Aspergillosis

• Aspergillus is a mould you breathe in every day; it usually does nothing, but in the right host it becomes a disease with a very wide spectrum.
• The same fungus causes radically different illnesses depending on the host: allergy in people with asthma or cystic fibrosis, a cavity-dwelling aspergilloma in old damaged lungs, chronic pulmonary aspergillosis in people who are not strongly immunocompromised but have bad lungs, and invasive aspergillosis in people whose neutrophils or cell-mediated immunity are failing.
• There is no "antifungal for aspergillosis" that fits all patients. Allergic disease is treated with steroids and itraconazole; a fungal ball that bleeds is removed surgically; invasive disease is treated first with voriconazole or isavuconazole.
• Diagnosis rests on imaging plus the right test for the right syndrome: galactomannan for invasive disease, Aspergillus IgG for chronic disease, total and Aspergillus-specific IgE for allergic disease.
• Invasive aspergillosis still carries significant mortality, so think of it early in febrile neutropenia and in transplant recipients, and start treatment before the diagnosis is proved.

By the end of this page you should be able to:

1. List the main clinical forms of aspergillosis and say which host and mechanism produces each.
2. Recognise the halo sign and the air-crescent sign on CT, and know what each tells you about the patient.
3. Explain what galactomannan, beta-D-glucan, culture, Aspergillus IgG, precipitins and Aspergillus-specific IgE each measure, and which syndrome each is best for.
4. Describe the hyphae of Aspergillus in tissue and why histology alone cannot name the species.
5. Choose first-line therapy for invasive pulmonary aspergillosis, chronic cavitary pulmonary aspergillosis, aspergilloma and allergic bronchopulmonary aspergillosis, with doses and duration.
6. Outline antifungal prophylaxis for neutropenic and transplant patients.
7. Recognise a patient with aspergilloma bleeding and know when surgery is indicated.
8. State how diagnosis and treatment change when CT, microbiology laboratories or antifungal drugs are not available.

Not every patient who inhales conidia gets disease, and the same fungus produces very different illnesses. A useful way to think about aspergillosis is by the host's immune response rather than by the fungus:

• Normal or immunocompetent host with damaged lungs: colonisation of a pre-existing cavity, producing an aspergilloma (a fungal ball) or chronic pulmonary aspergillosis.
• Atopic or allergic host: a hypersensitivity reaction to colonising fungus, producing allergic bronchopulmonary aspergillosis (ABPA) or allergic fungal rhinosinusitis.
• Immunocompromised host with neutropenia or T-cell defect: true invasive disease, with tissue invasion and angioinvasion.

One species can also disseminate and cause sinus, cerebral, cardiac, bone, skin or renal disease. Tracheobronchial aspergillosis is a further syndrome on the spectrum between colonisation and invasion, mostly in lung transplant recipients.

Aspergillus species are ubiquitous, so exposure is universal. Many serious fungal diseases, including aspergillosis, are estimated to cause a large global burden, but country-specific figures are scarce and disease counts are often derived from modelling rather than registration. Invasive aspergillosis occurs mainly in hospitalised patients with prolonged neutropenia, haematopoietic stem cell transplantation or solid organ transplantation, especially lung transplantation, and in patients receiving high-dose corticosteroids or biologics that impair T-cell function. Chronic and allergic forms affect far larger numbers than invasive disease and are a major cause of morbidity outside hospitals.

Risk is therefore driven more by host factors than by geography: the patients you will see are the ones with neutropenia after induction or re-induction therapy for acute leukaemia, allogeneic haematopoietic stem cell transplant recipients, lung transplant recipients, patients with severe or protracted neutropenia after chemotherapy, and patients on prolonged high-dose cort (steroid) therapy.

There is no modifiable lifestyle risk for invasive aspergillosis. The risk factors are those that remove the defences that normally clear inhaled conidia in the terminal airways: alveolar macrophages in health and neutrophils during infection. The classical high-risk groups are:

• prolonged neutropenia, especially an absolute neutrophil count below roughly 500 cells per microlitre for more than a week, after induction or re-induction for acute leukaemia;
• allogeneic haematopoietic stem cell transplantation, particularly early after conditioning and during treatment of graft-versus-host disease;
• solid organ transplantation, especially lung (because the lung is exposed to inhaled antigen continuously) and heart;
• inherited or acquired immunodeficiency affecting phagocytes or T-cells, such as chronic granulomatous disease;
• high-dose corticosteroids (equivalent to more than 1 mg/kg/day prednisone for more than two weeks) and T-cell-suppressive or depleting drugs;
• reactivation of the risk from influenza or severe COVID-19, where influenza-associated and COVID-19-associated pulmonary aspergillosis are now recognised syndromes.

Chronic and allergic forms have different predispositions. Chronic pulmonary aspergillosis usually develops in damaged lung: post-tuberculosis cavities (especially in high-burden regions), bronchiectasis, chronic obstructive lung disease or prior lung surgery. ABPA occurs almost only in people with asthma or cystic fibrosis.

In health, inhaled conidia that reach the distal airways are swallowed by alveolar macrophages. When macrophage or neutrophil function fails, conidia germinate and hyphae grow into tissue and vessels. Angioinvasion, especially of small pulmonary arteries, produces thrombosis and infarction of wedge-shaped lung, which is why IPA presents with nodules and pleuritic pain and why early CT shows a halo of haemorrhage around a central infarct. The reverse process is also clinically important: as neutrophils recover, immune recognition of fungal antigen drives inflammation and an air-crescent forms between the healing lesion and collapsing necrotic tissue, usually two to three weeks into treatment.

In allergic disease the fungus is not invading at all. Colonisation of the airways with A. fumigatus in a patient with asthma triggers IgE- and eosinophil-mediated inflammation, mucus plugging and central or proximal bronchiectasis. Total IgE and Aspergillus-specific IgE rise. Chronic granulomatous and saprophytic forms, where the fungus grows in an old cavity without true tissue invasion, produce localised mass effect and recurring haemoptysis.

Fever that does not respond to broad-spectrum antibacterial therapy in a febrile neutropenic patient is the classic trigger. Early, the patient may have no localising signs at all, which is why a chest CT should be obtained whenever invasive aspergillosis is a real possibility, irrespective of the chest radiograph. With progression: cough, pleuritic chest pain, dyspnoea, haemoptysis, and neurological, visual or sinus symptoms if angioinvasive disease has seeded elsewhere. Distinctive syndromes include invasive Aspergillus sinusitis (pain, fever, nasal discharge, epistaxis) with a risk of orbital or intracranial extension, tracheobronchial disease with ulceration and pseudomembranes in transplant recipients, and cerebral disease with ring-enhancing lesions.

This creeps in over months: weight loss, chronic cough, sputum, fatigue and haemoptysis that is often large. Many patients are malnourished and have fibrosis on examination. The clinical picture overlaps with tuberculosis and lung cancer, and many patients previously had tuberculosis; distinguishing them is one of the recurring diagnostic problems in high-burden regions.

The majority are found on imaging done for another reason. Haemoptysis is the presentation that matters because it can be massive and sudden, from erosion into a bronchial or systemic artery. The classic chest sign is a dense, mobile, intracavitary mass with a crescent of air around it; it shifts when the patient changes position.

Wheezing that does not respond to asthma treatment, brown or black mucus plugs expectorated, recurrent "flares" with fleeting pulmonary infiltrates and raised total IgE. Symptoms may be surprisingly modest relative to the immunological activity, and bronchiectasis can develop silently, so screening matters in poorly controlled asthma and in cystic fibrosis.

The main traps are:

• Bacterial or viral pneumonia and sepsis in neutropenic patients; fever, antibiotic-refractory, with nodular CT rather than lobar consolidation.
• Mucormycosis and other moulds: clinically and radiologically similar, but mucormycosis is more often associated with the reverse halo sign, tissue infarction and diabetic ketoacidosis.
• Tuberculosis and lung cancer, which mimic chronic cavitary aspergillosis; both can also cavitate and both can produce haemoptysis.
• Thrombus, tumour or other mural mass when imaging suggests a fungal ball; a mobile intracavitary mass in an old cavity with a positive Aspergillus IgG is almost diagnostic of aspergilloma.
• Vasculitis (such as granulomatosis with polyangiitis) or eosinophilic pneumonia, which mimic ABPA.
• Invasive sinus disease may look like bacterial sinusitis early; think again if the patient is immunocompromised, the disease is rapidly progressive, or there is vascular or orbital involvement.

Chest CT should be performed whenever invasive pulmonary aspergillosis is suspected, whatever the chest radiograph shows. Early invasive disease classically shows nodules, consolidation or wedge-shaped infarcts; a halo sign (a nodule surrounded by ground-glass opacity representing haemorrhage) is especially common in neutropenic patients. An air-crescent sign or cavity within a mass usually appears later, often as neutrophils recover, and implies a better prognosis. Pleural effusions are uncommon; look hard for disease outside the lungs when the host is profoundly immunocompromised. Contrast is not routinely needed, but should be used when a nodule lies close to a large vessel.

In ABPA and chronic aspergillosis, CT shows the airway and cavity disease described above, including high-attenuation or hyper-dense mucus, which is highly suggestive of ABPA.

Specimens should go for histopathology and culture at the same time. In tissue, Aspergillus shows narrow, septate hyphae that branch at an acute angle of about 45 degrees. ^[2] Histology alone cannot confirm the species, and cannot distinguish Aspergillus from other filamentous fungi such as Fusarium and Scedosporium in tissue; culture or molecular confirmation is needed. Aspergillus species grow well on most fungal media after two to five days, but culture yield is low, and a negative culture does not exclude invasive aspergillosis. ^[1]

• Galactomannan (GM), a polysaccharide released by growing Aspergillus, is measured in serum and in bronchoalveolar lavage fluid. Serum and bronchoalveolar lavage GM is recommended as an accurate marker in patients with haematological malignancy or stem cell transplantation. It is not recommended for routine screening in solid organ transplant recipients, chronic granulomatous disease, or in patients receiving mould-active antifungal therapy or prophylaxis, though it can still be applied to bronchoalveolar lavage samples. GM cross-reacts with other fungi that produce related polysaccharides (for example Histoplasma and Fusarium), so interpret it in context.
• Beta-D-glucan is recommended in high-risk patients (haematological malignancy, allogeneic stem cell transplantation) to support a diagnosis of invasive fungal infection. It is not specific for Aspergillus, and false-positives occur; it is also negative in Mucorales infection and cannot be used to define definite invasive aspergillosis on its own.
• Culture provides species identification and antifungal susceptibility testing, which is essential when treatment is failing, in azole-exposed environments and in salvage settings.
• Molecular tests (PCR) are useful but debated; there is no current recommendation for routine blood-based PCR because assays have not been conclusively validated. When PCR is used, it should be interpreted alongside imaging, antigen testing and clinical findings.

• Aspergillus IgG is the cornerstone test for chronic pulmonary aspergillosis and supports aspergilloma.
• Aspergillus-specific and total IgE establish the diagnosis of ABPA and are useful for screening in asthma and cystic fibrosis. ^[1]
• Precipitating antibodies (Aspergillus precipitins) support chronic and allergic disease; together with elevated IgE they point to hypersensitivity rather than invasion.

Bronchoscopy with bronchoalveolar lavage should be performed when invasive pulmonary aspergillosis is suspected, in patients well enough to tolerate it, with a standardised lavage sent for routine culture, mycology and GM. The yield is low for peripheral nodular lesions, so percutaneous or endobronchial biopsy may be needed. Echocardiography and CT of the sinuses and brain are added when extrapulmonary disease is suspected.

The EORTC and Mycoses Study Group (MSG) consensus criteria define "possible", "probable" and "proven" invasive fungal disease using host factors, imaging and microbiology; proven infection requires histopathology or a positive culture from a sterile site. Use these criteria to think clearly, but remember they are consensus definitions, not a bedside protocol.

Chronic cavitary pulmonary aspergillosis requires about three months of chronic pulmonary symptoms or progressive radiographic abnormality, with cavitation, pleural thickening and often pericavitary infiltrates, plus an elevated Aspergillus IgG or other microbiological evidence, and little or no immunocompromise, usually with underlying lung disease. Simple asymptomatic single aspergilloma, where there is no progression over six to twenty-four months, can be observed. ^[1]

ABPA is diagnosed in a patient with asthma or cystic fibrosis, with immediate hypersensitivity to Aspergillus fumigatus, elevated total and Aspergillus-specific IgE, positive precipitins or IgG, and central or proximal bronchiectasis. The revised ISHAM ABPA working group criteria are the current international standard for diagnosis and classification.

Primary treatment of invasive pulmonary aspergillosis is voriconazole (strong recommendation, high-quality evidence): 6 mg/kg intravenously every 12 hours for the first day, then 4 mg/kg intravenously every 12 hours; oral treatment 200 to 300 mg every 12 hours is used once stable, with weight-based dosing in children. Early initiation of antifungal therapy is warranted whenever invasive aspergillosis is strongly suspected, while the diagnostic evaluation is running, because delay worsens outcome. ^[1]

Alternatives as primary therapy are isavuconazole (200 mg every 8 hours for six doses, then 200 mg daily) and liposomal amphotericin B (3 to 5 mg per kg daily intravenously); standard amphotericin B deoxycholate is retained for resource-limited settings where no alternative is available. An echinocandin alone is not recommended for primary therapy, but caspofungin and micafungin are useful in settings where azoles and polyenes are contraindicated, and combination therapy (voriconazole plus an echinocandin) can be considered in selected patients with documented disease. ^[1]

Adjuvant measures matter greatly: reduce or remove immunosuppression when this is clinically feasible; colony-stimulating factors may be considered in neutropenia. The duration is a minimum of 6 to 12 weeks, guided by the degree and duration of immunosuppression, the site of disease and evidence of response. Serial monitoring of serum galactomannan in haematology or stem-cell patients with a baseline raised value helps to track response and prognosis. If an echinocandin is used as salvage, micafungin (100 to 150 mg daily) or caspofungin (70 mg on day one, then 50 mg daily) are the listed regimens. ^[1]

For extrapulmonary disease the first-line agent is still voriconazole in most sites, including central nervous system, sinus, bone, heart, kidney, eye, cutaneous and gastrointestinal aspergillosis, with surgery when the disease is localised or debridement is feasible.

When the patient is not responding, take an individualised approach: exclude a new pathogen, reconsider the azole level (drug interactions, absorption and suboptimal exposure are common), reduce immunosuppression, consider surgical resection of necrotic foci, add or switch to an agent from a different class, and obtain susceptibility testing where possible. Suspected or documented azole resistance is a growing problem and requires specialist advice.

Patients with chronic cavitary disease but no significant symptoms, no weight loss and no loss of lung function can be observed closely, every three to six months. Symptomatic patients or those with progressive disease should receive at least six months of oral therapy with itraconazole or voriconazole as the preferred oral agents, and posaconazole as a useful third-line choice if there is failure or intolerance. Further courses or even lifelong therapy may be needed; monitor for triazole toxicity, resistance and drug interactions. Haemoptysis may be managed with tranexamic acid or bronchial artery embolisation, with antifungal therapy to prevent recurrence; patients who fail these measures, or with pan-azole-resistant disease, may need surgical resection, although outcomes are less good than for single aspergilloma.

Asymptomatic patients with a single aspergilloma that has not grown over six to twenty-four months can be observed. Patients with symptoms, especially significant haemoptysis, with a single aspergilloma and no contraindication should have the lesion resected. Peri- and postoperative antifungal therapy is not routinely required, but is suggested when the risk of operative spillage is moderate, to prevent Aspergillus empyema.

Treatment of allergic forms is directed at immunological disease rather than infection. Corticosteroids are a cornerstone for exacerbations. For asthmatic patients with bronchiectasis or mucoid impaction despite inhaled or oral corticosteroid therapy, oral itraconazole with therapeutic drug monitoring is suggested, because it has a demonstrable corticosteroid-sparing effect. In cystic fibrosis, itraconazole is suggested in patients with frequent exacerbations or a falling FEV1, with the aim of minimising steroid use. Therapeutic drug monitoring is recommended after steady state for patients on prolonged triazole therapy. Allergic fungal rhinosinusitis is managed primarily with polypectomy and sinus washout plus topical nasal steroids; oral antifungals are used for refractory or frequently relapsing disease. ^[1]

Primary prevention targets the highest-risk groups and is itself an IDSA strong recommendation:

• During prolonged neutropenia, prophylaxis with posaconazole (strong), voriconazole (moderate) or micafungin (weak) is recommended in high-risk patients; itraconazole is effective but limited by absorption and tolerability. Aerosolised amphotericin B may be considered in prolonged neutropenia and in lung transplant recipients. ^[1]
• In allogeneic stem cell transplant recipients with graft-versus-host disease, prophylaxis with posaconazole is recommended, continuing throughout the period of immunosuppression (corticosteroid equivalent above 1 mg/kg/day prednisone for more than 2 weeks, or other anti-graft-versus-host disease therapies). ^[1]
• In lung transplant recipients, prophylaxis with a systemic triazole (voriconazole or itraconazole) or inhaled amphotericin B is recommended for 3 to 4 months after transplantation, longer if there is colonisation, infection in the explant or recent high-dose immunosuppression. ^[1]
• Solid organ transplant recipients other than lung should receive individualised prophylaxis based on institutional epidemiology and personal risk factors (pre-transplant colonisation, re-operation, cytomegalovirus infection, renal dysfunction).

Empirical antifungal therapy is recommended in high-risk patients with prolonged neutropenia who remain persistently febrile despite broad-spectrum antibiotics (liposomal amphotericin B, caspofungin or micafungin, or voriconazole); it is not recommended when neutropenia is expected to last less than ten days unless there are other suspicious findings. A biomarker-driven (pre-emptive) approach can reduce unnecessary antifungal use without worsening survival. ^[1]

Invasive disease: respiratory failure, pleural effusion or empyema, haemoptysis, central nervous system seeding (brain abscess, stroke), vertebral or rib osteomyelitis, and endocarditis on prosthetic or damaged valves. Mortality remains substantial even with modern therapy and depends largely on recovery from neutropenia. ABPA: progressive bronchiectasis, mucus plugging and respiratory failure if untreated. Aspergilloma: massive, sometimes fatal haemoptysis. Chronic aspergillosis: progressive fibrosis, respiratory failure, long-term steroid and antifungal exposure.

Outcome is driven by reversibility of the underlying immunosuppression more than by the choice of antifungal. Successfully treated invasive aspergillosis does not have to be permanent: secondary prophylaxis is advised whenever further chemotherapy or transplantation is required. Recovery of neutrophils is the milestone that changes the picture from necrosis and potential disaster to the healing phase with its air-crescent sign.

Low-cost measures reduce exposure in high-risk patients: protected environments for allogeneic transplant recipients (and reasonable application in other highly immunocompromised patients), private rooms, no plants or cut flowers, no connection to construction sites, and avoidance of gardening, compost spreading and renovation exposures in outpatients. Transplant and leukaemia centres should monitor their baseline incidence of invasive mould disease, because a rise or a case in a non-classical patient implies a hospital source that must be found.

For allergic forms, the "prevention" is earlier screening: test total and Aspergillus-specific IgE in poorly controlled asthma and in cystic fibrosis, and monitor FEV1 and imaging, so that bronchiectasis is detected before it is established.

Children. Paediatric aspergillosis is treated with the same drug classes as in adults, but dosing differs and for some agents is not defined; voriconazole and caspofungin in particular have paediatric-specific doses. Invasive forms in adolescents with cystic fibrosis or leukaemia should be managed in specialist centres. ^[1]

Pregnancy and breastfeeding. The triazoles are generally avoided or used with caution in pregnancy and many are associated with fetal risk; the decision between amphotericin formulations and the timing of therapy must be made jointly with obstetric, infectious disease and respiratory teams. Wording on drug safety should be checked against current product information.

Solid organ transplant recipients. Lung transplant carries the highest risk and warrants aggressive screening and prophylaxis. Cardiac, liver and other recipients need individualised strategies based on institutional epidemiology and personal risk factors.

People with chronic granulomatous disease. Aspergillus is a particular threat; recombinant interferon-gamma is recommended as prophylaxis in this group.

• Amphotericin B deoxycholate is retained specifically for settings where no alternative agent is available; lipid formulations and the newer triazoles should be used where they exist, but deoxycholate is life-saving when they are not.
• Many of the recommendations above assume technology (CT, PCR, drug levels) that is not universally available. A transthoracic approach and bedside skills still carry weight: in a febrile neutropenic patient, a new respiratory symptom should be taken seriously, imaging obtained wherever possible and empirical therapy started without waiting for proof.
• Chronic pulmonary aspergillosis and aspergilloma are in practice diseases of regions with a heavy tuberculosis burden, because post-tuberculosis cavities are their most common substrate; when CT is unavailable, recurrent or massive haemoptysis in such a patient should prompt consideration of an aspergilloma and referral for surgical or bronchial artery intervention where possible.
• ABPA can be managed where total and Aspergillus-specific IgE assays are available; where they are not, diagnosis is clinical and treatment may need to be empirical and corticosteroid-directed, with a low threshold to involve specialist help.
• Antifungal susceptibility testing and therapeutic drug monitoring are often out of reach. In that environment, weight-based dosing, attention to drug interactions (especially antituberculous drugs, antiretrovirals and immunosuppressants) and early referral for failing patients take on greater importance, and care should follow the drug's product information and national formulary.

• Aspergillosis is a syndrome spectrum determined by the host, not a single disease.
• The same inhaled mould causes allergy in the atopic, colonises damaged cavities, causes chronic disease in damaged lungs, and invades when neutrophils or T-cells fail.
• Think of it early: a neutropenic patient with fever not responding to antibiotics needs a chest CT and, often, early empirical antifungal therapy.
• Halo sign on CT in neutropenia is early invasive aspergillosis; an air-crescent is a later, recovery-associated sign with a better outlook.
• Hyphae of Aspergillus in tissue are narrow, septate and branch at about 45 degrees, but histology does not prove species or distinguish Aspergillus from other septate moulds.
• Galactomannan is the marker for invasive disease; beta-D-glucan is supportive but non-specific; Aspergillus IgG and precipitins point to chronic and allergic disease; Aspergillus-specific and total IgE point to ABPA.
• Voriconazole is first-line for invasive pulmonary aspergillosis and runs for at least 6 to 12 weeks; isavuconazole and liposomal amphotericin B are the alternatives.
• Aspergilloma, chronic cavitary disease and ABPA are treated differently: surgery for the bleeding fungal ball, oral itraconazole or voriconazole for chronic cavitary disease, steroids plus itraconazole for ABPA.
• Amphotericin B deoxycholate is retained for resource-limited settings.
• Prophylaxis in prolonged neutropenia and transplant care uses posaconazole, voriconazole, micafungin or inhaled amphotericin B depending on the patient group.
• Invasive outcome tracks immune recovery more than it tracks drug choice; reduce immunosuppression where you can.

Pneumonia; Bronchiectasis; Tuberculosis; Asthma; Cystic fibrosis; Febrile neutropenia; Haematopoietic stem cell transplantation; Lung transplantation; Diagnostic imaging of the chest; Fungal infections; Antifungal drugs.

References live in the front matter: the IDSA practice guidelines for the diagnosis and management of aspergillosis (2016 update, cited as Ref 1) and a current review of pulmonary mycoses (cited as Ref 2).