Aspergillus infection

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Aspergillus conidia are inhaled every day. Intact mucociliary clearance and phagocytes normally prevent disease. Structural airways disease allows colonisation; asthma or cystic fibrosis can generate an allergic response; pre-existing cavities permit a mobile fungal ball; and impaired neutrophil or macrophage function permits hyphal invasion through lung and blood vessels.

A clinical label must precede treatment. Allergic bronchopulmonary aspergillosis presents with difficult asthma, eosinophilia, high total IgE, Aspergillus sensitisation, mucus plugging and bronchiectasis. Chronic pulmonary aspergillosis develops over months in damaged lungs with cough, weight loss, fatigue, haemoptysis and expanding cavities. Invasive aspergillosis progresses over days to weeks in a vulnerable host and can disseminate.

The most informative diagnostic plan combines host risk, high-resolution imaging, mycology and pathology. Samples obtained before mould-active treatment have better yield, but haemodynamic or respiratory instability and strong invasive suspicion justify immediate therapy. Susceptibility testing is important for every clinically significant Aspergillus isolate because azole resistance alters prognosis and treatment.

Key points

Aspergillus causes distinct syndromes: allergic bronchopulmonary aspergillosis, aspergilloma, chronic pulmonary aspergillosis and invasive disease; a positive respiratory culture must be interpreted within that phenotype.
Invasive pulmonary aspergillosis is especially associated with prolonged neutropenia, acute leukaemia, allogeneic transplantation, solid-organ transplantation, corticosteroids, chronic granulomatous disease and severe influenza or COVID-19 critical illness.
First-line imaging for suspected invasive pulmonary disease is urgent thin-section CT chest; nodules, surrounding ground-glass halo, wedge infarcts or cavitation support but do not independently prove infection.
Serum and bronchoalveolar-lavage galactomannan plus Aspergillus PCR support diagnosis in the right host; 1,3-beta-D-glucan is a pan-fungal marker and is not Aspergillus specific.
Reference-standard confirmation is compatible histopathological tissue invasion with culture or molecular identification, but treatment must not wait when invasive disease is strongly suspected.
First-line treatment of invasive aspergillosis is voriconazole, commonly 6 mg/kg intravenously every 12 hours for two doses then 4 mg/kg every 12 hours, with therapeutic drug monitoring.
Isavuconazole or liposomal amphotericin B is an alternative when toxicity, interaction, resistance, pregnancy or possible Mucorales changes the risk-benefit balance.
Chronic pulmonary disease uses symptoms for at least three months, progressive cavities or nodules and Aspergillus IgG or microbiological evidence; long-term oral triazole therapy belongs with a specialist service.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Airborne conidia

Environmental Aspergillus spores are inhaled from soil, dust and decaying vegetation, with A. fumigatus causing most human disease.

Structural lung disease

Tuberculosis cavities, bronchiectasis, COPD, sarcoidosis and previous thoracic surgery permit colonisation, fungal-ball formation and chronic pulmonary infection.

Impaired host defence

Prolonged neutropenia, transplantation, corticosteroids, chronic granulomatous disease and critical viral pneumonia impair conidial killing and hyphal containment.

Allergic sensitisation

Asthma or cystic-fibrosis airways can mount exaggerated IgE and eosinophilic responses to persistent Aspergillus antigen without tissue invasion.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Conidial germination
Spores reaching distal airways swell and germinate into septate hyphae when macrophage and neutrophil clearance is inadequate.
2
Angioinvasion
Hyphae penetrate pulmonary vessels, causing thrombosis, haemorrhagic infarction, tissue necrosis and haematogenous spread to brain and other organs.
3
Cavity colonisation
Hyphae, mucus and cellular debris accumulate within a pre-existing air space to form a partly mobile aspergilloma.
4
Chronic tissue injury
Persistent fungal growth at cavity margins drives progressive fibrosis, pleural thickening, new cavities, constitutional illness and vascular erosion.
5
Allergic airway damage
Repeated type I and type III hypersensitivity to airway antigen causes mucus impaction, eosinophilic inflammation and central bronchiectasis.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Invasive pulmonary diseaseRed flag

Persistent fever, dry cough, pleuritic chest pain, dyspnoea or haemoptysis occurs in an immunocompromised host, sometimes with few auscultatory findings.

Chronic cavitary disease

Cough, fatigue, weight loss, breathlessness and recurrent haemoptysis evolve over at least three months with cavities, pleural thickening or nodules.

Aspergilloma

A fungal ball moves within a pre-existing cavity and may be asymptomatic or cause recurrent, occasionally catastrophic, haemoptysis.

Allergic phenotype

Poor asthma control, fleeting infiltrates, brown mucus plugs, central bronchiectasis and eosinophilia suggest allergic bronchopulmonary aspergillosis rather than tissue invasion.

Extrapulmonary invasionRed flag

Sinus pain, cranial neuropathy, skin nodules, visual change, embolic phenomena or neurological deficits may reflect direct extension or haematogenous dissemination.

Red flags requiring action

Massive or recurrent haemoptysis with an aspergilloma or chronic cavitary disease requires emergency airway, interventional-radiology and thoracic-surgical assessment.
Focal neurological deficit, seizure, confusion or severe headache may reflect cerebral infarction, abscess or haemorrhage from angioinvasive spread.
Black nasal eschar, facial pain, ophthalmoplegia or visual loss in an immunocompromised patient suggests invasive fungal sinusitis and needs immediate ENT and surgical review.
Persistent fever with pulmonary nodules during prolonged neutropenia demands urgent mould investigation even when chest radiography is normal.
Breakthrough disease during mould-active prophylaxis raises non-adherence, low exposure, azole-resistant Aspergillus or a non-Aspergillus mould and should trigger a class change plus tissue diagnosis.
Pregnancy, liver failure, major QT risk and interacting transplant or oncology medicines can make standard triazole therapy unsafe without specialist pharmacy input.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line CT chestFirst stepFirst line
Why
Detect early nodules, infarct-shaped lesions, halo sign, consolidation, cavitation, air-crescent change and chronic structural progression.
Interpretation and limitations
CT is substantially more sensitive than plain radiography in high-risk disease. Patterns guide bronchoscopy or biopsy but are not organism-specific and may change with neutrophil recovery.
02
Serum and BAL galactomannan
Why
Detect an Aspergillus cell-wall antigen that supports probable invasive disease in selected vulnerable populations.
Interpretation and limitations
BAL is often more sensitive for pulmonary disease. Antifungal prophylaxis, host group and local assay threshold affect performance; false positives and negative results require clinical interpretation.
03
Respiratory microscopy, culture and PCR
Why
Identify Aspergillus to species, increase diagnostic sensitivity and enable susceptibility testing.
Interpretation and limitations
Send large-volume sputum or BAL before antifungal exposure when feasible. Growth may represent colonisation in structural lung disease, while PCR can detect non-viable DNA.
04
Tissue histology and culture
Why
Demonstrate tissue invasion and distinguish Aspergillus from Mucorales or another mould.
Interpretation and limitations
Septate hyphae with acute-angle branching suggest Aspergillus but morphology alone is imperfect; pair histology with culture, PCR or sequencing and susceptibility.
05
Aspergillus IgG
Why
Support chronic pulmonary aspergillosis in a patient with compatible symptoms and progressive imaging.
Interpretation and limitations
Raised IgG is sensitive but not fully specific. A normal result does not exclude every species or immunocompromised presentation; combine with culture and radiology.
06
Allergic disease panel
Why
Confirm sensitisation and inflammatory burden when allergic bronchopulmonary aspergillosis is suspected.
Interpretation and limitations
Check total IgE, Aspergillus-specific IgE, eosinophils and CT bronchiectasis or mucus impaction; corticosteroids can suppress eosinophils and IgE changes over time track response.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Mucormycosis

Rhino-orbital disease, reverse-halo imaging or breakthrough on voriconazole raises Mucorales; tissue morphology and molecular identification direct amphotericin and surgery.

Pulmonary tuberculosis

Weight loss, haemoptysis and cavities overlap chronic aspergillosis and can coexist, requiring mycobacterial culture and molecular testing.

Cavitating malignancy

Squamous carcinoma or metastasis can create thick-walled cavities and constitutional symptoms; serial growth, PET and biopsy help distinguish it.

Other invasive mould

Fusarium, Scedosporium and other moulds mimic invasive aspergillosis but differ in susceptibility, making culture, sequencing and tissue essential.

Bacterial lung abscess

Aspiration risk, air-fluid level and polymicrobial culture suggest abscess, although bacterial and fungal infection may coexist in damaged lungs.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01SUSPECT INVASIONBuild an urgent mould diagnosisFirst stepA high-risk host develops persistent fever, focal chest symptoms, hypoxaemia, nodules or extrapulmonary signs.

1Obtain urgent thin-section CT chest and targeted sinus or brain imaging, then send serum galactomannan, beta-D-glucan and Aspergillus PCR according to local diagnostic policy.
2Collect sputum or BAL for microscopy, fungal culture, galactomannan and PCR before treatment when safe; pursue tissue from a peripheral lesion or involved site if feasible.
3Ask the laboratory for species identification and antifungal susceptibility and tell them about mould-active prophylaxis or prior azole exposure.
4Start mould-active therapy immediately when suspicion is strong; diagnostics refine treatment but should not create a dangerous wait.

02FIRST-LINETreat invasive aspergillosisFirst lineInvasive disease is proven, probable or strongly suspected and no overriding contraindication changes drug choice.

1Load intravenous voriconazole at 6 mg/kg every 12 hours for two doses, then give 4 mg/kg every 12 hours; convert to an exposure-guided oral regimen when stable and absorbing.
2Check baseline liver tests, ECG, renal function and interacting medicines, especially calcineurin inhibitors, sirolimus, rifamycins, anticonvulsants and some anticancer agents.
3Measure a trough after about four to five days and after dose, formulation, organ-function or interaction changes; use the local mycology target, commonly above 1 to 1.5 mg/L and below 5 to 6 mg/L.
4Continue for at least six to twelve weeks, guided by clinical and radiological response and reversal of immunosuppression rather than a fixed end date.

03ALTERNATIVEChoose another mould-active agentAlternativeVoriconazole is contraindicated, not tolerated, interacting, subtherapeutic or the isolate is resistant, or Mucorales remains plausible.

1Use isavuconazole 200 mg intravenously or orally every eight hours for six doses, then 200 mg once daily for susceptible invasive aspergillosis, considering its QT-shortening effect.
2Use liposomal amphotericin B 3 to 5 mg/kg intravenously every 24 hours when azole resistance, pregnancy, severe interaction or possible mucormycosis favours a polyene.
3EscalationFor breakthrough during a triazole, verify adherence and level, obtain tissue and susceptibility, and switch drug class rather than simply escalating the same agent blindly.
4Reserve combination therapy or an echinocandin-containing salvage regimen for selected refractory disease under expert mycology care; echinocandin monotherapy is not standard primary treatment.

04CHRONICManage chronic pulmonary aspergillosisSymptoms and progressive cavities, nodules or pleural change persist for at least three months with Aspergillus evidence.

1Exclude active tuberculosis, non-tuberculous mycobacteria, malignancy and another cavitating disorder, then discuss complex disease with a specialist aspergillosis or respiratory service.
2Use oral itraconazole or voriconazole for progressive or symptomatic chronic disease, with susceptibility, interaction review and therapeutic drug monitoring.
3Treat for at least six months and often longer; compare symptoms, weight, inflammatory markers, IgG and interval CT rather than expecting rapid radiological normalisation.
4For significant haemoptysis, stabilise the airway and circulation, stop aggravating anticoagulation when appropriate and involve interventional radiology for embolisation plus thoracic surgery for selected resectable disease.

05ALLERGICControl allergic bronchopulmonary aspergillosisAsthma or cystic fibrosis is accompanied by Aspergillus sensitisation, raised IgE, eosinophilia and characteristic mucus or bronchiectasis.

1Confirm the phenotype using total and Aspergillus-specific IgE, eosinophils, imaging and respiratory function rather than treating a positive sputum culture alone.
2Use a specialist-directed systemic corticosteroid course for an acute exacerbation while optimising inhaled asthma or cystic-fibrosis care.
3Add itraconazole or another triazole when fungal burden reduction or corticosteroid sparing is required, with exposure monitoring and interaction review.
4Follow total IgE trend, symptoms, exacerbations, lung function and imaging; a rising IgE plus clinical decline suggests relapse.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

First-line treatment for invasive aspergillosis and a specialist option for chronic pulmonary disease.

Voriconazole

Give 6 mg/kg intravenously every 12 hours for two doses, then 4 mg/kg intravenously every 12 hours; oral loading above 40 kg is 400 mg every 12 hours for two doses, then usually 200 mg every 12 hours.

Use therapeutic drug monitoring; check liver toxicity, visual or neurotoxicity, photosensitivity, skin cancer risk, QT prolongation, CYP2C19 variability and extensive drug interactions.

Alternative primary therapy for susceptible invasive aspergillosis when voriconazole toxicity or interaction is problematic.

Isavuconazole

Give 200 mg intravenously or orally every eight hours for six doses over 48 hours, followed by 200 mg once daily starting 12 to 24 hours after the last loading dose.

It shortens rather than prolongs QT and is contraindicated in familial short-QT syndrome; review liver function, pregnancy and CYP3A4 interactions and consider exposure monitoring.

Alternative primary or salvage treatment, particularly with azole resistance, pregnancy or possible Mucorales.

Liposomal amphotericin B

Give 3 to 5 mg/kg intravenously every 24 hours for invasive mould disease, selecting the exact dose by organism, site and local mycology protocol.

Monitor creatinine, potassium, magnesium, blood count and infusion reactions; formulations are not interchangeable and renal toxicity accumulates.

Long-term oral treatment for chronic pulmonary aspergillosis and steroid-sparing therapy in selected allergic disease.

Itraconazole

For chronic pulmonary or allergic disease, use a specialist formulation-specific regimen commonly equivalent to 200 mg orally twice daily after loading, adjusted to measured exposure.

Capsules, solution and super-bioavailable formulations are not directly interchangeable; monitor levels, liver, heart failure risk, neuropathy, QT and major CYP3A4 interactions.

Mould-active prophylaxis in defined high-risk haematology populations and specialist salvage treatment.

Posaconazole modified-release

For selected prophylaxis or salvage use, give 300 mg orally twice on day one, then 300 mg once daily from day two, with therapeutic drug monitoring.

Do not substitute the oral suspension regimen; check liver tests, QT, absorption, levels and interactions with tacrolimus, ciclosporin, sirolimus and anticancer medicines.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Massive haemoptysis

Fungal-ball movement or chronic cavity erosion damages fragile bronchial vessels, causing recurrent or catastrophic airway bleeding.

Cerebral dissemination

Angioinvasive haematogenous spread causes brain abscesses, infarction, haemorrhage, seizures and focal neurological deficits with high mortality.

Respiratory failure

Progressive pulmonary infarction, consolidation, airway obstruction or chronic destruction can produce severe hypoxaemia and ventilatory failure.

Endovascular disease

Valve, graft or myocardial infection causes large vegetations, emboli and persistent disease requiring combined antifungal and surgical management.

Bronchiectatic progression

Repeated allergic inflammation and mucus plugging cause irreversible central bronchiectasis, recurrent respiratory infection and declining lung function.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Assess fever, oxygen need, haemoptysis, neurological findings, weight and functional recovery; sudden decline may reflect bleeding, immune recovery or dissemination.
Repeat CT after an interval appropriate to severity, commonly around two weeks in invasive disease unless earlier deterioration requires imaging; lesions can enlarge initially during neutrophil recovery.
Measure voriconazole, itraconazole and posaconazole exposure after steady state and whenever dose, adherence, formulation, organ function or interacting medicines change.
Monitor liver tests and ECG with triazoles and renal function, potassium and magnesium with amphotericin; document visual, neurological and photosensitivity adverse effects.
Reassess immune suppression and prophylaxis with haematology or transplant teams, balancing fungal control against graft rejection or malignancy treatment.
For chronic disease, track symptoms, weight, CRP, Aspergillus IgG and serial CT over months and maintain a haemoptysis action plan.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

A culture is not a phenotype

Aspergillus in sputum may mean contamination, colonisation, allergy, chronic infection or invasion; host, imaging, serology and tissue determine its meaning.

Halo is not exclusive

Ground-glass surrounding a nodule represents haemorrhage and supports angioinvasion in the right host, but other infections and malignancy can reproduce it.

Air crescent can be late

Cavitation and an air-crescent sign often appear during neutrophil recovery, so waiting for them misses earlier treatable disease.

Therapeutic levels matter

Triazole absorption and metabolism vary widely, while underexposure drives failure and overexposure causes toxicity; measured concentrations turn dosing into controlled therapy.

Haemoptysis needs a plan

Antifungals rarely control life-threatening bleeding quickly; airway protection, bronchial-artery embolisation and selected surgery are separate lifesaving interventions.

11Common pitfallsFrequent interpretation and management errors.

01
Do not call every positive Aspergillus sputum culture invasive disease, and do not dismiss growth as colonisation in a profoundly immunocompromised host.
02
Do not rely on a normal chest radiograph when invasive disease is plausible; obtain CT promptly.
03
Do not wait for biopsy or culture before treating a strongly suspected angioinvasive presentation.
04
Do not use voriconazole without reviewing transplant, oncology, anticoagulant, anticonvulsant and QT-active medicines or arranging drug-level monitoring.
05
Do not use an echinocandin alone as routine primary treatment of invasive aspergillosis.
06
Do not treat a simple stable asymptomatic aspergilloma like invasive infection; symptoms, bleeding risk and surgical fitness determine management.