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Table 1 Summary of findings

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

  1. Abbreviations: ALL Acute Lymphoblastic Leukemia, AML Acute Myeloid Leukemia, AML97 and AML02: multicentre protocols for pediatric patients with AML, BAL Bronchoalveolar lavage, BDG β-D-glucan, CAS Caspofungin, CT Computed tomography, d days, EIA Ezyme Immunoassay, EC Esophageal candidiasis, EORTC/MSG European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and The National Institute of Allergy and Infectious Disease Mycoses Study Group, GM galactomannan, HSCT Hematopoietic Stem Cell Transplant, IA Invasive Aspergillosis, IC Invasive candidiasis, IFD Invasive Fungal Disease, IQR Interquartile range, L-AmB Liposomal amphotericin B, m months, NPV Negative predictive value, OD Optical density, PCR Polymerase Chain Reaction, PPV Predictive positive value, Pts Patients, y years, US United States