Yannick Auffret, Tania Marx, Patricia Jabre, Cochrane Pre-hospital and Emergency Care Group (Author)

Non-invasive positive pressure ventilation for acute asthma in children: Very uncertain results

Source:
Korang SK, Baker M, Feinberg J et al. (2024) Non-invasive positive pressure ventilation for acute asthma in children. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD012067 http://doi.org/10.1002/14651858.CD012067.pub3

Clinical Question
Asthma is the most common chronic disease in children and accounts for 2.3% of pediatric hospitalizations. This condition has a major medico-economic impact, affecting both children’s quality of life and healthcare costs. In 10–12% of cases, intensive conventional treatment based on bronchodilators and corticosteroids is insufficient, and management must be escalated to endotracheal intubation and invasive mechanical ventilation. Some  observational studies suggest that non-invasive positive pressure ventilation (NPPV) could reduce the need for intubation.

Bottom Line
To assess the effects of NPPV combined with conventional treatments compared with conventional treatments alone in children with moderate to severe acute asthma, in terms of mortality, occurrence of serious adverse events (SAEs), length of stay in intensive care, and asthma symptom scores during the acute phase.

Main Results
No all-cause mortality was reported in either group. Only one randomized study assessed SAEs, namely the intubation rate. Bilevel positive airway pressure (BiPAP) may substantially reduce the intubation rate and appears to shorten the length of stay in intensive care, but these results are very uncertain (very low level of evidence). Acute asthma symptoms score was evaluated in only two studies using different outcome measures, which did not allow meta-analysis. BiPAP may have a beneficial effect on the score, but this result is also very uncertain (very low level of evidence).

Caveats
Current data are limited, with small sample sizes, resulting in very uncertain evidence and preventing a comprehensive evaluation of the benefits and risks of NPPV in children with acute asthma. Large, well-designed randomized controlled trials with low risk of bias are therefore needed.
In the trials included in the review, the positive end-expiratory pressure (PEEP) was relatively low (4–5 cmH₂O), whereas pressures of 8 to 12 cmH₂O may be necessary to compensate for intrinsic PEEP.

Author contributions
All authors contributed equally and validated the final version of record.
Acknowledgments
This editorial is a summary of a systematic review previously published in the Cochrane Database of Systematic Reviews (see https://www.cochranelibrary.com/ for more information). This summary is prepared in coordination with Patricia Jabre, Daniel Meyran, Julie Dumouchel, Yannick Auffret, Nordine Nekhili, Nicolas Cazes, Aurélien Renard et Tania Marx from the Cochrane Pre-hospital and Emergency Care Group.
Declarations
Conflicts Of Interests
The Authors declare that there is no conflict of interest.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Registration
No registration applicable.
Data availability statement
No new data were created or analyzed in this study. Data sharing is not applicable to this article.
Ethical approval
Ethical approval for this study was not required.

Chady El Tawil, Imane Chedid, Amy Bergeron, Isabelle Gagnon, Ilana Greenstone (Author)

Risk Factors for Return Visits to the Pediatric Emergency Department: Systematic Search and Review

Objectives: Return visits (RVs) to the emergency department (ED) has always been a major concern. RVs to the emergency department are a big burden on the healthcare system as its cost is higher than the cost of the initial visit. This review was performed to identify factors associated with risk of RVs to the pediatric ED.

Methods and Analysis: One researcher searched Medline, Embase, Cochrane Library and Web of Science. Studies were identified by using MeSH and keywords and included RVs to the pediatric ED up to 1 year a primary outcome. All studies were screened by two independent reviewers for eligibility and in case of disagreement, a meeting was held to discuss the problematic studies and a consensus was achieved.

Results: The search identified 539 reports from which 28 articles were included. Data was then extracted from the included studies according to a preset format. The exposures were grouped in 3 different groups: very probable, possible, and less likely.
As a result, young age, language barrier and high acuity were identified as very probable risk factors. Having a public insurance or with low income, patients with comorbidities and patients who had multiple previous ED visits were found to be possible risk factors for return visits.

Conclusion: Young age, high acuity and language barrier among others are risk factors for return visits to the pediatric ED. Physicians should be aware of these factors and have a low threshold for admission or a good discharge plan for patients with one or more factors.

Key Messages:

Ø  What is already known on this topic – Return visits (RV) to the pediatric emergency department has always been a major concern and a big burden on the healthcare system as its cost is higher than the cost of the initial visit. The risk factors for RV vary widely. 
Ø  What this study adds – Young age, language barrier and high acuity were identified as very probable risk factors. Having a public insurance or with low income, patients with comorbidities and patients who had multiple previous ED visits were found to be possible risk factors for return visits.
Ø  How this study might affect research, practice, or policy – Physicians should be aware of these factors and have a low threshold for admission or a good discharge plan for patients with one or more factors.

Introduction
     Return visits (RVs) to the emergency department (ED) have always been a major concern. In fact, since the 1980s, emergency physicians recognized return visits, also known as bounce back visits, as a “red flag” for low quality of care [1]. In general, RVs to the emergency (ED) constitute an enormous burden on the healthcare system. For instance, on a financial level, the cost of a RV is higher than the cost of the initial visit [2]. Further, on a medical level, patients admitted to the Pediatric Intensive Care Unit (PICU) following a RV to the pediatric ED, are more likely to be put on a ventilator [3]. For these reasons, RVs have often been used as a quality metric in the pediatric ED [4]. 

     As traditionally reported in many studies, a visit occurring within 72-hours of an index presentation for the same complaint is considered to be a RV because it reflects either an inadequate treatment or a missed diagnosis [5-7]. However, more recently, the 72-hour limit has been challenged by many as it might not mirror neither of both classifications (i.e., inadequate treatment or missed diagnosis) [8]. Indeed, some of the most common pediatric presentations to the ED, such as allergic reaction, asthma, fever, and bronchiolitis, can either deteriorate or have symptoms requiring a RV to the ED after more than 3 days, which in this case, doesn’t constitute a low quality of care. Longer time periods have also been proposed in adult EDs. For example, a recently published large retrospective study including more than one million adult ED RVs over 10 years used an upper limit of 14 days after the initial visit. The authors concluded that these patients should be identified early to avoid intensive care unit (ICU) admission during the RV [9].

     Identifying risk factors leading to RVs could contribute to improved care for children presenting to pediatric EDs. An initial search performed in preparation for our study identified one literature review published in 2016 on the topic of risk factors and interventions that affected RVs to the pediatric ED [8]. This review concluded that mental health problems, younger age, acuity of illness, medical history of asthma, and social factors are risk factors for RVs. However, this review looked at studies published prior to November 2012 and identified only 6 studies looking at RVs ranging from 48 hours to 1 year. Also, as the authors mentioned in their study limitations’ section, they only investigated Medline without grading the reviewed studies for quality. Further, 3 out of the 6 studies were limited to a specific condition (2 included only patients with asthma and 1 included patients with mental health-related issues), limiting therefore the diversity of the collected data and hence its generalizability to the context of RVs. 

     To fill out the previous gap, we performed a systematic search and review to identify factors associated with risk of RVs to the pediatric ED in children of any age as defined by the authors in each article. As there is no true consensus on the delay where a subsequent visit would be considered a RV, we considered 1 year as a reasonable cutoff as considered in the previous review mentioned prior. However, no differentiation was made between RVs for the same problem and RVs for an unrelated complaint to the initial visit. We aimed to answer the following question: in pediatric patients of any age presenting to the emergency department, what risk factors on the first presentation would predict a RV within 1 year?

Materials and Methods

Search Strategy
The following databases were searched for relevant records on April 22 2021: Medline (via Ovid 1946 to 2021 April 21), Cochrane (via Wiley, from the Cochrane Database of Systematic Reviews, Issue 3 of 12, March 2021), Embase (via Ovid 1947 to 2021 April 21), and Web of Science (via Clarivate, Indexes SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI, CCR-EXPANDED, & IC).
The search strategies designed by a librarian (AB) used text words and relevant indexing to identify records on risk factors for pediatric emergency readmission. 
The final Medline strategy (Appendix 1) was adapted for all databases, with modifications to search terms and syntax as necessary. No language limits were applied. 

Inclusion Criteria
The included studies were limited to randomized controlled trials (RCTs), controlled studies, systematic reviews, cohort studies, case control studies and cross-sectional studies written in English or French without any date limit for inclusion. Case reports and series were excluded. Also, studies looking into one diagnosis (like asthma, bronchiolitis…) were excluded because risk factors for RVs can be confounding factors and not true risk factors (for example, bronchiolitis is diagnosed in kids less than 12-24 months making young age a confounding factor), however, studies with a large scope of presentation and low risk for confounding factors (like trauma) were included.
No restriction was made on the past medical history, perinatal history, previous hospitalizations, medications, gender, acuity on presentation, medical interventions on the first visit, length of stay (LOS), left without being seen (LWBS), left against medical advice (AMA) or any other criteria. However, according to our search, these might be identified as risk factors for RVs.

Screening
All studies were screened by title first then by abstract by two independent reviewers (CET and IC). Duplicated studies in different databases were removed. Studies not satisfying the inclusion criteria were then excluded. Further, following an independent extraction of data, both reviewers compared results to reach a consensus. 

Data extraction
Data were extracted by the two independent reviewers according to a predefined format (Table 1). Data points collected included the first author’s name, the study characteristics (type of study, date of publication, total number of RVs and country where the study was conducted), the timing of the RV (i.e., outcome) and the identified risk factors (i.e., exposures).

Results

The initial search identified 539 articles (Figure 1). 
     After removal of duplicate studies and screening of titles and abstracts by the 2 independent reviewers, 79 articles were included. Forty reports were then excluded after full manuscript review by both reviewers. For the remaining articles, a meeting between the 2 reviewers and a consensus to include 28 articles was achieved [8, 10-36].

     Data were then extracted from the included studies according to the preset format (Table 1). The data in italic format in the table represent a negative or neutral finding (for example, in Daymont et al. discharge heart rate was not found to affect RVs). The risk factors were then divided into 3 different groups according to how many times they were cited as there was no other practical way to weigh and compare the studies (Figure 2). 

Discussion

This review identified multiple risk factors for RVs to the pediatric ED. 

Young Age
Infant and young children were, by far, more likely to have a RV to the ED than older children and adolescents even though the definition of young age was different between studies ranging from younger than 1 year to younger than 5 years. While these RVs might be due to progression of the disease, such as bronchiolitis, in this age group, clear discharge instructions and explanation of  signs of deterioration were found to be a protective factor against unnecessary RVs [37].

Language
Language barrier between patients and healthcare providers has been associated with increased pediatric ED visit length of stay and resource utilization in addition to increased RVs [38, 39 ]. With the increased number of refugees worldwide, language barrier is becoming more relevant and the need for multilingual healthcare professionals is constantly increasing [40].

High Acuity
Pediatric patients who are sicker at triage are more likely to be admitted especially in a crowded ED [41]. If those patients with higher acuity are discharged from the ED, they are more likely to bounce back. Physicians should probably maintain a low threshold for admission at the time of the initial visit [42].

Other Risk Factors 
This review identified more risk factors like patients with public insurance or with low income, patients with comorbidities and patients who had multiple previous ED visits. How to classify a RV after LWBS and, to a lesser extent AMA, is controversial. It might be considered as the first visit and not a RV since the patient was not assessed by the physician and/or did not receive the proper management for their condition.

Studies Quality and Limitations
     Most of the studies were retrospective (86%) with only two prospective studies, one of which was a planned secondary analysis of a prospective cohort. The majority were North American studies (68%), limiting therefore the diversity and generalizability of our findings. The primary outcome was different across the articles: although it was mostly risk factors for RVs, there was a big discrepancy in the risk factors studied as some of the risk factors were frequent, cited up to 16 times (age), while others were rare, with only 2 citations (season).
     Due to these limitations and the heterogeneity of the articles, the wide variety of variables, as well as a lack of a true definition of the outcome (RV ranged from 48 hours to 1 year), and of a grading system for most observational studies in this review, a systematic review and meta-analysis were not feasible. Therefore, a systematic search and review was conducted [43]. Most of the articles were also retrospective and arguably have low weight to form a robust meta-analysis. In addition, RV can have different expressions ranging from unplanned revisits to readmissions visits, among others. This means that despite the comprehensive search (Appendix 1), we might have missed some articles. However, this would probably not affect the results significantly as there is a visible consensus between the different studies that were included. Also, using such a wide time limit of one year and not differentiating between RVs for the same problem and RVs for an unrelated complaint to the initial visit might have influenced the results however, most studies did not specify if the RV complaint was different from the initial visit. Finally, this review did not look at the disposition of patients during the RV as the RV outcome can range from discharging the patient home to admission to wards/ICU to mortality and would obviously affect the weight and importance of each identified risk factor. 

Conclusion
    Young age, high acuity at presentation and language barrier, among others, are risk factors for return visits to the pediatric ED. Physicians should be aware of these factors and have a low threshold for admission or a good discharge plan for patients with one or more factors to improve quality care in the pediatric ED. While pediatric ED overcrowding is a burden worldwide, such studies can help decompress the EDs by identifying high risk patients and reducing RVs.

Declarations
Author contributions: All authors contributed equally and validated the final version of record.

Conflicts Of Interest: The Author(s) declare(s) that there is no conflict of interest.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Registration: No registration applicable

Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical approval: Ethical approval for this study was not required.

References

1.      Lerman B, Kobernick MS. Return visits to the emergency department. J Emerg Med. 1987 Sep 1;5(5):359–62. https://doi.org/10.1016/0736-4679(87)90138-7.

2.      Duseja R, Bardach NS, Lin GA, Yazdany J, Dean ML, Clay TH, et al. Revisit Rates and Associated Costs After an Emergency Department Encounter. Ann Intern Med. 2015 Jun 2;162(11):750–6. https://doi.org/10.7326/M14-1616.

3.      Chiang CY, Cheng FJ, Huang YS, Chen YL, Wu KH, Chiu IM. ICU admission following an unscheduled return visit to the pediatric emergency department within 72 hours. BMC Pediatrics. 2019 Aug 2;19(1):268. https://doi.org/10.1186/s12887-019-1644-y.

4.      Ostrow O, Zelinka A, Shim A, Azmat SK, Masood S, Chartier LB. Pediatric Emergency Department Return Visits: An Innovative and Systematic Approach to Promote Quality Improvement and Patient Safety. Pediatr Emerg Care. 2020;36(12):e726–31. https://doi.org/10.1097/PEC.0000000000001999.

5.      Ko M, Lee Y, Chen C, Chou P, Chu D. Incidence of and Predictors for Early Return Visits to the Emergency Department: A Population-Based Survey. Medicine. 2015;94(43):e1770. https://doi.org/10.1097/MD.0000000000001770.

6.      Benbassat J, Taragin M. Hospital Readmissions as a Measure of Quality of Health Care: Advantages and Limitations. Arch Intern Med. 2000 Apr 24;160(8):1074–81. https://doi.org/10.1001/archinte.160.8.1074.

7.      Trivedy CR, Cooke MW. Unscheduled return visits (URV) in adults to the emergency department (ED): a rapid evidence assessment policy review. Emerg Med J. 2015 Apr 1;32(4):324. https://doi.org/10.1136/emermed-2013-202719.

8.      Tran QK, Bayram JD, Boonyasai RT, Case MA, Connor C, Doggett D, et al. Pediatric Emergency Department Return: A Literature Review of Risk Factors and Interventions. Pediatr Emerg Care. 2016;32(8):570–7. https://doi.org/10.1097/PEC.0000000000000876.

9.      Aaronson E, Jansson P, Wittbold K, Flavin S, Borczuk P. Unscheduled return visits to the emergency department with ICU admission: A trigger tool for diagnostic error. Am J Emerg Med. 2020 Aug 1;38(8):1584–7. https://doi.org/10.1016/j.ajem.2019.158430.

10.  Ehwerhemuepha L, Yu PT, Guner YS, Wallace E, Feaster W. A Nested Mixed Effects Multicenter Model Examining the Risk Factors for Pediatric Trauma Return Visits Within 72 Hours. J Surg Res. 2021 Jan 1;257:370–8. https://doi.org/10.1016/j.jss.2020.08.021.

11.  Pershad J, Jones T, Harrell C, Ajayi S, Giles K, Cross C, et al. Factors Associated With Return Visits at 7 Days After Hospital Discharge. Hosp Pediatr. 2020 Apr 1;10(4):353–8. https://doi.org/10.1542/hpeds.2019-0207.

12.  Türe E, Yazar A. Retrospective Evaluation of Return Visits to the Paediatric Emergency Department. Eurasian J Emerg Med. 2020 Jun 22;19(2):115–20. https://doi.org/10.4274/eajem.galenos.2019.68926.

13.  Drouin O, D’Angelo A, Gravel J. Impact of wait time during a first pediatric emergency room visit on likelihood of revisit in the next year. Am J Emerg Med. 2020 May 1;38(5):890–4. https://doi.org/10.1016/j.ajem.2019.07.005.

14.  Daymont C, Balamuth F, Scott HF, Bonafide CP, Brady PW, Depinet H, et al. Elevated Heart Rate and Risk of Revisit With Admission in Pediatric Emergency Patients. Pediatr Emerg Care. 2021 Apr;37(4):e185–91. https://doi.org/10.1097/PEC.0000000000001552.

15.  de Vos-Kerkhof E, Geurts DHF, Steyerberg EW, Lakhanpaul M, Moll HA, Oostenbrink R. Characteristics of revisits of children at risk for serious infections in pediatric emergency care. Eur J Pediatr. 2018 Apr 1;177(4):617–24. https://doi.org/10.1007/s00431-018-3095-0.

16.  Kim BS, Kim JY, Choi SH, Yoon YH. Understanding the characteristics of recurrent visits to the emergency department by paediatric patients: a retrospective observational study conducted at three tertiary hospitals in Korea. BMJ Open. 2018 Feb 1;8(2):e018208. https://doi.org/10.1136/bmjopen-2017-018208.

17.  Michelson KA, Lyons TW, Bachur RG, Monuteaux MC, Finkelstein JA. Timing and Location of Emergency Department Revisits. Pediatrics. 2018 May 1;141(5):e20174087. https://doi.org/10.1542/peds.2017-4087.

18.  Meyer-Macaulay CB, Truong M, Meckler GD, Doan QH. Return visits to the pediatric emergency department: A multicentre retrospective cohort study. CJEM. 2018;20(4):578–85. https://doi.org/10.1017/cem.2017.40.

19.  Ruttan T, Lawson KA, Piper K, Wilkinson M. Risk Factors Associated With Emergency Department Return Visits Following Trauma System Discharge. Pediatr Emerg Care. 2018;34(3):202–7. https://doi.org/10.1097/PEC.0000000000001182.

20.  Hu YH, Tai CT, Chen SCC, Lee HW, Sung SF. Predicting return visits to the emergency department for pediatric patients: Applying supervised learning techniques to the Taiwan National Health Insurance Research Database. Comput Methods Programs Biomed. 2017 Jun 1;144:105–12. https://doi.org/10.1016/j.cmpb.2017.03.022.

21.  Kilicaslan O, Sönmez FT, Gunes H, Temizkan RC, Kocabay K, Saritas A. Short Term Unscheduled Revisits to Paediatric Emergency Department - A Six Year Data. J Clin Diagn Res. 2017 Mar 1;11(3):SC12-SC15. https://doi.org/10.7860/JCDR/2017/25098.9484.

22.  Samuels-Kalow ME, Stack AM, Amico K, Porter SC. Parental Language and Return Visits to the Emergency Department After Discharge. Pediatr Emerg Care. 2017 Jun;33(6):402-404. https://doi.org/10.1097/PEC.0000000000000592.

23.  Wilson PM, Florin TA, Huang G, Fenchel M, Mittiga MR. Is Tachycardia at Discharge From the Pediatric Emergency Department a Cause for Concern? A Nonconcurrent Cohort Study. Ann Emerg Med. 2017 Sep;70(3):268-276.e2. https://doi.org/10.1016/j.annemergmed.2016.12.010.

24.  Goh GL, Huang P, Kong MC, Chew SP, Ganapathy S. Unplanned reattendances at the paediatric emergency department within 72 hours: a one-year experience in KKH. Singapore Med J. 2016;57(6):307-13. https://doi.org/10.11622/smedj.2016105.

25.  Schneider M, Chen C, Menoch M, Levasseur K. Primary language and return visits in the pediatric emergency department. SAEM Annual Meeting Abstracts. Acad Emerg Med. 2016 May 1;23(S1):S103-4. https://doi.org/10.1111/acem.12974.

26.  de Vos-Kerkhof E, Geurts DH, Wiggers M, Moll HA, Oostenbrink R. Tools for 'safety netting' in common paediatric illnesses: a systematic review in emergency care. Arch Dis Child. 2016 Feb;101(2):131-9. https://doi.org/10.1136/archdischild-2014-306953.

27.  Saunders N, To T, Parkin P, Guttmann A. The relationship between immigrant status and pediatric emergency department return visits. Paediatrics and Child Health (Canada). 2015;20:e93. https://doi.org/10.1093/pch/20.5.e93.

28.  Sung SF, Liu KE, Chen SC, Lo CL, Lin KC, Hu YH. Predicting Factors and Risk Stratification for Return Visits to the Emergency Department Within 72 Hours in Pediatric Patients. Pediatr Emerg Care. 2015 Dec;31(12):819-24. https://doi.org/10.1097/PEC.0000000000000417.

29.  Gallagher RA, Porter S, Monuteaux MC, Stack AM. Unscheduled return visits to the emergency department: the impact of language. Pediatr Emerg Care. 2013 May;29(5):579-83. https://doi.org/10.1097/PEC.0b013e31828e62f4

30.  Samuels-Kalow ME, Stack AM, Amico K, Porter SC. The association between parental language and 72-hour revisits following pediatric emergency department discharge. SAEM Annual Meeting Abstracts. Acad Emerg Med. 2013 May 1;20(s1):S188. https://doi.org/10.1111/acem.12115.

31.  Gaucher N, Bailey B, Gravel J. Impact of physicians' characteristics on the admission risk among children visiting a pediatric emergency department. Pediatr Emerg Care. 2012 Feb;28(2):120-4. https://doi.org/10.1097/PEC.0b013e318243f8e0.

32.  Reinke DA, Walker M, Boslaugh S, Hodge D 3rd. Predictors of pediatric emergency patients discharged against medical advice. Clin Pediatr (Phila). 2009 Apr;48(3):263-70. https://doi.org/10.1177/0009922808323109.

33.  Costabel S, Piccotti E, Sartini M, Magnani M, Di Pietro P. Return visits to the Paediatric Emergency Department: first analysis in Italy. J Prev Med Hyg. 2008 Dec;49(4):142-7. https://doi.org/10.15167/2421-4248/jpmh2008.49.4.133

34.  Goldman RD, Ong M, Macpherson A. Unscheduled return visits to the pediatric emergency department-one-year experience. Pediatr Emerg Care. 2006 Aug;22(8):545-9. https://doi.org/10.1097/01.pec.0000230553.01917.05.

35.  LeDuc K, Rosebrook H, Rannie M, Gao D. Pediatric emergency department recidivism: demographic characteristics and diagnostic predictors. J Emerg Nurs. 2006 Apr;32(2):131-8. https://doi.org/10.1016/j.jen.2005.11.005.

36.  Alessandrini EA, Lavelle JM, Grenfell SM, Jacobstein CR, Shaw KN. Return visits to a pediatric emergency department. Pediatr Emerg Care. 2004 Mar;20(3):166-171. https://doi.org/10.1097/01.pec.0000117924.65522.a1.

37.  Navanandan N, Schmidt SK, Cabrera N, Topoz I, DiStefano MC, Mistry RD. Seventy-two-hour Return Initiative: Improving Emergency Department Discharge to Decrease Returns. Pediatr Qual Saf. 2020 Sep 25;5(5):e342. https://doi.org/10.1097/pq9.0000000000000342.

38.  Hampers LC, Cha S, Gutglass DJ, Binns HJ, Krug SE. Language barriers and resource utilization in a pediatric emergency department. Pediatrics. 1999 Jun;103(6):1253-6. https://doi.org/10.1542/peds.103.6.1253.

39.  Zamor R, Byczkowski T, Zhang Y, Vaughn L, Mahabee-Gittens EM. Language Barriers and the Management of Bronchiolitis in a Pediatric Emergency Department. Acad Pediatr. 2020 Apr;20(3):356-363. https://doi.org/10.1016/j.acap.2020.01.006.

40.  Hampers LC, McNulty JE. Professional interpreters and bilingual physicians in a pediatric emergency department: effect on resource utilization. Arch Pediatr Adolesc Med. 2002 Nov;156(11):1108-13. https://doi.org/10.1001/archpedi.156.11.1108.

41.  Doan Q, Wong H, Meckler G, Johnson D, Stang A, Dixon A, et al. The impact of pediatric emergency department crowding on patient and health care system outcomes: a multicentre cohort study. CMAJ. 2019 Jun 10;191(23):E627-35. https://doi.org/10.1503/cmaj.181426.

42.  Al-Qahtani MH, Yousef AA, Awary BH, Albuali WH, Al Ghamdi MA, AlOmar RS, et al. Characteristics of visits and predictors of admission from a paediatric emergency room in Saudi Arabia. BMC Emerg Med. 2021 Jun 21;21(1):72. https://doi.org/10.1186/s12873-021-00467-7.

43.  Grant MJ, Booth A. A typology of reviews: an analysis of 14 review types and associated methodologies. Health Info Libr J. 2009 Jun;26(2):91-108. https://doi.org/10.1111/j.1471-1842.2009.00848.x.

 

 

Fatima Allaw, Rozana El Eid, Michel Almardini, Nabih Habib, Imad Bou Akl, Aline El Zakhem, Souha S. Kanj (Author)

Influenza Associated Pulmonary Aspergillosis: A Retrospective Study from a Tertiary Care Center in Lebanon

Introduction

Influenza-associated pulmonary aspergillosis (IAPA) has been reported in multiple cohort studies, typically in the immunocompromised host. Limited data is available from the Middle Eastern region.

Methods

This is a retrospective study conducted at the American University of Beirut Medical Center (AUBMC) between January 1 2014 and March 1 2019, to describe the clinical characteristics, risk factors and outcomes of patients with influenza and invasive pulmonary aspergillosis (IPA). Six hundred fifty six patients were admitted with influenza pneumonia. Data about positive cultures for Aspergillus sp. isolated from sputum, deep tracheal aspirates (DTA) or bronchoalveolar lavage (BAL) or a positive aspergillus galactomannan test (GM) in serum or BAL was collected. Cases were identified based on the definitions and criteria for influenza and invasive aspergillosis suggested by the European Organization for Research and Treatment of Cancer/Mycoses study Group (EORTC/MSG), EORTC/MSG intensive care unit (EORTC/MSGERC ICU) Working Group, and IAPA definition.

Results

Nine patients had a positive result for Aspergillus sp. in culture or GM. Based on the EORTC/MSG criteria, 7 patients were classified as probable cases of IPA, and one as a possible case. On the other hand, only 2 patients were classified as probable cases of invasive fungal infection (IFI) based on the IAPA criteria. Only 1 out of 9 patients died. There was a preponderance of aspergillosis among immunocompromised patients.

Conclusion

Our study showed that the incidence of IPA in influenza patients was low compared to the data reported from European countries. This calls for national and regional surveillance to better understand the epidemiological variation in the regions.

Introduction
     The association between influenza and superimposed pulmonary aspergillosis has been described as early as 1979.[1] Influenza-associated pulmonary aspergillosis (IAPA) has been reported in multiple cohort studies.[2, 3] The associated mortality is high ranging between 22.2% to 100%, especially in patients admitted to the intensive care unit (ICU).[4] While invasive pulmonary aspergillosis (IPA) typically occurs in immunocompromised hosts and isolation of Aspergillus species in immunocompetent patients is most often considered a colonization,[5] IAPA has been described in many patients without the traditional risk factors for IPA, including immunocompetent individuals.[6] Since the associated mortality of IAPA is 51% compared to 28% in patients with influenza admitted to the ICU without IAPA, criteria have been proposed for the diagnosis and early identification of IAPA.[7-11] Limited data on IAPA is available from the Arab countries in the Middle East region.  In Lebanon, a country with low vaccination rates for influenza, seasonal influenza is a significant burden on the population, with a hospital admission rate in one center estimated at 26.6%.[12] The purpose of this study is to describe the clinical characteristics, risk factors and outcomes of patients with influenza who had Aspergillus sp. isolated from cultures of respiratory specimens or positive aspergillus galactomannan (GM) test. 

Methods

Study design

     This is a retrospective chart review conducted at the American University of Beirut Medical Center (AUBMC), a teaching hospital with 364 beds and 50 adult ICU beds. We reviewed the electronic medical records of patients hospitalized between January 1, 2014, and March 1, 2019, before the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic started. We included those with a primary diagnosis of influenza (confirmed either by a reverse transcriptase polymerase-chain-reaction (RT-PCR) or by a rapid antigen tests). We then checked which patients had positive cultures for Aspergillus sp. isolated from sputum, deep tracheal aspirates (DTA) or bronchoalveolar lavage (BAL) or a positive aspergillus GM in serum or BAL in patients who had worsening respiratory symptoms. Until 2020, our center had not been speciating the Aspergillus sp. nor had access to 1,3- β-D-Glucan (BDG). We collected data on patients characteristics including age, gender, Charlson’s score, body mass index (BMI), presence of neutropenia with neutrophils count at the time of influenza diagnosis (<500 neutrophils/mm3), bacterial co-infection at the time of influenza diagnosis, presence of type II diabetes mellitus (DM II), chronic kidney disease (CKD), hemodialysis use, chronic lung disease (chronic obstructive pulmonary disease COPD, asthma and other lung diseases like bronchiectasis), active hematological or solid organ malignancy, and active chemotherapy intake. 
Reviewed hospitalization course included length of hospital stay in days, intake of neuraminidase-inhibitor and/ or corticosteroids, radiographic characteristics of the lung findings, the need for oxygen supplementation, and the need for invasive or non-invasive mechanical ventilation. In-hospital mortality was defined as mortality anytime during the hospital stay.  

The study protocol was approved by the AUBMC Institutional Review Board under number BIO-2019-0166 and informed consents were waived due to the retrospective nature of the study.

Case definitions and analysis 

     Cases were identified by clinical, microbiological and radiological criteria based on the definitions and criteria for influenza and invasive aspergillosis suggested by the European Organization for Research and Treatment of Cancer/Mycoses study Group (EORTC/MSG), [7] European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) ICU Working Group [9] and IAPA definition (supplementary material 1). [8] According to EORTC/MSG criteria, patients were classified into three types of IAPA (proven IPA, probable IPA, and possible IPA). [7] The EORTC/MSERG ICU working group updated definitions specifically for invasive candidiasis and invasive aspergillosis that are relevant for ICU patients, focusing on the host factors. [9]
As for IAPA, although patients were classified as either proven or probable, authors suggested that clinicians should not distinguish between proven and probable disease and might consider these differences only for clinical trials [8]. Two categories were included in this definition: Invasive Aspergillus tracheobronchitis (ATB) and IAPA without ATB, based on expert consensus. [8]
Since our study population included all hospitalized patients and not only those admitted to the ICU, we opted to include all the aforementioned definitions to assess our patients.

Results

     During the study period, we identified a total of 656 cases of severe influenza pneumonia requiring hospital admission.  Of these, nine patients had a positive result for Aspergillus sp. in culture or positive GM. The clinical and laboratory characteristics of the 9 patients are presented in Table 1. 
Based on the EORTC/MSG criteria, 7 patients were classified as probable cases of IPA, and one as a possible case. On the other hand, only 3/9 patients were admitted to the ICU and thus met the entry criteria for the IAPA definition and 2 were classified as probable cases of IAPA. (Table 2). 
Seven patients were infected by influenza virus A and 2 patients by influenza virus B. Five patients had influenza confirmed by PCR and 4 by a positive rapid respiratory antigen test and had a typical clinical presentation. The mean time from influenza diagnosis to positive aspergillus test in respiratory samples was 4.66 days (interquartile range (IQR) 0–9 days). The mean age of patients was 52.5 years (standard deviation [SD] 16.9). Four out of 9 patients were males. 
Six patients had underlying medical conditions classically considered risk factors for IPA, including malignancy under treatment. Three patients had no immune compromising conditions, but two of them had chronic lung disease. None of the patients had DM and one had CKD. Three patients were treated in ICUs, one of which required mechanical ventilation, with a length of ICU stay of 5, 5 and 23 days respectively.
     There were 5 patients who underwent bronchoscopy, all of which had a positive GM in BAL, 4 of which had a GM index ≥1.0. Two of those patients grew Aspergillus sp. from BAL culture in addition to sputum culture, however they had a negative GM in serum. A total of 5 Aspergillus isolates were cultured from 5 different patients. As mentioned previously, during the study period speciation of Aspergillus sp. was not available at our center. Among those who did not undergo bronchoscopy, 3 patients had an elevated serum GM >0.5 while 1 had a positive sputum culture for Aspergillus sp. None of the patients had evidence of ATB by bronchoscopy.
All patients demonstrated radiologic abnormalities.  One patient had a cavitary lesion on chest computed tomography (CT), 6 patients had dense circumscribed lesions, and none showed a halo sign (Table 2). 
Prednisone at a dose of 40 mg per day had been administered to 4/9 patients for an average duration of 3 days prior to the positive fungal results. All patients were treated with voriconazole at the recommended dose. Only one of the 9 patients died from respiratory failure during the hospital stay.
     Seven patients were treated with antibiotics for superimposed bacterial infections, mostly consisting of quinolones alone or in combination with extended spectrum beta-lactam antibiotics. 

Discussion

     This is the first case series from the Arab countries of the Middle East region describing the association between influenza pneumonia and pulmonary aspergillosis and providing added insight to the regional epidemiology of this disease. Our results demonstrated a low incidence of concurrent influenza infection and pulmonary aspergillosis (1.4%) in our hospitalized patients with influenza and a subsequent low mortality in these patients (1/9). Eight out of the 9 patients met the criteria for definitions set by the EORTC/MSG and/or the IAPA criteria, resulting in a cumulative incidence rate of only 1.2%.
     Two very recent systematic review/meta-analyses have been published; one summarizing the clinical characteristics of IAPA in critically ill patients, and the second in all hospitalized patients.[4, 13] Studies on hospitalized patients with a sample size >50 were included and all were observational except for one randomized control trial (RCT).[4] These studies were mostly conducted in Europe and China.[4] Therefore, more high-quality evidence needs to be generated globally, particularly in regions such as the Middle East and Africa in which there is a paucity of data.
     Our results demonstrated a very low incidence rate of IAPA in comparison to other published studies. This could partly be explained by the fact that we explored the incidence in all hospitalized patients, and not only those admitted to the ICU. Most studies reporting on the incidence of IAPA have focused on critically ill patients. The proportion of IAPA among this population varies across studies, with as high as 32% in immunocompromised individuals.Even in the non-immunocompromised, the reported incidence was 14% in the same study, including 7 ICUs from the Netherlands and Belgium.[6] However, other studies have also expanded the analysis to include all patients hospitalized for influenza (including those requiring ICU admission). One large scale study from the United States which analyzed 477,556 hospitalizations identified with the principal diagnosis of influenza, found that IAPA was diagnosed in 823 (0.17%) of total admissions. [14]Another study on the total number of influenza admissions in a Chinese institution showed an incidence rate of 5.4%.[15] One cohort study from Canada also found an incidence of 7.2% in ICU patients.[16] Thus, the rates of IAPA are variable according to the countries. Low rates could be partly due to underdiagnosis of aspergillosis probably from the lack of physicians’ awareness of the relationship between influenza and aspergillosis. This has been observed globally, with Thevissen et. al reporting that outside Europe, only a minority of physicians have heard of or diagnosed IAPA in the past 5 years (17% in the United States and 39% in other countries) and lower respiratory sampling were performed less often. Additionally, while 39% of respondents globally did take lower respiratory samples for microbiologic analysis, the majority of respondents (79%) rarely requested GM from BAL samples.[17] The unavailability and the cost of GM particularly in low and middle income countries might play a role in underdiagnosing IAPA. In the absence of a high degree of suspicion physicians may have opted not to pursue the diagnosis of IAPA especially given the low mortality rate in our patient population. Another possible explanation to the low incidence in our study is that our population of admitted influenza patients might be less sick than in other studies as AUBMC is a private hospital and not unfrequently patients are admitted for IV hydration and antipyretics, whereas conditions for admitting influenza patients might be stricter in other settings.
The mean or median ages of hospitalized patients in pooled studies in a systematic review ranged from 52 to 65 years, and the proportions of males ranged from 50.6% to 69.3%.[4] Although we had a low number of patients, this was similar to our findings, where the average age was 52.5. Additionally, the systematic review done by Shi et al found that development of IAPA was significantly associated with a history of DM, COPD, and presence of EORTC/MSGERC host factors.[4] Our study also demonstrated a preponderance of IPA among immunocompromised patients. Only one case occurred in a patient with no risk factors. In our study, four patients were receiving steroids. In the meta-analysis on critically ill patients in particular, pooled studies comparing those with IAPA and no IAPA, showed that significantly more patients with IAPA were on chronic corticosteroids whereas there was no significant difference in pre-existing chronic lung diseases, DM and solid/hematological cancer. Thus, the concerning factors with IAPA despite the variations in prevalence, is the fact that it can manifest in patients without traditional risk factors for aspergillosis.
     Our population included mostly hospitalized non-critically ill patients and in general, this group of patients represents a challenge in classification, diagnosis as well as management.  The EORTC/MSGERC consensus definitions in combination with the ICU working groups’ definition captured the most patients (7 out of 9, 77.7%) in this case series. Compared to the EORTC/MSGERC definitions, the IAPA definition is more useful in an immunocompetent patient population. However, restricting the inclusion criteria to critically ill patients limits its use in the larger demographic of non-critically ill patients who may still incur significant morbidity such as a prolonged hospital stay. Indeed, studies have shown that in both total hospitalized patients and those only admitted to the ICU, the mortality rate, use of mechanical ventilation, and length of hospital stay are significantly increased in patients with IAPA versus patients without IAPA.[4, 13] Though these results mostly stem from observational data, the available evidence does seem to suggest that infection with aspergillosis in patients with influenza is independently associated with mortality, and not just a marker of clinical severity. [18]

     Our results showed that the interval from the diagnosis of influenza to Aspergillus growth was on average 4.6 days and is consistent with other studies frequently demonstrating a median time to diagnosis of up to 5 days.[19-22] This relatively short interval suggests that the patient might have been colonized by Aspergillus sp. preceding hospital admission through inhalation of spores. Therefore, the environmental surroundings will incur a differential risk to each patient and can also be center specific given differences in ventilation systems. 
A recent systematic review summarized the available evidence on the diagnostic performance of the various definitions for the diagnosis of IPA in non-hematological, non-solid organ transplant, critically ill patients. There was significant heterogeneity across studies in terms of population, prevalence, used reference definitions for IPA, (non-standardized) ad hoc variations of reference definitions, limiting comparisons across studies.[23] A proven diagnosis of IAPA in both the EORTC/MSGERC and the IAPA definition requires invasive procedures, though experts generally agree that the distinction between proven and probable IAPA is more important for clinical trials rather than clinical practice.[8] A presumptive diagnosis of IAPA can therefore be established in a relatively easier and quicker manner. This is important to consider, since early initiation of antifungal treatment has been shown to improve outcomes in critically ill patients,[24] however more evidence should be generated to assess early treatment benefit in non-critically ill patients. In our study, all patients received voriconazole as the first line agent, which is the appropriate initial antifungal therapy for IPA as per guidelines.[24]

     There is uncertainty as to whether patients with influenza admitted to the ICU would benefit from prophylactic therapy against infection with Aspergillus sp.. One recent randomized control trial assessed posaconazole as a prophylactic agent. The majority of patients were diagnosed within 48 hours of ICU admission, excluding them from the modified intention-to-treat population, while in the remaining patients the incidence of IAPA was not significantly reduced compared to those receiving standard of care.[25] 
This study was limited by its retrospective nature, small sample size and single center experience. Additionally, some pulmonary aspergillosis cases could have been missed since diagnostic testing may not have been ordered if a physician did not suspect the diagnosis. We did not compare patients with influenza who developed pulmonary aspergillosis versus those who didn’t, which limits the ability to form associations of the different patient factors with outcomes. 

Conclusion 

     Although influenza associated aspergillosis was less common in our study than reported elsewhere, the heterogeneity of incidence rates across studies published in the literature highlights the importance of conducting national and regional surveillance studies to better understand the epidemiological variations. Moreover, there are important differences between hospitalized patients on regular wards and those in the ICU, and the lack of data in the former group warrants more studies in order to optimize diagnosis and management in different patient populations. 

List of abbreviations:
IAPA, Influenza-associated aspergillosis; ICU, Intensive care unit; IPA, Invasive pulmonary aspergillosis; GM, galactomannan; AUBMC, American University of Beirut Medical Center; RT-PCR, Reverse transcriptase polymerase-chain-reaction; DTA, Deep tracheal aspirate; BAL, Bronchioalveolar lavage; BDG, 1,3- β-D-Glucan; BMI, Body mass index; DM II, Type II diabetes mellitus; CKD, Chronic kidney disease; COPD, Chronic obstructive pulmonary disease; EORTC/MSG, European Organization for Research and Treatment of Cancer/Mycoses study Group; EORTC/MSGERC, European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium; ATB, Aspergillus tracheobronchitis; SARS-COV-2, Severe acute respiratory syndrome coronavirus 2; IQR, Interquartile range; SD, Standard deviation; CT, Computed tomography; NSLC, Non-small cell lung cancer ; BIPAP, Bi-level positive airway pressure; IFI, Invasive fungal infection; RCT, Randomized controlled trial.

Declarations
Authorship statement
Fatima Allaw and Rozana El Eid contributed equally. Michel Almardini and Nabih Habib contributed equally. All authors validated the final version of record.
Conflicts Of Interest
The Author(s) declare(s) that there is no conflict of interest.
Funding statement
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Registration
No registration applicable.
Data availability statement 
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethical approval
The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocol was approved by the AUBMC institutional Review Board under number BIO-2019-0166.
Patient consent was waived due to the retrospective nature of the study.

References

1.      Fischer JJ, Walker DH. Invasive pulmonary aspergillosis associated with influenza. JAMA. 1979;241(14):1493-4.

2.      Duan Y, Ou X, Chen Y, Liang B, Ou X. Severe Influenza With Invasive Pulmonary Aspergillosis in Immunocompetent Hosts: A Retrospective Cohort Study. Front Med. 2021;7:602732. https://doi.org/10.3389/fmed.2020.602732.

3.      Waldeck F, Boroli F, Suh N, Wendel Garcia PD, Flury D, Notter J, et al. Influenza-associated aspergillosis in critically-ill patients-a retrospective bicentric cohort study. Eur J Clin Microbiol Infect Dis. 2020;39(10):1915-23. https://doi.org/10.1007/s10096-020-03923-7.

4.      Shi C, Shan Q, Xia J, Wang L, Wang L, Qiu L, et al. Incidence, risk factors and mortality of invasive pulmonary aspergillosis in patients with influenza: A systematic review and meta-analysis. Mycoses. 2022;65(2):152-63. https://doi.org/10.1111/myc.13410.

5.      Patterson TF, Thompson GR, 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, 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. https://doi.org/10.1093/cid/ciw326.

6.      Schauwvlieghe A, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med. 2018;6(10):782-92. https://doi.org/10.1016/s2213-2600(18)30274-1

7.      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. 2019;71(6):1367-76. https://doi.org/10.1093/cid/ciz1008.

8.      Verweij PE, Rijnders BJA, Brüggemann RJM, Azoulay E, Bassetti M, Blot S, et al. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. Intensive Care Med. 2020;46(8):1524-35. https://doi.org/10.1007/s00134-020-06091-6.

9.      Bassetti M, Azoulay E, Kullberg BJ, Ruhnke M, Shoham S, Vazquez J, et al. EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the Intensive Care Unit Working Group. Clin Infect Dis. 2021 Mar 15;72(Supplement_2):S121–7. https://doi.org/10.1093/cid/ciaa1751.

10.  Hamam J, Navellou J-C, Bellanger A-P, Bretagne S, Winiszewski H, Scherer E, et al. New clinical algorithm including fungal biomarkers to better diagnose probable invasive pulmonary aspergillosis in ICU. Ann Intensive Care. 2021;11(1):41. https://doi.org/10.1186/s13613-021-00827-3.

11.  Blot SI, Taccone FS, Van den Abeele AM, 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;186(1):56-64. https://doi.org/10.1164/rccm.201111-1978OC.

12.  Assaf-Casals A, Saleh Z, Khafaja S, Fayad D, Ezzeddine H, Saleh M, et al. The burden of laboratory-confirmed influenza infection in Lebanon between 2008 and 2016: a single tertiary care center experience. BMC Infect Dis. 2020;20(1):339. https://doi.org/10.1186/s12879-020-05013-7.

13.  Chong WH, Saha BK, Tan CK. Clinical characteristics and outcomes of influenza-associated pulmonary aspergillosis among critically ill patients: a systematic review and meta-analysis. J Hosp Infect. 2022;120:98-109. https://doi.org/10.1016/j.jhin.2021.11.016.

14.  Robinson KM. Mechanistic Basis of Super-Infection: Influenza-Associated Invasive Pulmonary Aspergillosis. J Fungi (Basel). 2022;8(5). https://doi.org/10.3390/jof8050428.

15.  Zou P, Wang C, Zheng S, Guo F, Yang L, Zhang Y, et al. Invasive Pulmonary Aspergillosis in Adults With Avian Influenza A (H7N9) Pneumonia in China: A Retrospective Study. J Infect Dis. 2020;221(Suppl 2):S193-s7. https://doi.org/10.1093/infdis/jiz682.

16.  Schwartz IS, Friedman DZP, Zapernick L, Dingle TC, Lee N, Sligl W, et al. High Rates of Influenza-Associated Invasive Pulmonary Aspergillosis May Not Be Universal: A Retrospective Cohort Study from Alberta, Canada. Clin Infect Dis. 2020;71(7):1760-3. https://doi.org/10.1093/cid/ciaa007.

17.  Thevissen K, Jacobs C, Holtappels M, Toda M, Verweij P, Wauters J. International survey on influenza-associated pulmonary aspergillosis (IAPA) in intensive care units: responses suggest low awareness and potential underdiagnosis outside Europe. Crit Care. 2020;24(1):84. https://doi.org/10.1186/s13054-020-2808-8.

18.  Rijnders BJA, Schauwvlieghe A, Wauters J. Influenza-Associated Pulmonary Aspergillosis: A Local or Global Lethal Combination? Clin Infect Dis. 2020;71(7):1764-7. https://doi.org/10.1093/cid/ciaa010.

19.  Wauters J, Baar I, Meersseman P, Meersseman W, Dams K, De Paep R, et al. Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study. Intensive Care Med. 2012;38(11):1761-8. https://doi.org/10.1007/s00134-012-2673-2.

20.  van de Veerdonk FL, Kolwijck E, Lestrade PP, Hodiamont CJ, Rijnders BJ, van Paassen J, et al. Influenza-Associated Aspergillosis in Critically Ill Patients. Am J Respir Crit Care Med. 2017;196(4):524-7. https://doi.org/10.1164/rccm.201612-2540LE.

21.  Ku YH, Chan KS, Yang CC, Tan CK, Chuang YC, Yu WL. Higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections. J Formos Med Assoc. 2017;116(9):660-70. https://doi.org/10.1016/j.jfma.2017.06.002.

22.  Wu CJ, Cia CT, Wang HC, Chen CW, Lin WC, Lee JC, et al. Clinical and Microbiological Characteristics of Culture-Positive, Influenza-Associated Pulmonary Aspergillosis: A Single-Center Study in Southern Taiwan, 2016-2019. J Fungi (Basel). 2022;8(1). https://doi.org/10.3390/jof8010049.

23.  Bassetti M, Giacobbe DR, Grecchi C, Rebuffi C, Zuccaro V, Scudeller L, et al. Performance of existing definitions and tests for the diagnosis of invasive aspergillosis in critically ill, adult patients: A systematic review with qualitative evidence synthesis. J Infect. 2020;81(1):131-46. https://doi.org/10.1016/j.jinf.2020.03.065.

24.  Cadena J, Thompson GR, 3rd, Patterson TF. Invasive Aspergillosis: Current Strategies for Diagnosis and Management. Infect Dis Clin North Am. 2016;30(1):125-42. https://doi.org/10.1016/j.idc.2015.10.015.

25.  Vanderbeke L, Janssen NAF, Bergmans D, Bourgeois M, Buil JB, Debaveye Y, et al. Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial. Intensive Care Med. 2021;47(6):674-86. https://doi.org/10.1007/s00134-021-06431-0.