Ignite Creation Date:
2024-05-06 @ 7:21 PM
Last Modification Date:
2024-10-26 @ 3:05 PM
Study NCT ID:
NCT05982912
Status:
RECRUITING
Last Update Posted:
2023-08-09
First Post:
2023-08-01
Brief Title:
VOC in Breath Samples for the Diagnosis of IPA
Sponsor:
Rambam Health Care Campus
Organization:
Rambam Health Care Campus
Study Overview
Official Title:
The Identification of Volatile Organic Compunds Profiles Predictive of Invasive Pulmonary Aspergillosis in Breath Samples
Status:
RECRUITING
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The diagnosis of invasive pulmonary aspergillosis IPA bears grave implications for the prognosis and treatment plan of the immunosuppressed patient Thus far such diagnosis in the immunosuppressed patient such as patients with acute myeloid leukemia AML relied heavily on chest computed tomography CT and bronchoalveolar lavage BAL an invasive approach bearing many caveats Volatile organic compounds VOC are compounds that could be detected in exhaled air and have shown some potential in the non-invasive diagnosis of various conditions including IPA
In this prospective longitudinal study we aim to compare the VOC profiles of patients diagnosed with AML baseline to the profile of the same patient diagnosed with IPA later on and to the post recovery profile in the same patient This approach should resolve many of the issues plaguing prior attempts at VOC based IPA diagnosis mainly the lack of properly designed controls
Samples will be collected from consenting patients using Tedlar bags and analyzed using thermal desorption gas chromatography mass spectrometry TD-GC-MS VOCs detected will be digitally analyzed to construct different classification models with predictive performances compared to the clinical diagnosis using the accepted methods will be assessed by binary logistic regression
In this prospective longitudinal study we aim to compare the VOC profiles of patients diagnosed with AML baseline to the profile of the same patient diagnosed with IPA later on and to the post recovery profile in the same patient This approach should resolve many of the issues plaguing prior attempts at VOC based IPA diagnosis mainly the lack of properly designed controls
Samples will be collected from consenting patients using Tedlar bags and analyzed using thermal desorption gas chromatography mass spectrometry TD-GC-MS VOCs detected will be digitally analyzed to construct different classification models with predictive performances compared to the clinical diagnosis using the accepted methods will be assessed by binary logistic regression
Detailed Description:
BACKGROUND The diagnosis of invasive pulmonary aspergillosis IPA bears grave implications for the prognosis and treatment plan of the immunosuppressed patient The omnipresence of Aspergillus spp in the environment and by extension - the ubiquity of such isolates in the respiratory system of healthy subjects poses a great diagnostic challenge Namely the differentiation of IPA from non-invasive colonization of the respiratory tract may be challenging The vast increase in prevalence of patients who are immunosuppressed including malignancies and oncological treatments hematopoietic stem cells and solid organ transplantations and immunomodulatory medications accentuates this dilemma1 Particularly patients with acute myelogenous leukemia AML are at high risk of developing IPA with 5-15 of such patients developing IPA during the first 3 months after AML diagnosis1-3 As up to 5 of patients with AML may have IPA at presentation patients admitted to Rambam Medical Center RMC with a new diagnosis of AML routinely undergo chest computerized tomography CT which serves as screening for the presence of IPA at diagnosis and a baseline for further reference should IPA be suspected later on3 Diagnosis of probable or proven IPA in an AML patient requires suggestive imaging findings along with microbiologic evidence While in some cases the diagnosis can be made using biomarkers mainly the d-galactomannan antigen and or Aspergillus spp polymerase chain reaction in peripheral blood the sensitivity of these assays is low and often this minimally invasive approach does not yield sufficient diagnostic certainty In such cases bronchoscopy with bronchoalveolar lavage is usually performed This invasive procedure is particularly hazardous in patients with suspected IPA the vast majority of whom are very frail due to their underlying illness4 These considerations have led the quest for additional non-invasive modalities in the diagnosis of IPA 5 One such approach has been volatile organic compounds VOC analysis in exhaled air samples Characterized by low vapor pressure at room temperature VOC profile analysis of exhaled air is an emerging field of diagnostics with the potential of non-invasive screening and diagnosis of various diseases including neoplasms6 infections7 and inflammatory processes8 Previous studies have identified potential VOC markers of metabolically active Aspergillus spp9 with one small prospective study in humans10 showing encouraging diagnostic performance for VOC based IPA identification However these attempts have been hampered by several pitfalls Firstly VOC profiles of in vitro Aspergillus spp seem to have little relation with VOCs found in breath analysis of colonized patients5 Secondly exhaled VOCs tend to differ greatly between individuals making the absence of temporal controls ie VOC profile changes in the same individual before and after IPA development a crucial caveat10 Thirdly to our knowledge no longitudinal studies have assessed the response of VOC profiles to IPA treatment
In this prospective longitudinal study we aim to overcome these hurdles taking advantage of two key characteristics of hematologic patients treated in RMC First patients with newly diagnosed AML have a relatively high prevalence of IPA Second a chest CT is performed at the diagnosis of AML in all patients Thus collecting breath samples from patients with normal baseline CT will serve as negative controls allowing for the comparison of VOC profiles before and after the development of IPA in the same patient Further sampling after the patient has recovered from IPA will provide additional longitudinal control
GOALS The identification of VOC profiles predictive of IPA in breath samples
METHODS
Study design
This is a single center non randomized prospective cohort study Breath samples from consenting patients will be analyzed for VOC profiles at the time of initial CT screening for IPA In addition samples will also be collected at the time of diagnosis of any possible probable or confirmed IPA defined according to the EORTC criteria 4 as detailed below
Setting and participants
Patients newly diagnosed with AML initiating treatment in the RMC hematology department will be approached Inclusion period will be from October 1 2022 until March 31 2025
Inclusion criteria
New diagnosis of acute myeloid leukemia ANDOR planned hematopoietic stem cells transplantation HCT Chest CT performed within 30 days from sampling 18 years of age or older The ability to provide tidal breath samples totalling 10L directly into a Tedlar bag
Exclusion criteria
Any condition impairing the patients ability to provide informed consent
Sample collection
Breath samples will be collected in one of our hematological departments 23 dedicated hospitalization rooms - positively pressurized and climate controlled with E-pure high-efficiency particulate air HEPA filters ADS-Laminaire Israel Patients will be required to abstain from teeth brushing dental wash eating drinking or smoking in the 6 hours prior to sample collection After being seated for 10 minutes to avoid exercise induced isoprene concentration increase 11 the patient will be asked to fill 10L of tidal breath into a tedlar bag SKC South Korea Simultaneously an identical tedlar bag shall be filled with ambient air
Upon each sample collection the following data will be recorded
Patients characteristics including age hemato-oncological diagnosis time from initial diagnosis current treatment time from HCT if applicable background diagnoses Current pharmacological treatment including all antibiotics and antifungals prescribed the preceding month
Current diagnostic tests including all cultures serology assays nucleic acid amplification studies complete blood count and chemistry voriconazole plasma level and chest imaging performed during the past month
Sample handling and VOC extraction
All tedlar bags will be stored at 4 following collection Adsorption onto 2 parallel thermal desorption tubes shall be accomplished via Gilian LFS-113 Low Flow Personal Air Sampling Pump SRA instruments Milano Italy performed within 72 hours from sampling and stored under ambient conditions These samples will be labeled coded and transformed to the Environmental Chemistry Laboratory Kasali Institute of Chemistry Hebrew University of Jerusalem Israel
Analytics
Thermal desorption will be accomplished at 290 for 20 minutes using analytical grade 99999 helium gas as carrier Injection to tandem gas chromatography mass spectroscopy GC-MS shall be performed at similar inlet temperatures not exceeding the flow of 40 mLmin The initial GC temperature program will mimic previously reported 10 protocols 40C for 3 minutes raised to 70C at a rate of 5C per minute and held for 3 minutes raised to 203C at 7C per minute and held for 4 minutes raised rapidly to 270C and held for 5 minutes A triple quad mass spectrometer Agilent Technologies Santa Clara CA shall be connected in tandem with a range of mass measurement of 20-400 mz
The diagnosis of Invasive Pulmonary Aspergillosis will be defined according to the updated EORTC criteria 4 as either one of the following
Confirmed IPA defined as a respiratory biopsy specimen with positive culture of Aspergillus spp or histopathologic demonstration of tissue invasion by hyphae
Probable IPA defined 1 as compatible radiographic features on chest CT Dense well-circumscribed lesions with or without a halo sign air-crescent sign or a cavity and any of the following Evidence of Aspergillus spp upon cytology direct microscopy or culture from any respiratory specimen including sputum broncho-alveolar lavage BAL fluid or bronchial brush Positive D-galactomannan antigen detected in plasma serum or BAL fluid Positive polymerase chain reaction PCR for Aspergillus spp detected in plasma serum or BAL fluid Possible IPA defined 1 as compatible radiographic features on chest CT Dense well-circumscribed lesions with or without a halo sign air-crescent sign or a cavity without corroboratory laboratory findings
Additional information regarding the probability of IPA diagnosis will be collected by two independent observers IG and AS reviewing the full electronic medical record EMR at the end of the study period assigning a single probability score 1-10 1 being very low probability of IPA 10 corresponding to almost certain IPA in view of the full clinica course of the disease
Additional variables and data sources For all cohort patients epidemiological and clinical information will be extracted from the hospitals electronic medical records EMR system used in our hospital retrieved with the assistance of the MD-clone software We will need to obtain the personal information of patients in order to access their data recorded in the daily follow up in their medical chart as some data is not coded All data shall be later coded and stripped off any personal identifiers including name surname date of birth ID number and address All data shall be stored on a designated hard disk at the hands of the primary investigator Data sources will include the patients file on the prometheus EMR registry as well as retrieved data using MD-clone software Collected data will include demographics age sex background diagnoses length of stay and transfer to other units laboratory results vital signs recorded and the oxygenation method used as documented in the daily follow-up
Sample collection schedule The first sample of consenting patients included in this study will be collected within 7 days from baseline chest CT Subsequently following any clinical suspicion of IPA by the treating physician - a suspicion that invariably leads to a chest CT being performed samples will be collected within 7 days from chest CT Additional samples will be collected within 7 days from the discontinuation of antifungal treatment by the treating physician The sampling schedule are visualized in figure 1
Figure 1 - Sampling strategy This studys intervention is limited to sampling underlined in bold red - all other steps are part of the usual management of AML patients and are in no way affected by the participation in this study AML - Acute Myeloid Leukemia Dx - Diagnosis CT - Computerized Tomography IPA - Invasive Pulmonary Aspergillosis Tx - Treatment dc - discontinued GGO - Ground Glass Opacities
Data handling and statistical analysis
Clinical data shall be analyzed using descriptive statistics parametric and nonparametric tests as appropriate All statistical analysis shall be performed using R software version 400 Arbor day or later All identifiable data including patients baseline characteristics laboratory and imaging results and previous diagnoses and treatment records shall be stored by the primary investigator on a designated RAS encrypted solid phase memory device for the duration of the study Patients names ID numbers address and date of birth will not be stored
Mass spectroscopy outputs will be reviewed using the MassHunter workstation and software Agilent Technologies Santa Clara CA Partial least squares discrimination analysis will be preformed using the SIMCA software version 140 or later MKS Umetrics Sweden For each mz range a logistic regression model will be constructed allowing for the calculation of the variable importance for projection VIP For all VIPs 1 the corresponding ion profile will be selected as a potential target These will be compared with previously implicated metabolites indicative of IPA 1011 as well as our existing database as summarized in APPENDIX A Such identification is crucial since the same mz value can correspond to different metabolites as different substances may have the same germplasm charge ratio Next all identified substances will be confirmed against the National Institute of Standards and Technology NIST 11 Mass Spectral Library Scientific Instrument Services Ringoes New Jersey and a pure chemical standard Finally the digital matrix composed of the selected characteristic VOCs will be imported into python version 3105 or later to construct different classification models with predictive performances assessed by binary logistic regression The correlations between exhaled breath VOC expression levels and levels of serum and BAL d-gallactomannan and IPA diagnostic certainty confirmed probable or possible as defined below will be accomplished using Persons r
Sample size and power
In this prospective longitudinal study patients with high probability of developing IPA ie patients diagnosed with acute leukemia will be enrolled at diagnosis Since our center performs baseline chest CT screening to identify potential IPA at baseline VOC collected after normal radiography can serve as ample controls At least 15 of such patients go on to develop IPA in the ensuing months3 limiting the sample size needed at recruitment Based on previously reported adherence to follow-up12 we expect drop out rate to be low allowing for the detection of previously elusive post treatment changes in VOC profiles
For the purpose of these calculations we assumed the previously reported VOC assays sensitivity compared to microbiology or antigen testing in respiratory secretions BAL or patient serum of 80-95 each10 Recent retrospective surveys have identified the incidence of IPA to be 5 at initial screening CT and additional 10 within the initial hospitalization3 This translates into an estimated sample size of 124 patients calculated under the assumption of the accepted significance alpha 005 and power beta 08 Allowing for an estimated 70 enrolment and the additional 15 exclusion rate the total estimated sample size is 208 patients Projecting the average annual incidence of 90 new cases of acute leukemia treated in our hospital this sampling goal should be easily reached within the prespecified 30 months recruitment period We thus expect the number of participants to be 300
ETHICAL CONSIDERATIONS The development and amelioration of noninvasive techniques for IPA identification has been the stated goal of various professional societies for over two decades 14 The patients proposed diagnostic tool bears minimal to no inconvenience to the participants and we deem potential side effects and danger to be negligible in this entirely non-invasive modality
Following data extraction all data shall be stripped of any identification including name surname ID number case number date of birth and address - all destroyed when initial data extraction is completed Data shall be stored securely on a RAS encrypted designated SD device at the hands of the PI minimizing the probability of this study affecting data privacy or medical confidentiality of the patients included In view of the direct effect the results of this inquiry may have on the management and the prognosis of the severely ill we find the benefits of this study to outweigh any potential risks
Funding No external funding was provided for this study thus far
Bibliography
1 Blot SI Taccone FS Van den Abeele A-M Bulpa P Meersseman W Brusselaers N et al A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients Am J Respir Crit Care Med 2012 Jul 1186156-64
2 Souza L Nouér SA Morales H Simões B Solza C Queiroz-Telles F et al Epidemiology of invasive fungal disease in haematologic patients Mycoses 2021 Mar643252-6
3 Bitterman R Hardak E Raines M Stern A Zuckerman T Ofran Y et al Baseline Chest Computed Tomography for Early Diagnosis of Invasive Pulmonary Aspergillosis in Hemato-oncological Patients A Prospective Cohort Study Clin Infect Dis 2019 Oct 3069101805-8
4 Donnelly JP Chen SC Kauffman CA Steinbach WJ Baddley JW Verweij PE et al Revision and update of the consensus definitions of invasive fungal disease from the european organization for research and treatment of cancer and the mycoses study group education and research consortium Clin Infect Dis 2020 Sep 127161367-76
5 Savelieff MG Pappalardo L Novel cutting-edge metabolite-based diagnostic tools for aspergillosis PLoS Pathog 2017 Sep 7139e1006486
6 Tsou P-H Lin Z-L Pan Y-C Yang H-C Chang C-J Liang S-K et al Exploring Volatile Organic Compounds in Breath for High-Accuracy Prediction of Lung Cancer Cancers Basel 2021 Mar 21136
7 Kamal F Kumar S Edwards MR Veselkov K Belluomo I Kebadze T et al Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection Am J Respir Crit Care Med 2021 Nov 120491075-85
8 Castro-Rodriguez JA Cifuentes L Martinez FD Predicting asthma using clinical indexes Front Pediatr 2019 Jul 317320
9 Das S Pal M Review-Non-Invasive Monitoring of Human Health by Exhaled Breath Analysis A Comprehensive Review J Electrochem Soc 2020 Feb 31673037562
10 Koo S Thomas HR Daniels SD Lynch RC Fortier SM Shea MM et al A breath fungal secondary metabolite signature to diagnose invasive aspergillosis Clin Infect Dis 2014 Dec 1559121733-40
11 Li Z-T Zeng P-Y Chen Z-M Guan W-J Wang T Lin Y et al Exhaled volatile organic compounds for identifying patients with chronic pulmonary aspergillosis Front Med Lausanne 2021 Sep 238720119
12 Hardak E Fuchs E Leskes H Geffen Y Zuckerman T Oren I Diagnostic role of polymerase chain reaction in bronchoalveolar lavage fluid for invasive pulmonary aspergillosis in immunocompromised patients - A retrospective cohort study Int J Infect Dis 2019 Jun8320-5
In this prospective longitudinal study we aim to overcome these hurdles taking advantage of two key characteristics of hematologic patients treated in RMC First patients with newly diagnosed AML have a relatively high prevalence of IPA Second a chest CT is performed at the diagnosis of AML in all patients Thus collecting breath samples from patients with normal baseline CT will serve as negative controls allowing for the comparison of VOC profiles before and after the development of IPA in the same patient Further sampling after the patient has recovered from IPA will provide additional longitudinal control
GOALS The identification of VOC profiles predictive of IPA in breath samples
METHODS
Study design
This is a single center non randomized prospective cohort study Breath samples from consenting patients will be analyzed for VOC profiles at the time of initial CT screening for IPA In addition samples will also be collected at the time of diagnosis of any possible probable or confirmed IPA defined according to the EORTC criteria 4 as detailed below
Setting and participants
Patients newly diagnosed with AML initiating treatment in the RMC hematology department will be approached Inclusion period will be from October 1 2022 until March 31 2025
Inclusion criteria
New diagnosis of acute myeloid leukemia ANDOR planned hematopoietic stem cells transplantation HCT Chest CT performed within 30 days from sampling 18 years of age or older The ability to provide tidal breath samples totalling 10L directly into a Tedlar bag
Exclusion criteria
Any condition impairing the patients ability to provide informed consent
Sample collection
Breath samples will be collected in one of our hematological departments 23 dedicated hospitalization rooms - positively pressurized and climate controlled with E-pure high-efficiency particulate air HEPA filters ADS-Laminaire Israel Patients will be required to abstain from teeth brushing dental wash eating drinking or smoking in the 6 hours prior to sample collection After being seated for 10 minutes to avoid exercise induced isoprene concentration increase 11 the patient will be asked to fill 10L of tidal breath into a tedlar bag SKC South Korea Simultaneously an identical tedlar bag shall be filled with ambient air
Upon each sample collection the following data will be recorded
Patients characteristics including age hemato-oncological diagnosis time from initial diagnosis current treatment time from HCT if applicable background diagnoses Current pharmacological treatment including all antibiotics and antifungals prescribed the preceding month
Current diagnostic tests including all cultures serology assays nucleic acid amplification studies complete blood count and chemistry voriconazole plasma level and chest imaging performed during the past month
Sample handling and VOC extraction
All tedlar bags will be stored at 4 following collection Adsorption onto 2 parallel thermal desorption tubes shall be accomplished via Gilian LFS-113 Low Flow Personal Air Sampling Pump SRA instruments Milano Italy performed within 72 hours from sampling and stored under ambient conditions These samples will be labeled coded and transformed to the Environmental Chemistry Laboratory Kasali Institute of Chemistry Hebrew University of Jerusalem Israel
Analytics
Thermal desorption will be accomplished at 290 for 20 minutes using analytical grade 99999 helium gas as carrier Injection to tandem gas chromatography mass spectroscopy GC-MS shall be performed at similar inlet temperatures not exceeding the flow of 40 mLmin The initial GC temperature program will mimic previously reported 10 protocols 40C for 3 minutes raised to 70C at a rate of 5C per minute and held for 3 minutes raised to 203C at 7C per minute and held for 4 minutes raised rapidly to 270C and held for 5 minutes A triple quad mass spectrometer Agilent Technologies Santa Clara CA shall be connected in tandem with a range of mass measurement of 20-400 mz
The diagnosis of Invasive Pulmonary Aspergillosis will be defined according to the updated EORTC criteria 4 as either one of the following
Confirmed IPA defined as a respiratory biopsy specimen with positive culture of Aspergillus spp or histopathologic demonstration of tissue invasion by hyphae
Probable IPA defined 1 as compatible radiographic features on chest CT Dense well-circumscribed lesions with or without a halo sign air-crescent sign or a cavity and any of the following Evidence of Aspergillus spp upon cytology direct microscopy or culture from any respiratory specimen including sputum broncho-alveolar lavage BAL fluid or bronchial brush Positive D-galactomannan antigen detected in plasma serum or BAL fluid Positive polymerase chain reaction PCR for Aspergillus spp detected in plasma serum or BAL fluid Possible IPA defined 1 as compatible radiographic features on chest CT Dense well-circumscribed lesions with or without a halo sign air-crescent sign or a cavity without corroboratory laboratory findings
Additional information regarding the probability of IPA diagnosis will be collected by two independent observers IG and AS reviewing the full electronic medical record EMR at the end of the study period assigning a single probability score 1-10 1 being very low probability of IPA 10 corresponding to almost certain IPA in view of the full clinica course of the disease
Additional variables and data sources For all cohort patients epidemiological and clinical information will be extracted from the hospitals electronic medical records EMR system used in our hospital retrieved with the assistance of the MD-clone software We will need to obtain the personal information of patients in order to access their data recorded in the daily follow up in their medical chart as some data is not coded All data shall be later coded and stripped off any personal identifiers including name surname date of birth ID number and address All data shall be stored on a designated hard disk at the hands of the primary investigator Data sources will include the patients file on the prometheus EMR registry as well as retrieved data using MD-clone software Collected data will include demographics age sex background diagnoses length of stay and transfer to other units laboratory results vital signs recorded and the oxygenation method used as documented in the daily follow-up
Sample collection schedule The first sample of consenting patients included in this study will be collected within 7 days from baseline chest CT Subsequently following any clinical suspicion of IPA by the treating physician - a suspicion that invariably leads to a chest CT being performed samples will be collected within 7 days from chest CT Additional samples will be collected within 7 days from the discontinuation of antifungal treatment by the treating physician The sampling schedule are visualized in figure 1
Figure 1 - Sampling strategy This studys intervention is limited to sampling underlined in bold red - all other steps are part of the usual management of AML patients and are in no way affected by the participation in this study AML - Acute Myeloid Leukemia Dx - Diagnosis CT - Computerized Tomography IPA - Invasive Pulmonary Aspergillosis Tx - Treatment dc - discontinued GGO - Ground Glass Opacities
Data handling and statistical analysis
Clinical data shall be analyzed using descriptive statistics parametric and nonparametric tests as appropriate All statistical analysis shall be performed using R software version 400 Arbor day or later All identifiable data including patients baseline characteristics laboratory and imaging results and previous diagnoses and treatment records shall be stored by the primary investigator on a designated RAS encrypted solid phase memory device for the duration of the study Patients names ID numbers address and date of birth will not be stored
Mass spectroscopy outputs will be reviewed using the MassHunter workstation and software Agilent Technologies Santa Clara CA Partial least squares discrimination analysis will be preformed using the SIMCA software version 140 or later MKS Umetrics Sweden For each mz range a logistic regression model will be constructed allowing for the calculation of the variable importance for projection VIP For all VIPs 1 the corresponding ion profile will be selected as a potential target These will be compared with previously implicated metabolites indicative of IPA 1011 as well as our existing database as summarized in APPENDIX A Such identification is crucial since the same mz value can correspond to different metabolites as different substances may have the same germplasm charge ratio Next all identified substances will be confirmed against the National Institute of Standards and Technology NIST 11 Mass Spectral Library Scientific Instrument Services Ringoes New Jersey and a pure chemical standard Finally the digital matrix composed of the selected characteristic VOCs will be imported into python version 3105 or later to construct different classification models with predictive performances assessed by binary logistic regression The correlations between exhaled breath VOC expression levels and levels of serum and BAL d-gallactomannan and IPA diagnostic certainty confirmed probable or possible as defined below will be accomplished using Persons r
Sample size and power
In this prospective longitudinal study patients with high probability of developing IPA ie patients diagnosed with acute leukemia will be enrolled at diagnosis Since our center performs baseline chest CT screening to identify potential IPA at baseline VOC collected after normal radiography can serve as ample controls At least 15 of such patients go on to develop IPA in the ensuing months3 limiting the sample size needed at recruitment Based on previously reported adherence to follow-up12 we expect drop out rate to be low allowing for the detection of previously elusive post treatment changes in VOC profiles
For the purpose of these calculations we assumed the previously reported VOC assays sensitivity compared to microbiology or antigen testing in respiratory secretions BAL or patient serum of 80-95 each10 Recent retrospective surveys have identified the incidence of IPA to be 5 at initial screening CT and additional 10 within the initial hospitalization3 This translates into an estimated sample size of 124 patients calculated under the assumption of the accepted significance alpha 005 and power beta 08 Allowing for an estimated 70 enrolment and the additional 15 exclusion rate the total estimated sample size is 208 patients Projecting the average annual incidence of 90 new cases of acute leukemia treated in our hospital this sampling goal should be easily reached within the prespecified 30 months recruitment period We thus expect the number of participants to be 300
ETHICAL CONSIDERATIONS The development and amelioration of noninvasive techniques for IPA identification has been the stated goal of various professional societies for over two decades 14 The patients proposed diagnostic tool bears minimal to no inconvenience to the participants and we deem potential side effects and danger to be negligible in this entirely non-invasive modality
Following data extraction all data shall be stripped of any identification including name surname ID number case number date of birth and address - all destroyed when initial data extraction is completed Data shall be stored securely on a RAS encrypted designated SD device at the hands of the PI minimizing the probability of this study affecting data privacy or medical confidentiality of the patients included In view of the direct effect the results of this inquiry may have on the management and the prognosis of the severely ill we find the benefits of this study to outweigh any potential risks
Funding No external funding was provided for this study thus far
Bibliography
1 Blot SI Taccone FS Van den Abeele A-M Bulpa P Meersseman W Brusselaers N et al A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients Am J Respir Crit Care Med 2012 Jul 1186156-64
2 Souza L Nouér SA Morales H Simões B Solza C Queiroz-Telles F et al Epidemiology of invasive fungal disease in haematologic patients Mycoses 2021 Mar643252-6
3 Bitterman R Hardak E Raines M Stern A Zuckerman T Ofran Y et al Baseline Chest Computed Tomography for Early Diagnosis of Invasive Pulmonary Aspergillosis in Hemato-oncological Patients A Prospective Cohort Study Clin Infect Dis 2019 Oct 3069101805-8
4 Donnelly JP Chen SC Kauffman CA Steinbach WJ Baddley JW Verweij PE et al Revision and update of the consensus definitions of invasive fungal disease from the european organization for research and treatment of cancer and the mycoses study group education and research consortium Clin Infect Dis 2020 Sep 127161367-76
5 Savelieff MG Pappalardo L Novel cutting-edge metabolite-based diagnostic tools for aspergillosis PLoS Pathog 2017 Sep 7139e1006486
6 Tsou P-H Lin Z-L Pan Y-C Yang H-C Chang C-J Liang S-K et al Exploring Volatile Organic Compounds in Breath for High-Accuracy Prediction of Lung Cancer Cancers Basel 2021 Mar 21136
7 Kamal F Kumar S Edwards MR Veselkov K Belluomo I Kebadze T et al Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection Am J Respir Crit Care Med 2021 Nov 120491075-85
8 Castro-Rodriguez JA Cifuentes L Martinez FD Predicting asthma using clinical indexes Front Pediatr 2019 Jul 317320
9 Das S Pal M Review-Non-Invasive Monitoring of Human Health by Exhaled Breath Analysis A Comprehensive Review J Electrochem Soc 2020 Feb 31673037562
10 Koo S Thomas HR Daniels SD Lynch RC Fortier SM Shea MM et al A breath fungal secondary metabolite signature to diagnose invasive aspergillosis Clin Infect Dis 2014 Dec 1559121733-40
11 Li Z-T Zeng P-Y Chen Z-M Guan W-J Wang T Lin Y et al Exhaled volatile organic compounds for identifying patients with chronic pulmonary aspergillosis Front Med Lausanne 2021 Sep 238720119
12 Hardak E Fuchs E Leskes H Geffen Y Zuckerman T Oren I Diagnostic role of polymerase chain reaction in bronchoalveolar lavage fluid for invasive pulmonary aspergillosis in immunocompromised patients - A retrospective cohort study Int J Infect Dis 2019 Jun8320-5
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None