From: Management of pulmonary aspergillosis in children: a systematic review
Author | Year | Country | Aim | Study design | Number of patients | Age | Results |
---|---|---|---|---|---|---|---|
Anantasit et al. [7] | 2018 | Thailand | To validate EORT/MSG 2008 definition in paediatric population Histology vs EORTC/MSG 2008 | Retrospective Cross-sectional | 256 | 1 m- 18 y | EORT/MSG 2008 sensitivity 100% specificity 36% PPV 33% NPV 100% EORT/MSG useful as screening tool Neutropenia described as risk factor for IPA |
Avcu et al. [8] | 2017 | Turkey | To determine the utility of serum GM monitoring in early diagnosis of IA and its role in the management of children with ALL | Retrospective cohort study | 141 3264 samples | Median age 55 m (range 3–208 m) | False positive: 52.1% Multiple consecutive positive tests increased the incidence of true-positive tests and introduction of antifungal therapy |
Badiee et al. [9] | 2012 | Iran | To evaluate the diagnostic potential of EIA for GM, nested PCR and BDG test | Prospective matched cohort study | 62 patients 230 samples 36 pts (129 samples) with IA suspicion 26 pts (101 samples) controls | Mean age 9.3 y | Galactomannan EIA: sensitivity 90%, specificity 92%, PPV 81.8% NPV 96%, likelihood ratios for positive results 11.25, for negative results 0.1 beta–D–glucan: sensitivity 50%, specificity 46%, PPV 26%, NPV 70.6%, likelihood ratios for positive results 0.9, for negative results 0.9 nested-PCR: sensitivity 80%, specificity 96.2%, PPV 88.9%, NPV 92.6%, likelihood ratios for positive results 21, and negative results 0.2 Galactomannan and nested-PCR tests are useful as non-invasive methods for diagnosis of IA in children. Beta–D–glucan test is not an efficient diagnostic tool in those with hematologic disorders |
Burgos et al. [10] | 2008 | US | To describe risk factors, diagnostic tools, treatments and outcomes of IA in children | Retrospective cross-sectional study | 139 pts | Median age 10.1 y (17d-18y) | A. fumigatus was the most often reported species Risk factors: immunosuppressive therapies and allogenic HSCT Most common site: lungs (59%) Most frequent radiologic finding: nodules 34.6% with 2.2% showing the crescent sign, 11% the halo sign and 43.1% cavitation Treatment: 45.8% received more than 3 concomitant antifungal agents, no superiority among antifungal agents was found |
Caglar et al. [11] | 2020 | Turkey | To evaluate the diagnostic value of serum GM positivity for IA in children | Retrospective cohort study | 70 patients 104 samples | Median age 5 y (1–16) | Consecutive GM positivity has higher PPVs independently from the cut-off value chosen |
Choi et al. [12] | 2013 | Korea | To investigate the use of GM antigen assay as diagnostic tool in pediatric cancer and HCT patients; to assess the characteristics of patients with IA | Retrospective controlled cohort study | 83 patients 23 IA group 60 non-IA group 640 samples | Median age IA 12.3 y (0.7–18.4) Non-IA 6.4y (0.3–18.7) | The false-positive rate was 18.3% Being younger than 3 years of age, having a solid tumor, and receiving HCT within 4 weeks from the test caused false-positive results (p < 0.05) The most common clinical site of IA was the lung (91.3%), and consolidation was the most frequent finding in chest CT scans (36.8%). The mortality at 12 weeks was 43.5% Having a positive GM assay at least twice is useful in diagnosing IA in pediatric patients with cancer and HCT recipients |
de Mol et al. [13] | 2013 | Netherlands | To study the diagnostic value of BAL GM in immunocompromised children | Retrospective cross sectional study | 47 pts 47 bronchoscopies | Median age 9.8 (1.1–18.2) y | BAL GM for proven and probable IPA: Sensitivity 82.4%, specificity 87.5%, PPV 82.4, NPV 87.5% A significant relation for BAL GM and abnormal chest CT (p = 0.01) BAL GM and serum GM correlated significantly BAL GM test had good diagnostic value in children with suspected IPA. The decision to continue or start antifungal therapy was mainly determined by the clinical suspicion of IPA based on chest CT-outcome, serum GM index values and failure of antibiotic therapy |
Dinand et al. [14] | 2016 | India | To evaluate the use and optimal serum GM cut-off in children | Prospective cohort study | 145 pts 211 febrile episodes | Median age 5 (0.5–19) y | Serum GA is sensitive to diagnose IA in pediatric patients with excellent NPV with a cut-off of 0.7. Two consecutive values of 0.7 increases specificity to 91.0% |
Doring et al. [15] | 2012 | Germany | To analyse safety and efficacy of CAS and L-AmB in HSCT patients | Retrospective matched cohort study | 60 pts received CAS 60 pts received L-AmB | Median age Cas group 9.5y L-AmB group 7.5y | Similar efficacy between prophylaxis with CAS and L-AmB after allogenic HSCT More drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge in L-AmB receiving group |
Doring et al. [16] | 2015 | Germany | To assess safety, feasibility, and efficacy of posaconazole compared to fluconazole and itraconazole in neutropenic children and adolescent | Retrospective matched cohort study | 93 pts 31 fluconazole 32 itraconazole 30 posaconazole | Median age 12y (9 m-17.7y) | Posaconazole, fluconazole, and itraconazole are comparably effective in preventing invasive fungal infections in children Larger studies are required to define dose recommendations No statistical significant differences found in adverse events |
Fisher et al. [17] | 2012 | US | To evaluate GM EIA as diagnostic tool in children after intensive chemotherapy or HSCT | Multicentre prospective cohort study | 213 patients 1865 serum samples from 198 pts 886 urine samples from 183 pts 7 BAL samples from 4 pts | 7.8 y | Serum GM testing specificity 95% Urine GM testing specificity 80% The urine test resulted in a higher false positivity rate, but it successfully identified the only case of probable IA Screening for GM, or a related antigen in urine, needs to be further evaluated as it may be useful in surveillance strategies |
Fisher et al. [18] | 2019 | US and Canada | To compare the efficacy of CAS vs. fluconazole prophylaxis against proven or probable invasive fungal disease and IA in neutropenic patients following AML chemotherapy | Multicentre randomized open label clinical trial | 257 CAS 260 fluconazole | Median age 9 (0–36) y | Prophylaxis with CAS compared with fluconazole resulted in significantly lower incidence of invasive fungal disease and proven and probable IA |
Fisher et al. [19] | 2021 | US | To assess surveillance testing with GM EIA and BDG assay in children with AML receiving antifungal prophylaxis | Prospective cohort study | 425 pts 209 fluconazole 216 CAS 6103 samples | Median age 10(0–25) y | NPV > 99% for GM EIA and BDG test alone and in combination Sensitivity and PPV 0% GM EIA and BDG test should be discouraged for surveillance in patients with AML receiving antifungal prophylaxis |
Gefen et al. [20] | 2015 | Israel | To investigate serial serum GM assay screening on IPA diagnosis in children with HSCT or high risk leukemia | Prospective cohort study | 34 pts 510 samples in neutropenic children | Median age 8.5 y (6 m-19y) | GM assay: sensitivity 0.8, specificity 0.66, PPV 0.22 and NPV 0.96 |
Han et al. [21] | 2015 | Korea | To characterize IPA in children with hematological/oncological disorders | Retrospective matched cohort study | 166 pts | Neutropenia lasting more than 2 weeks (51.4% vs. 21.9%, p < 0.001) and halo signs at chest CT (78.4% vs. 40.7%, p < 0.001) were more frequent among children with IPA Early use of chest CT in children at risk of prolonged neutropenia could be helpful for early IPA diagnosis | |
Herbrecht et al. [22] | 2002 | Multicentre Invasive Fungal Infection Group of EORTC | To compare voriconazole with AmB as primary therapy of IPA | Randomized, unblinded clinical trial | 144 pts voriconazole 133 AmB | Mean age voriconazole group: 48.5 (13–79)y AmB group: 50.5 (12–75) y | Voriconazole led to better responses, improving survival with less severe side effects than amphotericin B |
Itsaradisaikul et al. [23] | 2021 | Thailand | To evaluate 1-year incidence of IFD after itraconazole prophylaxis in HSCT children; to identify risk factors, etiology and adverse events | Retrospective cohort study | 170 pts | Median age 8.43 (5.41–12.36) y | Itraconazole did not showed a excellent efficacy in preventing IFD after HSCT. It could be used in resource-limited settings. It requires appropriate drug level monitoring if used |
Jha et al. [24] | 2013 | India | To evaluate the role of GM assay in IA diagnosis in children on treatment for hematological malignancies and to identify the best cut-off values | Prospective cohort study | 78 pts 100 ferbile episodes | Mean age 6.1 y (1.5–13) | Best results with cut-off value of 1.0 GM assay (cut-off value 1.0): Sensitivity 60%, specificity 93%, PPV 75, NPV 87 A higher value of GM related with pulmonary nodules (p = 0.037) and mortality (p = 0.001) |
Kato et al. [25] | 2016 | Japan | To identify the daily therapeutic dose in children; to analyze association between voriconazole concentration and clinical outcomes | Retrospective cohort study | 20 pts 111 samples | Median age 9.5 (0–17) y | younger age and oral administration were associated with lower plasma voriconazole concentrations (p < 0.01). Unfavourable outcome was associated with low concentrations of voriconazole (p = 0.01) Higher doses are required in younger children and in case of oral administration |
Kazakou et al. [26] | 2020 | Greece | To evaluate the incidence of IFD in children with hematological malignancies and determine the clinical characteristics, risk factors, diagnosis, treatment efficacy and outcome | Retrospective cohort study | 297 pts | Mean age 6.64 (2–13) y | Most common underlying disease: ALL (79%) Most common site of infection: lungs (66.7%) Identified species: Aspergillus spp. (58.3%) Most prescribed treatment: L-AmB The crude mortality rate was 33.3% |
Lee et al. [27] | 2017 | Korea | To determine safety and efficacy of the combination of Voriconazole and CAS to treat IFDs | Retrospective cross-sectional study | 22 pts | Mean age 5 3 (0.8–13.3) y | Voriconazole plus CAS is an effective and safe treatment for serious IFD in children with leukemia |
Loeffler et al. [28] | 2017 | Germany | To determine the use of GM assay combined with PCR assay in HSCT recipients | Retrospective cohort study | 39 pts 543 samples | Median age male: 9.5 (4–21) y female: 10 (3–19) y | GM assay: specificity 89%, sensitivity 67%, PPV 50% NPV 100% PCR assay: specificity 63%%, sensitivity 100%, PPV 27% NPV 100% combined monitoring for GM and fungal DNA results in a higher diagnostic accuracy |
Maertens et al. [29] | 2010 | US and Europe | To evaluate CAS vs L-AmB for Empiric antifungal therapy in children with persistent fever and neutropenia | Randomized double blind clinical trial | 83 pts 57 CAS 26 L-AmB | Range 2–17 y | CAS and L-AmB were comparable in tolerability, safety and efficacy as empiric antimicotic therapy |
Maron et al. [30] | 2013 | US | To compare etiology, predisposing factors and outcomes of IFD in AML patients before and after implementation of voriconazole prophylaxis | Retrospective cohort study | 19 pts AML97 (no fungal prophylaxis) = 12 pts AML02 (voriconazole prophylaxis) = 11 pts | Median age AML97: 11 (0.3–21) y AML02: 8(1–19) y | Voriconazole prophylaxis was associated with improved survival and a significant reduction in aspergillosis |
Martin et al. [31] | 2017 | Multicentre Asia, Europe and North America | To evaluate safety, efficacy and exposure–response of voriconazole as treatment for IA, IC and EC | Prospective open-label, non-comparative phase 3 study | 53 pts 31 IA 22 IC/EC | Mean age IA 11.9 (SD 3.5) IC/EC 9.5 (SD 4.5) | In IA cohort: 22.6% treatment related hepatic AE and 16.1% visual AE; all-causality mortality 14.3% at week 6, no deaths attributed to voriconazole Voriconazole is effective in patients with IA with a favourable risk–benefit balance |
Mohammadi et al. [32] | 2015 | Iran | To evaluate the efficacy of BAL GM in immunocompromised patients | prospective case–control study | 16 pts immunocompromised, with possible/proven IPA by EORT/MSG criteria 54 controls | Mean age (IPA pts): 8.4 (11–15) y | BAL GM using an OD index of ≥ 0.5: Sensitivity 87.5% PPV 93.33% High diagnostic value of BAL GM in immunocompromised children with IPA |
Qiu et al. [33] | 2019 | China | To evaluate the diagnostic value for IPA of serum GM combined with CT in children after HSCT | Retrospective case control study | 46 cases 95 controls | Mean age Cases 7 ± 3.7 y Controls 6.2 ± 3.5y | GM testing combined with CT evaluation: PPV of 0.764, and NPV of 0.872, Sensitivity 0.793, and specificity 0.852 The combination of serum GM and chest CT might be used for early diagnosis of IPA in HSCT patients |
Vrioni et al. [34] | 2018 | Greece | To define the use of GM serum assay and PCR as routine methods for IA in immunosuppressed children | Prospective cohort study | 156 pts 744 samples | Age range 5 m-14y | Agreement of the two methods: 90% of pts, 96.1% of samples The combination of GM and PCR had a high diagnostic accuracy in consecutive samples (twice weekly) |
Zaoutis et al. [35] | 2006 | US | To describe the incidence and outcomes of IA in children | Retrospective cohort study | 666 pts | Median age 13 (IQR 8–15) | Highest incidence of IA in children with HSCT (4.5%) and AML (4%). The overall in- mortality of immunocompromised children was 18%. Children with malignancy and IA were at higher risk for death Children with IA had a longer hospital stay and higher hospital charges |