Question 21

a) Outline the risk factors for developing an invasive fungal infection in a critically ill patient. (60% marks)
b) Discuss the role and limitations of galactomannan and beta-Glucan antigen testing in diagnosing suspected invasive aspergillus infection. (20% marks)
c) List four situations where an azole would NOT be appropriate first line empiric treatment. (20% marks)

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College answer

Although reasonably well answered, many answers lacked structure, with various facets of information listed in a random order. Those answers that categorised well scored better. This is not to say that answers that were not categorised were penalised, but to state that those answers that used a sensible categorisation contained
more relevant information. Candidates should consider this when answering the questions in the paper, and whilst we appreciate that time management is critical in the paper, practicing answering written questions prior to the written exam in this manner will lead to improved answers in the exam itself. This reflects clinical practice
where you be required to outline the generic and specific problems of a patient has to a colleague. 


In a website that is often highly critical of the college examiners, one occasionally finds praise for their efforts, and this is one of those rare times. Not only did somebody create a clever question with some real clinical relevance, but they also composed a comment to the candidates which contained actual valuable information about what, and why, was expected. Quite right, an answer without structure should not be penalised for the lack of structure if the content is the same, but as the comment points out, often the use of structure improves the content of the answer by reminding you about points you would have otherwise forgotten. 

Anyway, fungus: for 60% of the marks, this would have needed to have a lot of meat. The list presented below is a melange of carefully curated findings from a meta-analysis by Muskett et al (2011) combined with what appears to be a list of random thoughts from Zabalza et al (2013).

  • Patient factors (comorbidities)
    • Extremes of age (<1 and >70 years)
    • Prolonged neutropenia (more than 14 days)
    • Malnutrition
    • Renal failure
    • Diabetes
  • Disease factors (features of the critical illness)
    • Bone marrow transplantation
      • GVHD
      • Delayed engraftment
    • Haematological malignancy with sepsis
    • Complicated abdominal surgery
  • Treatment factors
    • Total body irradiation
    • Steroid use (1mg/kg prednisolone for more than 2 weeks)
    • Broad spectrum antibiotics
    • Indwelling (urinary and venous) catheters
    • Mechanical ventilation
    • Parenteral nutrition
    • Chemotherapy (esp. ATG, high dose cytarabine and etoposide)


"Discuss the role and limitations of galactomannan and beta-Glucan antigen testing" for 20% of the marks would have been necessarily very brief. As most adults can only hand-write about twenty words per minute, and a 2-mark question should only be allocated two minutes, the candidates would have needed to discuss the role and limitations in forty words or less. What follows is an exactyly-eighty-word answer constructed using the excellent papers by Hites et al (for galactomannan) and Marty et al (for beta-glucan). 

  • Galactomannan:
    • ​​​​​​​Role: identifies colonisation (BAL), suggests invasive aspergillosis (blood)
    • Limitations: false positives from other fungi, β-lactams; low sensitivity (~70%); BAL samples do not confirm infection but do require invasive brionchoscopy
  • β-glucan antigen:
    • ​​​​​​​Role: identifies invasive aspergillosis and systemic fungaemia; more sensitive than galactomannan; improves confidence when both are positive
    • Limitations: false positives: present in the cell wall of other fungi, can be elevated in the absence of invasive fungal disease, eg. haemodialysis, immunoglobulin therapy, albumin, gauze packing, IV amoxycillin/clavulanate


There are actually probably more than just four such situations:

  • The organism is intrinsically resistant to all azoles (eg. Mucor)
  • The susceptibility profile locally suggests a high prevalence of azole resistance (eg. haematology inpatient population)
  • Where azoles are contraindicated by patient allergy or dangerous drug interaction
  • The patient is already on prophylactic azole therapy (i.e treatment failure)
  • Where the azole is not expected to penetrate into the infected tissue - for example,  according to this excellent paper by Felton et al (2014),  most azoles have pretty poor penetration into the CSF, the prostate and the vitreous humour of the eye


Schuster, Mindy G., et al. "Empirical Fluconazole versus Placebo for Intensive Care Unit PatientsA Randomized Trial." Annals of internal medicine 149.2 (2008): 83-90.

Fisher, Matthew C., et al. "Tackling the emerging threat of antifungal resistance to human health." Nature Reviews Microbiology 20.9 (2022): 557-571.

Van Rhijn, Norman, et al. "CYP51 paralogue structure is associated with intrinsic azole resistance in fungi." MBio 12.5 (2021): e01945-21.

Felton, Timothy, Peter F. Troke, and William W. Hope. "Tissue penetration of antifungal agents." Clinical microbiology reviews 27.1 (2014): 68-88.

Blot, Stijn I., et al. "A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients." American journal of respiratory and critical care medicine 186.1 (2012): 56-64.

Muskett, Hannah, et al. "Risk factors for invasive fungal disease in critically ill adult patients: a systematic review." Critical care 15.6 (2011): 1-15.

Shoham, Shmuel, and Shilpa Marwaha. "Invasive fungal infections in the ICU." Journal of intensive care medicine 25.2 (2010): 78-92.

Zabalza, Amaya, et al. "Voriconazole and its clinical potential in the prophylaxis of systemic fungal infection in patients with hematologic malignancies: a perspective review.Therapeutic Advances in Hematology 4.3 (2013): 217-230.

Hites, Maya, Eduardo Wilfrido Goicoechea Turcott, and Fabio Silvio Taccone. "The role of galactomannan testing to diagnose invasive pulmonary aspergillosis in critically ill patients." Annals of translational medicine 4.18 (2016).

Marty, Francisco M., and Sophia Koo. "Role of (1→ 3)-β-D-glucan in the diagnosis of invasive aspergillosis." Medical mycology 47.Supplement_1 (2009): S233-S240.