Pulmonary fungal disease ( including aspergillosis ) in the Immunocompetent adult

Pulmonary fungal disease ( including aspergillosis ) in the Immunocompetent adult - Diagnosis and Treatment of

Publication: 30/09/2012

Next review: 11/11/2025

Clinical Guideline

CURRENT

ID: 3097

Approved By: Improving Antimicrobial Prescribing Group

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Diagnosis and Treatment of Pulmonary fungal disease (including aspergillosis) in the Immunocompetent adult

Summary
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Background
Investigation
Treatment

Empirical Antimicrobial Treatment
Directed Antimicrobial Treatment (when microbiology results are known)
Switch to oral agent(s)
Treatment Failure

Referral Criteria

Summary
Pulmonary fungal disease ( including aspergillosis ) in the Immunocompetent adult

This guideline applies to adult non-neutropenic patients with pulmonary fungal disease (for immunocompromised patients see Guidelines for the use of Antifungal Treatments in Adult Haematology Patients). These people are typically seen in respiratory medicine as out- or in-patients. This guideline excludes people with cystic fibrosis (CF, see Diagnosis and Treatment of Allergic Bronchopulmonary Aspergillosis (ABPA) and Aspergillus bronchitis in Children and Adults with Cystic Fibrosis). This guideline relates almost entirely to Aspergillus disease, but also includes a condition SAFS (see below), which may also be caused by other fungi.

Allergic bronchopulmonary aspergillosis (ABPA).

ABPA occurs in people with a background of atopy and asthma. Diagnostic features include a high total IgE, specific IgE to Aspergillus and positive serum IgG to Aspergillus. CT imaging of the thorax may demonstrate central bronchiectasis. Treatment of ABPA is with corticosteroids and antifungal therapy.

Severe asthma with fungal sensitization (SAFS)

SAFS occurs in people with severe asthma. They have elevated total IgE levels and evidence of IgE sensitivity to Aspergillus or other moulds. Treatment is mainly with corticosteroids and antifungal therapy.

Sub-acute invasive aspergillosis (SAIA) and chronic pulmonary aspergillosis (CPA)

People with chronic obstructive pulmonary disease, other lung diseases or receiving long-term corticosteroid therapy may present acutely with lower respiratory tract infection due to Aspergillus. Other patients may present with a more chronically developing disease. Typical presentation is with dyspnoea, reduction in lung function and failure to respond to antibiotic therapy. This diagnosis may be indicated by sputum culture for Aspergillus and/or a positive serum Aspergillus IgG or antigen. Radiological features on CT thorax may include consolidation cavitation, and fibrosis. Treatment is with antifungal therapy.

Aspergilloma

People with a mobile fungal mass occupying a previously formed pulmonary cavity. Aspergillomas are usually associated with high levels of serum Aspergillus IgG. Best outcomes are from surgical resection.

Aspergillus nodule

Nodule, or nodules with or without cavitation, often with necrosis caused by Aspergillus which can only be diagnosed histologically. May mimic tumours and other fungal infections.

Background

In a setting of asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD) and other forms of chronic lung disease, pulmonary fungal disease is a significant problem. Allergic bronchopulmonary aspergillosis (ABPA) is seen in ~2.5% of people with asthma affecting an estimated 178,000 people in the UK²⁵. Invasive aspergillosis is estimated to affect about 1.3% of patients with COPD²⁵ and the incidence of chronic pulmonary aspergillosis complicating TB, ABPA and sarcoid has been estimated globally at over 2 millions³, affecting around 3600 patients in the U.K²⁵. Thus, it is likely that fungal disease, and aspergillosis in particular, creates a significant burden of disease within the setting of people with chronic lung disease.

Investigation

The following investigations should be ordered in cases of symptomatic asthma or chronic lung disease where the cause of symptoms is not known, antibiotic therapy is typically partially or totally ineffective and where some form of aspergillosis is suspected clinically.

Investigations for allergic forms of Aspergillosis		All of the following criteria need to be met (see Appendix 1 for details of serology tests)⁷	First line investigations	Second line investigations
ABPA	ABPA with bronchiectasis	Symptomatic asthma Central bronchiectasis Total IgE ≥417 kU/L Aspergillus IgE Grade 3 or greater	Send blood (red cap, yellow ring) for; total IgE, Aspergillus IgE inhaled allergens IgE Aspergillus IgG Send sputum for culture (where possible) and BAL for microscopy and culture where available. High resolution computerized tomography of the chest (HRCT chest) [Evidence level D]	send blood (red cap, yellow ring) for; Aspergillus antigen Send BAL fluid for; Aspergillus antigen testing may be indicated. For discussion with consultant Microbiologist or mycologist. [Evidence level D] N.B A. fumigatus isolates from patients on azole therapy should be subject to azole susceptibility testing. [Evidence level D]
ABPA	ABPA seropositive	Symptomatic asthma Total IgE ≥417 kU/L .Aspergillus IgE Grade 3 or greater Aspergillus IgG >40mg/L
Severe Asthma with fungal sensitization (SAFS) ^5,6	These patients: have insufficient criteria to meet ABPA (see above). may have various CT signs such as bronchiectasis and mucous plugging but these are not diagnostic. may or may not be positive IgG for Aspergillus.	severe or poorly controlled asthma – defined as asthma that is not controlled on high dose inhaled corticosteroids and long-acting beta2 agonists or requires frequent or continued use of systemic corticosteroids4 Evidence of fungal sensitization defined by fungal specific IgE e.g. IgE to Cladosporium, Alternaria, Aspergillus, Candida, Botrytis or Penicillium Grade 1 or greater by ImmunoCAP⁵ total IgE < 417 kU/L

Investigations for chronic forms of Aspergillosis		All of the following criteria need to be met (see Appendix 1 for details of serology tests)⁷	First line investigations
Sub-acute Invasive Aspergillosis (SAIA) ^3,8,12	Proven SAIA requires:	evidence of hyphal invasion of lung parenchyma in histopathological examination of needle aspirate or biopsy specimens from pulmonary sites that are 1-3months old, positive culture of Aspergillus from the biopsy or other lower respiratory tract (LRT) site positive Aspergillus IgG (>40mg/L) or positive serum or BAL Aspergillus antigen (sometimes both antibody and antigen are detected)	send: sputum for culture blood (red cap, yellow ring) for Aspergillus IgG High resolution computerized tomography of the chest (HRCT chest)
	Probable SAIA in COPD⁸	Severe or very severe COPD (NICE stage III or IV11) Recent exacerbation of dyspnoea Suggestive chest imaging – pulmonary lesions unresponsive to antibacterial therapy. And one of the following: Positive culture of Aspergillus from a LRT specimen Positive Aspergillus IgG (>40mg/L) Two consecutive positive serum galactomannan results
	Probable SAIA relating to corticosteroid use	Corticosteroid use equals or exceeds 0.3mg/kg/day prednisone or equivalent for 3 weeks On CT, presence of dense well circumscribed lesions with or without halo, an air crescent sign or a cavity. Culture of Aspergillus sp from sputum or BAL or bronchial brushings/washings, or a positive galactomannan result in serum or BAL
Chronic pulmonary aspergillosis ^3,16	All of the following criteria must be met in patients with chronic pulmonary or systemic symptoms (duration, ≥ 3 months) including: weight loss, productive cough, or haemoptysis	A consistent appearance in thoracic imaging preferably by computerised tomography. new or expanding cavitation (with or without intracavitary balls), pleural thickening, general parenchymal destruction, upper lobe fibrosis, unilateral or bilateral consolidation. Direct evidence of Aspergillus infection or an immunological response to it. Aspergillus IgG antibody ≥40mg/L Aspergillus IgE antibody ≥ Grade 3 if patient has asthma or ABPA BAL galactomannan (Aspergillus antigen) index ≥1.0 Positive sputum or BAL culture of Aspergillus sp. Positive microscopy of hyphae in respiratory sample (this is a good marker for infection but needs one of the above Aspergillus specific results above to confirm Aspergillus otherwise other fungi could be involved) Exclusion of alternative diagnoses (bearing in mind that co-infections and comorbidities are possible) Mycobacteria infection (TB or non-tuberculous infection) may precede, follow or occur at the same time Lung cancer Pulmonary infarction Vasculitis Bacterial infection (Streptococcus pneumonia, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa)
Aspergilloma³		In a person presenting with a mobile mass within a pre-exisiting lung cavity. This can be demonstrated on either chest X-ray or CT thorax. Associated symptoms with an Aspergilloma are persistant cough or haemoptysis. The diagnosis can be confirmed by a positive test for Aspergillus IgG antibody (>40mg/L) Aspergillus IgG antibody levels are often very high. Sputum culture may be positive for Aspergillus sp.
Aspergillus nodule		This can be diagnosed where nodules that are biopsied demonstrate the presence of hyphae which can be confirmed as Aspergillus by culture or positive antibody testing

Antifungal susceptibility testing

Antifungal susceptibility testing of Aspergillus isolates should be performed in patients on antifungal therapy, with invasive disease (whether or not on antifungal therapy), or in patients who are clinically suspected of having an azole resistant pathogen (AIII).

Treatment

Empirical Antimicrobial Treatment

In general, antifungal treatment based on clinical suspicion of aspergillosis without any positive laboratory investigation results (see above) is not advised.

Directed Antimicrobial Treatment (when microbiology results are known)

Treatment of allergic forms of Aspergillosis
Disease	Non-antimicrobial treatment	Directed Antimicrobial Treatment (when microbiology results are known)	Duration
SAFS	Inhaled or oral corticosteroid therapy ✛ should be considered (alongside any antifungal therapy) if not already used. [Evidence level A.] Omalizumab should be considered for severe allergic asthma in accordance with NICE guidelines²⁰	Itraconazole – capsules 200mg 12-hourly pending confirmation of a satisfactory trough serum level (see Itraconazole - Antimicrobial Prescribing Guidelines for Adults) Consideration of the interactions between Itraconazole and inhaled corticosteroids should be undertaken.	6 to 8 months ^{(5, 6)}. [Evidence level A]
ABPA			3 months initially and reviewed. [Evidence level A]
Aspergilloma	Surgical resection or embolism is usually considered the optimal intervention for isolated aspergillomas ^3,13. [Evidence level C]	Antifungal therapy is indicated only if surgical resection is contraindicated or the lesion is a component of parenchymal disease (e.g. chronic pulmonary aspergillosis). In patients where surgical resection or embolism is contraindicated, instillation of amphotericin B ^3,13 directly into the cavity containing the fungal ball may have some beneficial effect [Evidence level C]

Treatment for Chronic forms of Aspergillosis
Disease	Directed Antimicrobial Treatment (when microbiology results are known)	Alternatives
Sub-acute invasive aspergillosis (SAIA)	Intravenous Voriconazole * (loading dose) 6mg/kg every 12 hours for 2 doses, then 4mg/kg every 12 hours for 2 doses Then switch to: Adults 40kg and above: 200mg orally 12-hourly for 3 months. Adults under 40kg: 100mg orally 12-hourly for 3 months.	N.B Where Voriconazole * therapy is poorly tolerated consider: Isavuconazole 200 mg IV three times a day 1-2, then 200 mg once a day oral following discussion with Microbiology (AI)²¹ Ambisome † 3mg/kg/day by intravenous infusion for 2 weeks following discussion with Microbiology [Evidence level B] Or If Voriconazole *, isavuconazole and Ambisome † are contraindicated consider intravenous Caspofungin † following discussion with Microbiology† [Evidence level B] Adults under 80kg: Caspofungin † 70mg on day 1, then 50mg 24-hourly for 2 weeks. Adults over 80kg: Caspofungin † 70mg 24-hourly for 2 weeks. [Evidence level C] Subsequent switching to oral azoles should also be discussed with a Microbiologist
Chronic pulmonary aspergillosis (CPA)	Itraconazole – capsules 200mg 12-hourly pending confirmation of a satisfactory trough serum level (see Itraconazole - Antimicrobial Prescribing Guidelines for Adults) [Evidence level B]¹⁸	Where Itraconazole is poorly absorbed or poorly tolerated, prescribe either: Switch to liquid Itraconazole 200mg and recheck absorption with trough serum level. If this fails: Voriconazole * † tablets [Evidence level B]19 Adults 40kg and above: 400mg 12-hourly for 1 day, then 200mg 12-hourly for 3 months Adults under 40kg: 200mg 12-hourly for 1 day, then 100mg 12-hourly for 3 months If Itraconazole and Voriconazole * are contraindicated: Posaconazole † tablets 400mg 12-hourly orally for 3 months [Evidence level C]¹⁶ Where oral azole therapy is poorly tolerated or poorly absorbed consider intravenous therapy for 2 weeks, and then switch to an oral azole (preferably one that has not previously been used) and continue for 3 months and review: Ambisome † 3mg/kg/day by intravenous infusion for 2 weeks [Evidence level C]17 or Caspofungin† by intravenous infusion [Evidence level D] Adults under 80kg: 70mg on day 1, then 50mg 24-hourly for 2 weeks. Adults over 80kg: 70mg 24-hourly for 2 weeks.
Aspergillus nodules	Treat as for CPA. Duration of Treatment; SAFS 6-8 months [Evidence level D] ABPA 3 months then review [Evidence level D] SAIA Azoles 6 months ³[Evidence level D] Ambisome or Caspofungin 2 weeks, then switch to oral azole for 5 months [Evidence level D] CPA Azoles 6 months ³. [Evidence level D]

✛Important note: There are significant interactions between Itraconazole and a large number of other drugs particularly inhaled corticosteroids. Patients on inhaled corticosteroids and Itraconazole electronic Medicines Compendium information on Itraconazole should have their corticosteroid doses reduced to 25% of initial dose as Itraconazole electronic Medicines Compendium information on Itraconazole inhibits the CYP3A4 enzyme that metabolises inhaled steroids and high corticosteroid levels may lead to Cushing syndrome.¹⁴ Consider referring patients to a pharmacist for a medication review.

In patients whose clinical features don’t fit into these categories treatment should be agreed after discussion with a Microbiologist/mycologist.

* Voriconazole is known to be associated with a risk of liver toxicity, phototoxicity, and squamous cell carcinoma of the skin. Before commencing treatment with voriconazle, the following actions must be completed:

Complete the Vfend® (voriconazole) Healthcare Professional Checklist and discuss the risks of treatment with the patient (https://assets.digital.cabinet-office.gov.uk/media/5473080440f0b61312000045/con418526.pdf)
Issue all patients with a Vfend® (voriconazole) Patient Alert Card (available from Pharmacy)
Check LFTs at baseline, then weekly for one month, then monthly throughout treatment if stable.
Advise patients to avoid sunlight exposure, wear protective clothing and use sunscreen with a high sun protection factor if in sunlight.
Serum levels should be taken to ensure a therapeutic level and avoid toxic doses. A trough serum level should be taken after five days of treatment (see: http://www.pathology.leedsth.nhs.uk/pathology/ClinicalInfo/MycologyDiagnosticServices/Voriconazolelevels.aspx).

†NB: Posaconazole use is a protected antimicrobial with full restrictions and always requires a code from Microbiology. Voriconazole , Ambisome and Caspofungin are protected antimicrobials with partial restrictions, if used outside of LTHT guidelines it may only be prescribed after obtaining a code from Microbiology.

Long term therapy

It is increasingly realised that for many patients who tolerate and show response to azole therapy, long term treatment, possibly even lifelong treatment is likely to lead to the best outcomes. However, there is evidence that up to 10% of patients may suffer from peripheral neuropathy as a consequence of at least 4 months of triazole therapy. In most cases this is reversible on cessation of therapy 15. Long term therapy also clearly has economic implications.

Switch to oral agent(s)

Recommendation: Patients on intravenous antifungal therapy should be switched to an oral azole after two weeks of therapy assuming good clinical progress¹⁷. [Evidence level C]

Treatment Failure

Recommendations:

Switch antifungal class
Review diagnosis AND
Check antifungal sensitivity testing results

Table 3: Antifungal regimens in intrinsic resistance

Population	Intervention	SoR/QoE≠	Comment
Amphotericin B MIC^$ >1 mg/L	Replace L-AmB^§ with azole, if azole tested susceptible	B/II
IA^¥ due to A. terreus	Voriconazole Isavuconazole Posaconazole Itraconazole	A/II A/II B/III B/III	Avoid Ambisome
IA^¥ due to A. calidoustus	L-AmB^§	A/II	Avoid azoles
IA^¥ due to A. alliaceus (A. flavus complex)	Other than L-AmB^§ monotherapy	C/III	Avoid Ambisome
IA^¥ due to A. niger complex	Other than Itraconazole and isavuconazole	B/III	Isavuconazole, Posaconazole , and Voriconazole MIC^$ in general one dilution higher compared with A. fumigatus; Itraconazole MIC^$ in general two steps higher; limited clinical data
IA^¥ due to A. nidulans	Voriconazole	C/III	AmB^§ MIC^$ elevated, poor clinical responses in chronic granulomatous disease

Abbreviations for Table 3 and 4:
$MIC Minimum inhibitory concentration
¥ IA invasive aspergillosis,
§ L-AmB Liposomal Amphotericin B
≠ SoR/QoE Strength of recommendation, Quality of evidence

Table 4: Optimal therapy in documented azole-resistance

Population

Intervention

SoR/QoE≠

Comment

Isolate with Voriconazole
MIC^$ = 2 mg/mL

Voriconazole & echinocandincombination therapy or L-AmB^§
monotherapy for IA^¥ (as well as for CPA)

A/III

The probability of Voriconazole treatment failure may be higher than in
Voriconazole MIC^$ <2

Isolate with Voriconazole MIC^$
>2 mg/mL

L-AmB^§
L-AmB^§ lipid complex
Voriconazole & Anidulafungin
Posaconazole & Caspofungin
Caspofungin or micafungin

A/II
C/III
B/III

C/III

Posaconazole not licensed for primary
treatment

Patients with contra-indications to L-AmB^§
and other azoles

Abbreviations for Table 3 and 4:
$MIC Minimum inhibitory concentration
¥ IA invasive aspergillosis,
§ L-AmB Liposomal Amphotericin B
≠ SoR/QoE Strength of recommendation, Quality of evidence

Referral Criteria

All patients in which a diagnosis of pulmonary aspergillosis is considered should be referred to respiratory medicine.

Provenance

Record:	3097
Objective:	To improve the diagnosis and management of pulmonary fungal disease in immunocompetent people without CF. To provide evidence-based recommendations for appropriate diagnosis and investigation of allergic bronchopulmonary aspergillosis, aspergilloma, various forms of chronic and acute invasive pulmonary aspergillosis in the immunocompetent patient setting. To provide evidence-based recommendations for appropriate non-antimicrobial management of fungal disease in respiratory medicine. To provide evidence-based recommendations for appropriate empirical and directed antimicrobial therapy of fungal disease in respiratory medicine. To recommend appropriate dose, route of administration and duration of antimicrobial agents.
Clinical condition:	Fungal infections in the immunocompetent respiratory medicine patient
Target patient group:	Adults
Target professional group(s):	Secondary Care Doctors Pharmacists
Adapted from:

Evidence base

References

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Guinea J, Torres-Narbona M, Gijon P, Munoz P, Pozo F, Pelaez T, de Miguel J, Bouza E 2010 Pulmonary Aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors and outcome. Clin Microbiol Infect 16:870-877
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Prys Picard and Niven 2010 Severe asthma with fungal sensitization. In Aspergillosis from diagnosis to prevention. Ed Pasqualatto AC Springer, London
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Stevens DA, Schwartz HJ, Lee JY, Moskovitz BL, Jerome DC, Catanzaro A, Bamberger DM, Weinmann AJ, Tuazon TU, Judson MA, Platts-Mills TAE, DeGraff AC A randomized trial of Itraconazole electronic Medicines Compendium information on Itraconazolein allergic bronchopulomary aspsergillosis New England J Med 342: 756-762.
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Global Initiative for Chronic Obstructive Lung Disease 2009 Global Strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. http://www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=2003
De Pauw B, et al. 2008 Revised definitions of invasive fungal disease from the European organization for Research and treatment of Cancer /Invasive fungal infections cooperative group and the National Institute of Allergy and Infectious Diseases Mycoses study group (EORTC/MSG) Consensus group. Clin Infect. Dis 46:1813-21.
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Felton TW, Baxter C, Moore CB, Roberts SA, Hope WW, Denning DW 2010 Efficacy and safety of posaconazole for chronic pulmonary aspergillosis. Clin Infect Dis. 2010 51:1383-91.
Denning DW, Riniotis K, Dobrashian R, Sambatakou H (2003) Chronic Cavitary and Fibrosing Pulmonary. and Pleural Aspergillosis: Case Series, Proposed Nomenclature Change, and Review Clin Infect Dis; 37(Suppl 3):S265–80
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Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (secure): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016;387:
Guinea J, Torres-Narbona M, Gijon P, Munoz P, Pozo F, Pelaez T, et al. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect 2010;16:870e7.
He H, Ding L, Li F, Zhan Q. Clinical features of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive respiratory diseases: a prospective study. Crit Care 2011;15:R5.
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Pegorie M, et al., Estimating the burden of invasive and serious fungal disease in the United Kingdom, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.10.005
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Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 2.0

Related information

Appendix 1 Serology tests mentioned in this guideline see also Tests and Tubes

Aspergillus IgG
IgG (non-allergic) response to Aspergillus also often called ImmunoCAP, equates to precipitin test
Aspergillus IgE
IgE (allergic response) to Aspergillus formerly called RAST
Total IgE
General marker of allergy/atopy
Aspergillus antigen
Direct detection of antigen in invasive disease also called galactomannan

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