The Prevalence of Influenza Related Invasive Aspergillosis in Swedish Intensive Care Units
Conditions: Invasive Pulmonary Aspergillosis, Influenza, Human
Sponsor: Karolinska University Hospital

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
Protocol, version 1.2   
Karolinska Sjukhuset, diarienummer K 2019-9546 
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PIRAIA-study  
(Prevalence of Influenza RelAted Invasive Aspergillosis)  
A Multicenter Prospective Observational Cohort Study  
  
  
Study Protocol  
Version: 1.2  
Date of last version: 14/11/2019  
Author: Anders Krifors   
 
  
  
  
  
  
  
  
  
  
  
  
  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
Protocol, version 1.2   
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TABLE OF CONTENTS  
  
  
1. STATEMENT OF COMPLIANCE  
2. ABBREVIATIONS  
3. PROTOCOL SUMMARY  
4. KEY ROLES AND CONTACT INFORMATION  
5. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
5.1 Background  
5.2 Scientific rationale  
5.3 Potential risks and benefits  
6. STUDY OBJECTIVES   
6.1 Primary objective  
6.2 Secondary objective  
7. STUDY DESIGN  
7.1 Study overview  
7.2 Study inclusion  
7.3 Inclusion criteria  
7.4 Exclusion criteria  
7.5 Study locations  
7.6 Screening  
7.7 Informed consent  
8. WORKFLOW: OVERVIEW 9. DATA COLLECTION  
9.1 Data to be collected  
9.2 Confidentiality  
9.3 Access to data  
10. QUALITY ASSURANCE AND QUALITY CONTROL  11. STUDY ENDPOINTS  
11.1 Proven invasive pulmonary aspergillosis  
11.2 Probable invasive pulmonary aspergillosis  
12. STATISTICAL ANALYSIS  
13. FUNDING  
14. INSURANCE  
15. PUBLICATION  
16. REFERENCES  
  
  
  
  
  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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1. STATEMENT OF COMPLIANCE  
  
The signature below constitutes that this study will be comply with the requirements 
of Good Clinical Practice (ICH E6) and the Swedish Ethical Review Authority.   
  
  
  
  
  
  
  
  
  
  
Principal Investigator  
 
Signed:  
  
Date:    
 
 
  
Name: Anders Krifors  
 
  
Title: M.D. PhD-student   
   
  
   
   
  
  
  
  
  
  
  
  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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2. ABBREVIATIONS  
ARDS  
Acute Respiratory Distress Syndrome  
BAL  
Bronchoalveolar Lavage  
CI  
Confidence Interval  
CRF  
Case Report Form  
eCRF  
electronic Case Report Form  
CT  
Computed Tomography  
EORTC  
European Organization for Research and Treatment of Cancer  
GM  
Galactomannan  
GCP  
Good Clinical Practice  
ICU  
Intensive Care Unit  
IPA  
Invasive Pulmonary Aspergillosis  
MSG  
Mycoses Study Group  
PCR  
Polymerase Chain Reaction  
SAPS3  
Simplified Acute Physiology Score  
SOFA  
Sequential Organ Failure Assessment  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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3.    PROTOCOL SUMMARY  
Title:   
Prevalence of Influenza Related Invasive Aspergillosis; A  
Multicenter Prospective Observational Cohort Study  
Overview:  
A multicenter prospective observational study conducted at 12 
intensive care units in Sweden. All patients >18 years of age with 
a PCR-verified influenza A or B diagnosed up to 7 days before 
admission to the ICU or during ICU care, will be included in the 
study. A new clinical routine will be implemented: During the ICU 
stay screening with Beta-D-glucan and Galactomannan in 
blood/serum will be performed twice weekly and a respiratory 
sample will be retrieved for fungal culture and microscopy once 
weekly. All results from collected samples will be available to the 
patient responsible physicians. Clinical and microbiological data 
will be collected, and the diagnosis of invasive aspergillosis will be 
made using predefined diagnostic criteria.  
Objectives:  
1. To determine the prevalence of influenza-related invasive 
pulmonary aspergillosis in Swedish intensive care units  
2. To assess the clinical impact of and risk factors for 
influenzarelated invasive pulmonary aspergillosis   
Population:  
≥ 18 years of age. Confirmed influenza A or B diagnosed <7 days 
before admission to the ICU or during ICU stay. At least 50 
patients will be enrolled in the study.  
Number of sites:  12  
  
Study duration:   1 year  
Enrolment:  
Until the end of April 2020 if ≥50 patients have been enrolled.  
Enrolment will continue until ≥50 patients have been recruited. 
  
  
  
  
  
  
  
  
  
  
  
  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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4. KEY ROLES AND CONTACT INFORMATION  
  
Principal Investigator:  
Anders Krifors  
M.D., Ph.D.-student  
Department of Physiology and Pharmacology 
Karolinska Institutet  
+46707705044 anders.krifors@ki.se 
Infektionsmottagningen  
Västmanlands sjukhus  
72189 Västerås  
Co-Investigators:  
Ola Blennow  
M.D. PhD.  
Patientområde Infektionssjukdomar 
Karolinska Universitetssjukhuset Huddinge 
ola.blennow@sll.se  
  
Johan Petersson  
M.D. PhD., Associate Professor  
Perioperativ Medicin och Intensivvård  
Karolinska Universitetssjukhuset Site 
investigator: Karolinska Solna 
johan.petersson@sll.se  
  
Markus Castegren  
M.D. PhD., Adjunct Senior Lecturer  
Perioperativ Medicin och Intensivvård  
Karolinska Universitetssjukhuset Site 
investigator: Karolinska Huddinge 
markus.castegren@sll.se  
             Site Investigators:  
Helena Janols, Uppsala   
Johan Tham, Malmö  
Patrik Gille-Johnson, Danderyd Stockholm  
Jesper Sperber, Eskilstuna  
Lina De Geer and Anita Hällgren, Linköping  
Jan Källman, Örebro  
Lisa Påhlman, Lund  
Anna Stjärne Aspelund, Helsingborg  
Fredrik Hammarskjöld, Jönköping  
Marie Lemberg, Västerås  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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5. INTRODUCTION:  BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
5.1 Background  
Bacterial pneumonia is a well-known complication of influenza infection and 
contributes to both increased morbidity and mortality. A less known complication is a 
fungal infection with aspergillus species. Aspergillus is omnipresent and is commonly 
found in soil, dust, and food. We regularly inhale Aspergillus spores, but our immune 
system effectively takes care of the fungus, why disease does not occur [2]. Invasive 
pulmonary aspergillosis (IPA) has typically only been considered in 
immunosuppressed patients such as in haematological malignancies, hematopoietic 
stem cell transplantation, organ transplantation, or prolonged neutropenia [3]. 
Isolation of Aspergillus in respiratory samples from patients without these risk factors 
has been interpreted as colonization without any clinical relevance.   
In recent years, several reports of influenza-related IPA in patients lacking classical 
risk factors have been published [4,5]. A possible explanation could be a viral injury 
to the respiratory epithelium as well as local and systemic lymphopenia [6]. The 
prevalence of IPA in influenza patients admitted to the ICU has been reported to be 
upwards of 23% [4]. In a large retrospective cohort study from the Netherlands and 
Belgium, published in The Lancet in October 2018, the prevalence of IPA was 19% 
among the 432 influenza patients admitted to the ICU [10]. The mortality was 
significantly higher among patients diagnosed with IPA. Most patients with influenza 
admitted to ICU lack classical risk factors for IPA and have, therefore, not been 
routinely investigated for IPA.  
Aspergillus infections are challenging to diagnose and require specific culture media 
or the use of indirect diagnostic methods such as detection of Galactomannan in 
serum or BAL and detection of Beta-D-Glucan in serum. However, microbiological 
tests cannot distinguish between colonization and infection, which is why 
internationally recognized criteria that combine host factors, radiological signs, and 
microbiological findings have been published [7]. The infection is graded being 
confirmed, probable, or possible IPA. The criteria were originally developed for 
immunosuppressed patients, but modified criteria that are useful in the ICU has been 
published [8].   
Effective treatment for Aspergillus is available and must be started promptly in cases 
of suspected IPA. If left untreated, IPA is associated with significant mortality.  
The reports of influenza-related IPA have led the Netherland national guidelines to 
recommend that all influenza patients admitted to the ICU should undergo 
bronchoscopy with BAL sampling for Aspergillus diagnostics [9]. In Sweden, 300-400 
influenza patients are annually admitted to intensive care units. Swedish data on the 
prevalence of aspergillosis are lacking, and there is a risk that IPA remains both an 
unknown and underdiagnosed complication of influenza infection in Swedish 
intensive care units.   

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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5.2 Scientific Rationale  
IPA is associated with significant mortality, and routine tests are often incapable of 
diagnosing the infection. The infection may, therefore, remain undetected without 
specific testing aimed to diagnose IPA. Reports of influenza-related IPA has emerged 
from several parts of the world. Still, the prevalence cannot be assumed to be equal 
in different settings as the transmission is dependent on exogenous exposure.   
  
By accounts of the accumulated evidence, a new clinical routine will be introduced at 
study centers; Patients ≥18 years of age admitted to ICU with PCR-verified influenza A 
or B will be routinely tested to diagnose IPA early. The study will collect clinical and 
microbiological data of the patients subject to this new clinical routine. If the study 
provides evidence of IPA prevalence similar to the published reports, the clinical 
importance would be significant. New national guidelines regarding testing of 
influenza patients admitted to the ICU should be created with the potential to save 
both life and reduce suffering.  
 
5.3 Potential Risks and Benefits  
IPA testing is introduced as a clinical routine and is not part of the study. The study is 
a prospective observational cohort study where clinical and microbiological data of 
patients subjected to the new clinical routine will be collected and assessed. Study 
participants admitted to any of study centers will receive the benefit of routine IPA 
testing and the possibility of early intervention if IPA is diagnosed.  
  
6. STUDY OBJECTIVES  
6.1 Primary objective  
To determine the prevalence of influenza-related invasive pulmonary aspergillosis in 
Swedish intensive care units.   
6.2 Secondary objective  
To assess the clinical impact and risk factors related to influenza-related invasive 
pulmonary aspergillosis. Patients with proven or probable IPA will be compared to 
patients that do not meet the criteria for proven and probable IPA. Baseline 
characteristics and clinical data such as SAPS3, SOFA score, need for invasive 
ventilation and need for continuous renal replacement therapy, will be assessed to 
find risk factors for IPA.  
  
  
  
 

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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7. STUDY DESIGN  
  
7.1 Study overview  
The study is a Swedish, nationwide, multicenter, prospective observational cohort 
study to determine the prevalence of IPA among patients admitted to the ICU with 
confirmed influenza infection.   
A new clinical routine regarding IPA-testing will be implemented at the participating 
centers, similar to the current guidelines in the Netherlands. All samples will be 
retrieved and analyzed using local methods and logistics. All test results will be 
available to the patient responsible physician, who is free to act on them as deemed 
appropriate.  
  
The study is non-interventional, no measurements or sampling will be made 
mandatory by the protocol and data collection at these pre-specified time-points will 
only take place if decided acceptable by the patient responsible physician. All 
aspergillus testing is part of the new clinical routine, and no additional sampling will 
be performed on accounts of the study.   
  
All patients ≥18 years of age with confirmed influenza A or B diagnosed up to 7 days 
before ICU admission, or during ICU care, will be included in the study. Patient 
consent was waived in the ethics approval from the Swedish Ethical Review Authority 
(Dnr 201900557).   
  
Recruitment is planned to begin in December 2019. Recruitment of patients is 
expected to stop in April 2020 if ≥50 patients have been recruited, or after that when 
50 patients have been recruited.  
    
7.2 Study inclusion  
 
At least 50 patients will be enrolled in the study. The target sample size has been 
calculated using the expected prevalence of 15% IPA. The sample size is then 
sufficient to describe the prevalence with 10 % margin of error at the 95% confidence 
level. Approximately 100 influenza patients are admitted to ICUs of the participating 
centers every influenza season.  
7.3  Inclusion criteria  
  
Patients must meet all the inclusion criteria to be eligible for the study:  ≥18 
years of age, PCR-verified influenza A or B diagnosed within 7 days of ICU 
admission, or during ICU stay.  
  
 
 

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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7.4 Exclusion Criteria  
  
Patients ≤18 years of age cannot be enrolled in the study as the evidence motivating 
the implemented routine IPA testing does not contain patients under 18 years of age.  
 
7.5 Study locations  
ICU (CIVA) at Karolinska Universitetssjukhuset Solna, Stockholm  
ICU at Karolinska Universitetssjukhuset Huddinge, Stockholm  
ICU at Danderyds sjukhus, Stockholm  
ICU (CIVA) at Akademiska sjukhuset, Uppsala  
ICU at Universitetssjukhuset, Linköping  
ICU, at Västmanlands sjukhus, Västerås  
ICU at Mälarsjukhuset, Eskilstuna  
ICU at Universitetssjukhuset, Örebro  
ICU at Länssjukhuset Ryhov, Jönköping  
ICU at Skånes universitetssjukhus, Malmö  
ICU at Skånes universitetssjukhus, Lund  
ICU at Helsingborgs lasarett  
  
7.6 Screening  
Influenza testing will be performed on the basis of clinical suspicion, and part of 
routine care.  
7.7 Informed consent  
This is a non-interventional study and the need for informed consent was waived in 
the approval from the Swedish Ethical Review Authority (DNR (Dnr 201900557)   
  
  
  
  
  
  
  
  
  
  
  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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8. WORKFLOW: OVERVIEW  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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9.  DATA COLLECTION  
All patient responsible physicians in the participating ICUs will be eligible to enrol 
patients in the study. All participating ICUs will receive both written and oral 
instructions about the study from the study site investigator. Data will be obtained 
from the participant’s medical records and initially entered on a paper CRF. The 
empty CRF will be made available by sending prepared folders to the study sites. 
Additional CRFs will be made available for print from study website (piraiastudy.se). 
Study site investigators will then enter the collected data into a web-based eCRF. The 
procedure will ensure continuous monitoring of the collected data.  
  
9.1 Data to be collected Baseline 
characteristics  
Date of ICU admission  
Age  
Sex  
SAPS3-score on arrival to the ICU SOFA-
score on arrival to the ICU Presence of:  
Liver cirrhosis (defined as Child-Pugh-score ≥A)  
Heart failure (defined as ejection fraction <40%)  
Diabetes mellitus (not diet treated)  
Renal failure (defined as creatinine clearance <30 mL/min/1.73m2  
Body Mass Index >30 kg/m2  
Haematological malignancy  
Hematopoietic stem cell transplantation  
Organ transplantation  
Daily smoking in the last year  
Solid tumour  
Neutropenia (defined as <0,5 x109 neutrophils)  
Chronic obstructive pulmonary disease  
New lung infiltrate  
Treatment with corticosteroids in the last 28 days  
Treatment with corticosteroids in a dose equal to or above 15 mg/day 
prednisone  
  
At enrolment  
Date of enrolment  
Influenza A or B  
Treatment with oseltamivir or zanamivir  
SOFA-score the day of enrolment  
Use of vasopressor  
Use of continuous renal replacement therapy  
Use of invasive ventilation  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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Use of non-invasive ventilation  
Body temperature above 38.0 degrees Celsius in the last 24 hours  
ARDS grade (defined by PaO2/FiO2 300-200 mmHg mild, 200-100 
mmHg moderate, <100 mmHg severe) Treatment with corticosteroids  
Presence of haemoptysis  
Presence of pleural pain  
Ongoing treatment with antibiotics  
Ongoing treatment with antifungals  
  
Daily registration after enrolment  
SOFA-score 
Use of vasopressor  
Use of continuous renal replacement therapy  
Use of invasive ventilation  
Use of non-invasive ventilation  
Body temperature above 38.0 degrees Celsius in the last 24 hours ARDS 
grade (defined by PaO2/FiO2 300-200 mmHg = mild, 200-100 mmHg = 
moderate, <100 mmHg = severe)  
Treatment with corticosteroids  
Presence of haemoptysis  
Presence of pleural pain  
Ongoing treatment with antibiotics  
Ongoing treatment with antifungals  
  
At discharge from the ICU  
Date of discharge from the ICU  
Discharge to (home, ward, other ICU or death)  
Treatment with systemic antifungals during the care time in the ICU  
Microbiological findings: Positive Aspergillus culture or microscopy, GM in BAL 
or serum or Beta-D-Glucan.  
  
Medical records  
Medical records will be reviewed for information on microbiological findings 
and survival up to 90 days from ICU admission.  
  
9.2 Confidentiality  
Study participants will be assigned a unique study identification number (e.g., LU01 - 
first patient in Lund). CRF will be pseudo-anonymized using the identification 
number. Each study site will receive a "code list "where the personal number of the 
study participant will be linked to the study identification number. Study site 
investigators are responsible for keeping the “code list” separated from the CRFs. The 

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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study site investigators will continuously transfer the information to the eCRF to 
ensure the security of the data.   
  
9.3 Access to data  
All CRFs will be archived for 15 years. De-identified data (individual data that underlie 
the results reported in the study) will be made available beginning 3 months and 
ending 5 years after the publication of the study.  
  
10 QUALITY ASSURANCE AND QUALITY CONTROL  
The principal investigator will be responsible for organizing the study sites including 
education of study site investigators. Study folders will be prepared for the study 
investigators, including outlines of the data collection process, study protocol and 
CRF. After initiation of the study, the study site investigators will be responsible for all 
study-related procedures at their site.  
Using the eCRF, data collection will be continuously and closely monitored. The 
principal investigator will issue queries about missing data, out of range values, or 
illogical data relations.   
  
11 STUDY ENDPOINTS  
Enrolled patients will be categorized as proven or probable IPA at discharge from the 
ICU to answer the primary objective of evaluating the prevalence of influenza related 
invasive pulmonary aspergillosis. A modified version of the Asp-ICU criteria will be 
used, described below 11.1, 11.2.  
All recorded baseline characteristics will be compared between patients diagnosed 
with IPA and those that were not. The following outcome parameters will also be 
assessed: SOFA-score, use of mechanical ventilation, use of non-invasive ventilation, 
use of vasopressor, use of renal replacement therapy, ARDS-grade using the Berlin 
definition, median number of ICU stay, ICU mortality, and 90-day mortality after ICU 
admission. 
  
11.1 Proven invasive pulmonary aspergillosis  
Microscopic analysis on sterile material: histopathologic, cytopathologic, or direct 
microscopic examination of a specimen obtained by needle aspiration or sterile 
biopsy in which hyphae are seen accompanied by evidence of associated tissue 
damage. Culture on sterile material: recovery of Aspergillus by culture of a specimen 
obtained by lung biopsy.  
  

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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11.2 Probable invasive pulmonary aspergillosis (fulfil both clinical, radiological and 
mycological criteria)  
  
Clinical criteria: One of the following signs or symptoms must be present:  
• 
Fever refractory to at least 3 days of appropriate antibiotic therapy.  
• 
Recrudescent fever after a period of defeverscence of at least 48 h while still on 
antibiotics and without other apparent cause  
• 
Dyspnea  
• 
Hemoptysis  
• 
Pleural friction rubs or chest pain  
  
Radiological criteria:  
Any infiltrate on pulmonary imaging by portable chest x-ray or CT-scan of the lungs.  
   
Mycological criteria: One of the following findings:  
• 
Positive microscopy or culture of Aspergillus from BAL  
• 
Galactomannan optical index on BAL >0,8  
• 
Galactomannan optical index on serum ≥0,5  
  
  
12 STATISTICAL ANALYSIS  
Prevalence of Proven/Probable IPA will be calculated at the 95% confidence level. 
Patients meeting the criteria for proven/probable IPA will be compared to the 
influenza positive patients who do not meet the criteria, in terms of underlying risk 
factors and outcome measures. Categorical variables will be assessed by Fischer 
exact test and X2 test, and continuous variables with t-test or Mann Whitney U test 
where appropriate. We will also perform multivariable analysis by binary logistic 
regression to detect independent risk factors for IPA. All analyses will be conducted 
using a threshold of 95% confidence level (P-value 0.05). ICU mortality and 90 days 
after admission to the ICU mortality will be compare using survival analysis.  
13 FUNDING  
  
The study has received financial support from:  
  
• 
Regionala forskningsrådet i Uppsala-Örebroregionen  
• 
Centrum för klinisk forskning, Västerås  
  
 
 

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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14 INSURANCE  
  
Svenska patientförsäkringen  
  
15 PUBLICATION  
  
The study will be published in a peer-reviewed medical journal. All study site 
investigators will be awarded recognition as collaborator in the manuscript. To gain 
full authorship the site must include at least 10 participants and the investigator 
contribute according to the Vancouver definitions.   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   

PIRAIA-study                                                                                                   Date of last revision: 14/11/2019  
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16 REFERENCES  
1. 
Morens DM, Taubenberger JK, Fauci AS. Predominant Role of Bacterial 
Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic 
Influenza Preparedness. J Infect Dis. 2008;198(7):962-970. doi:10.1086/591708.  
2. 
Dagenais TRT, Keller NP. Pathogenesis of Aspergillus fumigatus in invasive 
aspergillosis. Clin Microbiol Rev. 2009;22(3):447-465. doi:10.1128/CMR.00055-08.  
3. 
Patterson TF, Thompson GR, Denning DW, et al. Practice guidelines for the 
diagnosis and management of aspergillosis: 2016 update by the infectious diseases’ 
society of America. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326.  
4. 
Wauters J, Baar I, Meersseman P, et al. Invasive pulmonary aspergillosis is a 
frequent complication of critically ill H1N1 patients: A retrospective study. Intensive 
Care Med. 2012;38(11):1761-1768. doi:10.1007/s00134-012-2673-2.  
5. 
Lat A, Bhadelia N, Miko B, Furuya EY, Thompson GR. Invasive aspergillosis after 
pandemic (H1N1) 2009. Emerg Infect Dis. 2010;16(6):971-973. 
doi:10.3201/eid1606.100165.  
6. 
Cunha BA, Pherez FM, Strollo S. Swine influenza (H1N1): Diagnostic dilemmas 
early in the pandemic. Scand J Infect Dis. 2009;41(11-12):900-902. 
doi:10.3109/00365540903222465.  
7. 
Pauw B De, Thomas J. Walsha, Donnellya JP, et al. Revised Definitions of 
Invasive Fungal Disease from the European Organization for Research and Treatment 
of Cancer/Invasive. Clin Infect Dis. 2008;46(12):1813-1821.  
doi:10.1086/588660.Revised.  
8. 
Bassetti M, Bouza E. 2017. Invasive mould infections in the ICU setting: 
Complexities and solutions. J Antimicrob Chemother.  
9. 
SWAB Guidelines for the Management of Invasive Fungal Infections, Kullberg et 
al, https://www.swab.nl  
  
10.      Schauwvlieghe A, et al. Invasive aspergillosis in patients admitted to the 
intensive care unit with severe influenza: a retrospective cohort study. Lancet resp. 
med. 2018; P782-792.