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

Publication: 30/09/2012  
Last review: 20/04/2016  
Next review: 20/10/2019  
Clinical Guideline
UNDER REVIEW 
ID: 3097 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2016  

 

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
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). 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 (see full guideline).

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 asperillus or other moulds. Treatment is mainly with corticosteroids and antifungal therapy (see full guideline).

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 (see full guideline).

Aspergilloma
People with a mobile fungal mass occupying a previously formed pulmonary cavity. Aspergillomas are associated with high levels of serum Aspergillus IgG. Best outcomes are from surgical resection. (see full guideline)

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.

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

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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 1-2% of people with asthma1, sub-acute invasive aspergillosis is seen in about 0.4% of in-patients admitted with COPD2 and the incidence of chronic pulmonary aspergillosis complicating TB, ABPA and sarcoid has been estimated globally at over 2 millions3. 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.

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Clinical Diagnosis

Allergic bronchopulmonary aspergillosis (ABPA)

Allergic bronchopulmonary aspergillosis (ABPA) may be diagnosed a) primarily radiologically with bronchiectasis, or b) primarily serologically.
a) ABPA with bronchiectasis: all of the following criteria need to be met (see Appendix 1 for details of serology tests)7

  1. Symptomatic asthma
  2. Central bronchiectasis
  3. Total IgE ≥417 kU/L
  4. Aspergillus IgE Grade 3 or greater

b) ABPA seropositive: all of the following criteria need to be met (see Appendix 1 for details of serology tests)7

  1. Symptomatic asthma
  2. Total IgE ≥417 kU/L
  3. Aspergillus IgE Grade 3 or greater
  4. Aspergillus IgG >40mg/L

Severe Asthma with fungal sensitization (SAFS)5,6
Patients with SAFS are characterized by the presence of all 3 criteria:

  1. 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
  2. evidence of fungal sensitization defined by skin prick testing or fungal specific IgE e.g. IgE to Cladosporium, Alternaria, Aspergillus, Candida, Botrytis or Penicillium Grade 1 or greater by ImmunoCAP5
  3. total IgE < 417 kU/L (see Appendix 1 for details of serology tests)

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.

Sub-acute Invasive Aspergillosis (SAIA) 3,8,12

a) 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, with 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) (see Appendix 1 for details of serology tests).

b) Probable SAIA in COPD8
Patient has the following critieria:

  1. Severe or very severe COPD (NICE stage III or IV11)
  2. Recent exacerbation of dyspnoea
  3. Suggestive chest imaging – pulmonary lesions unresponsive to antibacterial therapy.
  4. And one of the following:
    • Positive culture of Aspergillus from a LRT specimen
    • Positive Aspergillus IgG (>40mg/L)
    • Two consecutive positive serum galactomannan results

c) Probable SAIA relating to corticosteroid use

Patient has all three of the following criteria12

  1. Corticosteroid use equals or exceeds 0.3mg/kg/day prednisone or equivalent for 3 weeks
  2. On CT, presence of dense well circumscribed lesions with or without halo, an air crescent sign or a cavity.
  3. 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

  1. A consistent appearance in thoracic imaging preferably by computerised tomography.
    i)        new or expanding cavitation (with or without intracavitary balls),
    ii)       pleural thickening,
    iii)     general parenchymal destruction, upper lobe fibrosis,
    iv)     unilateral or bilateral consolidation.
  2. Direct evidence of Aspergillus infection or an immunological response to it.
    i) Aspergillus IgG antibody ≥40mg/L
    ii) Aspergillus IgE antibody ≥ Grade 3 if patient has asthma or ABPA
    iii)BAL galactomannan (Aspergillus antigen) index ≥1.0
    iv) Positive sputum or BAL culture of Aspergillus sp.
    v) 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)
  3. Exclusion of alternative diagnoses (bearing in mind that co-infections and comorbidities are possible)
    i)        Mycobacteria infection (TB or non-tuberculous infection) may precede, follow or occur at the same time
    ii)       Lung cancer
    iii)     Pulmonary infarction
    iv)     Vasculitis
    v)      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) (see Appendix 1 for details of serology tests), 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

Mixed presentations of aspergillosis
In many cases patients will present with a combinations of symptoms and signs suggesting more than one of the above disease manifestations.

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Investigation

First line investigations
These 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.

Recommendation: In suspected SAFS or ABPA send blood (for total IgE, specific IgE to Aspergillus and inhaled allergens, Aspergillus IgG), sputum culture (where possible) and high resolution computerized tomography of the chest (HRCT chest) (see Appendix 1 for details of serology tests). [Evidence level D]

Recommendation: In suspected SAIA/CPA or aspergilloma send sputum for culture, blood for Aspergillus IgG and HRCT Chest. [Evidence level D]

Second line investigations
Recommendation: In suspected SAIA or CPA send blood for Aspergillus antigen and BAL fluid for culture and 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]

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Treatment
Non-Antimicrobial Treatment

SAFS: Inhaled or oral corticosteroid therapy should be considered (alongside any antifungal therapy) if not already used.

ABPA: Oral corticosteroid therapy should be used (alongside any antifungal therapy) if not already13

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 Itraconazoleshould have their corticosteroid doses reduced by 25% as Itraconazole electronic Medicines Compendium information on Itraconazoleinhibits 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.
[Evidence level A.]

Omalizumab should be considered for severe allergic asthma in accordance with NICE guidelines20

COPD: See Leeds Guidelines for the Diagnosis & Management of Chronic Obstructive Pulmonary Disease.

Aspergilloma: Surgical resection or embolism is usually considered the optimal intervention 3,13.
[Evidence level C]

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Empirical Antimicrobial Treatment

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

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Directed Antimicrobial Treatment (when microbiology results are known)

Directed antifungal therapy in response to a positive diagnosis is usually indicated.
Recommendation for SAFS(5,6):
Itraconazole electronic Medicines Compendium information on Itraconazole– capsules 200mg 12-hourly pending confirmation of a satisfactory trough serum level (see Itraconazole - Antimicrobial Prescribing Guidelines for Adults)
The likely duration of treatment is 6 to 8 months (5, 6).
[Evidence level A]

Recommendation for ABPA(9,10,13):
Itraconazole electronic Medicines Compendium information on Itraconazolecapsules 200mg 12-hourly as a steroid sparing agent pending confirmation of a satisfactory trough serum level (see Itraconazole - Antimicrobial Prescribing Guidelines for Adults)
Treatment should continue for 3 months initially and reviewed.
[Evidence level A]

Recommendation for SAIA:3,8,13
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:
Ambisome 3mg/kg/day by intravenous infusion for 2 weeks following discussion with Microbiology
[Evidence level B]
Or
If voriconazole* 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

Recommendation for Chronic pulmonary aspergillosis (CPA)
Itraconazole electronic Medicines Compendium information on Itraconazole– capsules 200mg 12-hourly pending confirmation of a satisfactory trough serum level (see Itraconazole - Antimicrobial Prescribing Guidelines for Adults)
[Evidence level B]18
Or if poorly absorbed or poorly tolerated, prescribe either:
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 electronic Medicines Compendium information on Itraconazoleand voriconazole* are contraindicated:
Posaconazole liquid 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.

Recommendation for Aspergilloma:
The recommended treatment for isolated aspergillomas is surgical resection, and 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]

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:

  1. 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)
  2. Issue all patients with a Vfend® (voriconazole) Patient Alert Card (available from Pharmacy)
  3. Check LFTs at baseline, then weekly for one month, then monthly throughout treatment if stable.
  4. Advise patients to avoid sunlight exposure, wear protective clothing and use sunscreen with a high sun protection factor if in sunlight.
  5. 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 restricted and requires a code from Microbiology staff. Voriconazole, Ambisome and caspofungin are restricted antimicrobials if used outside of current guidelines and may only be prescribed after obtaining a code from microbiology. .

Aspergillus nodules

Treat as for CPA.

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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]

Long term therapy
It is increasingly realized 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 therapy15. Long term therapy also clearly has economic implications.

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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]

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Treatment Failure

Recommendations:
Switch antifungal class
Review diagnosis AND
Check antifungal sensitivity testing results

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Provenance

Record: 3097
Objective:

Aims

  • To improve the diagnosis and management of pulmonary fungal disease in immunocompetent people without CF.

Objectives

  • 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

  1. Stevens Stevens DA, Moss RB, Kurup VP, Knutsen AP, Greenberger P, Judson MA, Denning DW, Crameri R, Brody AS, Light M, Skov M, Maish W, Mastella G; Participants in the Cystic Fibrosis Foundation Consensus Conference. (2003) Allergic bronchopulmonary aspergillosis in cystic fibrosis--state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 37 Suppl 3:S225-64.
  2. 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
  3. Denning DW, Cadranel J, Beigelman-Aubrey C, Ader F, Chakrabarti A, Blot S, Ullman AJ, Dimopoulos G, Lange C on behalf of the European Society for Clinical Microbiologyt and Infectious Diseases and European Respiratory Society. 2016 Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Resp J 47: 45-68
  4. Prys Picard and Niven 2010 Severe asthma with fungal sensitization. In Aspergillosis from diagnosis to prevention. Ed Pasqualatto AC Springer, London
  5. Denning DW, O’Driscoll BR, Powell G, Chew F, Atherton GT, Vyas A, Miles, J, Morris J, Niven RM 2009 Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization. Am J Resp Crit Care Med 179:11-18
  6. Pasqualatto AC, Powell G, Niven R, Denning DW 2009 The effects of antifungal therapy on severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis Respirology 14:1121-27.
  7. Greenberger J 2002 Allergic Bronchopulmonary Aspergillosis J Allergy clin Immunol. 110:685-92.
  8. Bulpa P, Dive A, Sibille Y (2007)Invasive aspergillosis in patiens with chronic obstructive pulmonary disease Eur Resp J 30:782-800
  9. 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.
  10. Wark PAB, Hensley MJ, Saltos N, Boyle MJ, Toneguzzi R, Simpson JL, McElduff P, Gibson PG Anti-inflammatory effect of Itraconazole electronic Medicines Compendium information on Itraconazolein stable allergic bronchopulmonary aspergillosis: A randomized controlled trial. 2003 J Allerg. Clin Immunol 111:952-7.
  11. Global Initiative for Chronic Obstructive Lung Disease 2009 Global Strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
  12. 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.
  13. Walsh T. et al. 2008 Treatment of Aspergillosis: Clinical Practice guidelines of the Infectious Diseases Society of America Clin. Infect Dis. 46:327-60.
  14. Naef R, Schmid C, Hofer M, Minder S, Speich R, Boehler A 2007. Itraconazole electronic Medicines Compendium information on Itraconazolecomedication increases systemic levels of fluticasone in Lung transplant recipients. Respiration 74:418-22
  15. Baxter CG, Marshall A, Roberts M, Felton TW, Denning DW 2011 Peripheral neuropathy in patients on long term triazole antifungal therapy. J. Antimicrobial therapy Jun 17 Epub
  16. 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.
  17. 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
  18. De Beule K, De Doncker P, Cauwenbergh G, et al. The treatment of aspergillosis and aspergilloma with Itraconazole electronic Medicines Compendium information on Itraconazole, clinical results of an open international study (1982–1987). Mycoses 1988; 31:476–485.
  19. Jain LR, Denning DW. The efficacy and tolerability of voriconazole in the treatment of chronic cavitary pulmonary aspergillosis. J Infect 2006; 52:e133–e137.
  20. http://guidance.nice.org.uk/TA133

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)

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Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 1.0

Related information

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

Test

Function

Department

Notes

Aspergillus IgG

IgG (non-allergic) response to Aspergillus

Microbiology

also often called ImmunoCAP, equates to precipitin test

Aspergillus IgE

IgE (allergic response) to Aspergillus

Immunology

formerly called RAST

Total IgE

General marker of allergy/atopy

Immunology

 

Aspergillus antigen

Direct detection of antigen in invasive disease

Microbiology

also called galactomannan

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