers and transplant teams should work closely with organ procurement organizations (OPOs) to solicit additional donor information when a donor-derived infection is suspected so that reporting can be facilitated to ensure communication with the care-teams of other organ recipients from the same donors. National advisory committees work closely with federal agencies to provide oversight, guide policy development, and assess outcomes to assist with the prevention and management of donor-transmitted disease through organ transplantation. The clinical vignettes in this review highlight some of the complexities in the evaluation of potential donor transmission.

A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients.

Background: Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease. Methods: Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed. Results: We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively). Conclusions: Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.

Longitudinal Changes in Body Composition by Dual-energy Radiograph Absorptiometry Among Perinatally HIV-infected and HIV-uninfected Youth: Increased Risk of Adiposity Among HIV-infected Female Youth.

BACKGROUND: Combination antiretroviral therapy has allowed youth with perinatal HIV infection (PHIV+) to live into adulthood, but many youth may experience metabolic and body composition changes that predispose to greater cardiovascular disease (CVD) risk. This longitudinal study evaluated changes in body composition measured by dual-energy radiograph absorptiometry (DXA) in a cohort of PHIV+ youth compared with HIV- controls over a 7-year period. METHODS: PHIV+ youth and HIV- controls were prospectively enrolled in a single-site study to assess nutrition and CVD risk. Anthropometrics and DXA scans were longitudinally obtained to assess percent body fat and regional fat distribution. Using general linear models, we analyzed differences in body composition and anthropometric measures by sex between PHIV+ youth and controls over time. RESULTS: Two hundred thirty-five participants (156 PHIV+ and 79 HIV- controls) with at least 1 DXA performed since study enrollment were included for analysis. During the study period, 471 DXAs were obtained in the PHIV+ group and 95 in HIV- controls. PHIV+ females demonstrated greater increase in weight and body mass index over time compared with HIV- females, and significant increases in total percent body fat [estimate = 1.212 (95% confidence interval: 0.837-1.587) percent per year; P < 0.001) and percent trunk fat [1.3818 (95% confidence interval: 0.922-1.84); P < 0.001] compared with HIV- females and PHIV+ males. CONCLUSIONS: PHIV+ females demonstrate an unfavorable change in fat redistribution and percent body fat over time that exceeds the pattern seen in PHIV+ males or HIV- females. Providers should have heightened awareness of body composition changes of PHIV+ females that may eventually lead to increased CVD risk.

A Prospective, International Cohort Study of Invasive Mold Infections in Children.

BACKGROUND: Invasive mold infections (IMIs) are a leading cause of mortality in immunocompromised children, yet there has never been an international epidemiologic investigation of pediatric IMIs. METHODS: This international, prospective cohort study was performed to characterize the epidemiology, antifungal therapy, and outcomes of pediatric IMIs. Children (≤18 years) with proven or probable IMIs were enrolled between August 2007 and May 2011 at 22 sites. Risk factors, underlying diagnoses, and treatments were recorded. Outcomes were assessed at 12 weeks after diagnosis using European Organization for Research and Treatment of Cancer/Mycoses Study Group response criteria. RESULTS: One hundred thirty-one pediatric patients with IMIs were enrolled; the most common IMI was invasive aspergillosis ([IA] 75%). Children with IA and those with other types of IMIs had similar underlying risk factors, except that children with IMIs caused by non-Aspergillus species were more likely to have received mold-active antifungal agents preceding diagnosis. The most commonly used antifungal classes after diagnosis were triazoles (82%) and polyenes (63%). Combination therapy was used in 53% of patients. Use of combination therapy was associated with an increased risk of adverse events (risk ratio, 1.98; 95% confidence interval, 1.06-3.68; P = .031), although there was no detectable difference in outcome. CONCLUSIONS: Although risk factors for IMIs are similar across specific subtypes, preceding antifungal therapy may be an important modifier. Combination antifungal therapy requires further study to determine its true risks and benefits.