Invasive Pulmonary Aspergillosis
Also known as: Invasive Aspergillosis, IPA, COVID Associated Pulmonary Aspergillosis
Invasive pulmonary aspergillosis is angioinvasive or airway invasive infection of the lung by Aspergillus, usually Aspergillus fumigatus, in an immunocompromised or critically ill host. It is the commonest form of invasive aspergillosis and the leading mould infection in patients with prolonged neutropenia.
Without treatment mortality is near 100 percent. With modern therapy, 12 week mortality is 25 to 50 percent depending on the host. It is higher in allogeneic stem cell transplant recipients with graft versus host disease, patients with persistent neutropenia, patients on mechanical ventilation, and in influenza and COVID-19 associated disease.
| Group | Details |
|---|---|
| Prolonged severe neutropenia | Neutrophil count below 500 cells per microlitre for more than 10 days; acute myeloid leukaemia and myelodysplastic syndrome with induction chemotherapy |
| Allogeneic haematopoietic stem cell transplant | Neutropenia before engraftment, and later graft versus host disease treated with corticosteroids and other immunosuppression |
| Solid organ transplant | Lung transplant (highest risk, with airway colonisation), heart, liver, and kidney |
| Corticosteroids | Prednisolone equivalent of 0.3 mg per kg daily for 3 weeks or longer |
| Other immunosuppressants and targeted agents | Ibrutinib, ruxolitinib and other Janus kinase inhibitors, alemtuzumab, anti tumour necrosis factor agents, fludarabine, and tacrolimus in transplant |
| Chronic granulomatous disease and other inborn errors | NADPH oxidase defect; Aspergillus nidulans and Aspergillus fumigatus |
| Critically ill patients | Severe influenza (influenza associated pulmonary aspergillosis), severe COVID-19 (COVID-19 associated pulmonary aspergillosis), chronic obstructive pulmonary disease with corticosteroids, decompensated cirrhosis, severe burns, and prolonged intensive care stays |
| HIV | Rare, with advanced disease and CD4 count below 100 cells per microlitre, or with neutropenia and steroids |
| Construction and environmental exposure | Hospital construction, contaminated ventilation |
| Genetic polymorphisms | Toll like receptor, dectin 1, and plasminogen variants, in transplant |
Inhaled conidia reach the alveoli and germinate when they are not cleared. In neutropenia, hyphae invade the lung parenchyma and blood vessels, causing thrombosis, haemorrhagic infarction, necrosis, and haematogenous dissemination to brain, skin, eye, and other organs.
In non neutropenic patients (corticosteroid treated, critically ill, and influenza or COVID-19 patients), disease is more often airway invasive, with tracheobronchitis and bronchopneumonia, with less angioinvasion and a stronger inflammatory response. Viral injury of the respiratory epithelium and local immune dysregulation, together with corticosteroids and tocilizumab, explain the high risk in severe influenza and COVID-19.
- Persistent fever despite 4 to 7 days of broad spectrum antibacterials in a neutropenic patient, which is often the only sign early.
- Cough, dyspnoea, and pleuritic chest pain (pulmonary infarction), and haemoptysis, which can become massive when cavities form as the neutrophil count recovers.
- Tracheobronchitis: ulcerative or pseudomembranous airway disease, with cough, wheeze, stridor, and obstruction, in lung transplant (anastomosis), AIDS, and severe immunosuppression.
- Non neutropenic and critically ill patients: nonspecific deterioration, failure to wean from ventilation, and fever with new infiltrates, easily attributed to bacterial pneumonia.
- Dissemination: brain (focal deficits, seizures, stroke, and abscess), skin (necrotic nodules), eye, sinuses, kidney, liver, and bone.
| Pattern | Setting and meaning |
|---|---|
| Halo sign (nodules or masses with surrounding ground glass attenuation) | Early in neutropenic patients (first days), caused by haemorrhage; supports the diagnosis if present within 5 days of symptoms; not specific |
| Dense, well circumscribed nodules or masses with or without halo | A criterion for probable disease |
| Air crescent sign and cavitation | Later, as neutrophils recover, indicating necrotic lung separating from viable lung; associated with a risk of haemoptysis |
| Wedge shaped, pleural based consolidation | Pulmonary infarct |
| Reverse halo (atoll) sign | More typical of mucormycosis, and seen also in Aspergillus |
| Peribronchial consolidation, tree in bud, and bronchial wall thickening | Airway invasive disease and tracheobronchitis |
| Non specific consolidation or ground glass | Typical in influenza and COVID-19 associated disease, so imaging helps little |
Computed tomography is the imaging method of choice, and chest radiography is insensitive. Radiological progression in the first 1 to 2 weeks of effective therapy, particularly at neutrophil recovery, can reflect immune reconstitution and does not by itself mean failure.
Consensus definitions for research and clinical practice (European Organisation for Research and Treatment of Cancer and the Mycoses Study Group) classify disease as proven, probable, or possible.
| Category | Requirements |
|---|---|
| Proven | Histopathology or cytology showing hyphae with tissue damage, or culture from a normally sterile site (lung biopsy, pleural fluid) |
| Probable | Host factor, a compatible clinical and radiological picture, and mycological evidence (galactomannan, culture, or polymerase chain reaction) |
| Possible | Host factor and compatible findings, without mycological evidence |
Separate consensus definitions exist for influenza associated pulmonary aspergillosis and COVID-19 associated pulmonary aspergillosis, with proven, probable, and possible categories that rely on bronchoalveolar lavage galactomannan and culture, tracheobronchial lesions, or biopsy.
| Test | Performance and caveats |
|---|---|
| Serum galactomannan | Sensitivity about 70 to 80 percent in haematological malignancy and lower (about 40 to 50 percent) in non neutropenic patients; positive at an optical density index of 1.0 or above (or 0.7 or above in two samples) in current criteria, and 0.5 in the manufacturer's cutoff; false negatives with mould active prophylaxis and short disease; false positives with some beta lactam preparations and plasma expanders, intravenous immunoglobulin, and cross reaction with Fusarium, Histoplasma, Penicillium, and Talaromyces |
| Bronchoalveolar lavage galactomannan | Sensitivity about 85 to 90 percent and specificity about 90 percent at index 1.0; the best non invasive test, especially in non neutropenic patients |
| Aspergillus polymerase chain reaction (blood, serum, or lavage) | Sensitivity about 80 to 88 percent for blood and higher for lavage when two consecutive positives are required; adds sensitivity when combined with galactomannan |
| Aspergillus lateral flow device | Point of care test with sensitivity of 80 to 90 percent on lavage; limited data on serum |
| Beta D glucan | Panfungal marker; not specific for Aspergillus; a negative test makes invasive mycosis less likely |
| Culture of respiratory specimens | Sensitivity about 40 to 60 percent in neutropenic patients and lower in others; a positive result in a high risk patient with a compatible radiological picture is significant, but in a non immunocompromised patient it is colonisation |
| Direct microscopy of respiratory specimens | Septate hyphae with acute angle branching supports invasion in a high risk host |
| Bronchoscopy | Lavage for galactomannan, culture, and polymerase chain reaction; inspection for tracheobronchitis; transbronchial biopsy where safe |
| Percutaneous or surgical lung biopsy | Gold standard where safe (platelets and coagulation permitting); a diagnosis of proven disease |
| Serial galactomannan monitoring | Twice weekly screening in high risk patients without mould active prophylaxis; response monitoring |
| Resistance testing | cyp51A polymerase chain reaction or sequencing, and phenotypic susceptibility of the culture isolate |
Sputum and nasal swab cultures positive for Aspergillus are very common, and a single positive culture is not proof of invasive disease.
| Condition | Points that separate it |
|---|---|
| Mucormycosis | Reverse halo, sinus and orbit involvement, ketoacidosis, voriconazole prophylaxis, broad aseptate hyphae at 90 degrees, negative galactomannan |
| Fusariosis | Positive blood culture, skin lesions, hyaline moulds with crescent shaped macroconidia |
| Scedosporiosis and lomentosporiosis | Resistant to amphotericin B and often azoles; submerged conidia |
| Bacterial pneumonia, including Nocardia and Pseudomonas | Culture and response to antibacterials |
| Tuberculosis and non tuberculous mycobacterial infection | Acid fast bacilli |
| Pneumocystis jirovecii pneumonia | Diffuse ground glass, positive polymerase chain reaction |
| Cryptococcosis | Antigen |
| Cytomegalovirus and other viral pneumonia | Polymerase chain reaction |
| Pulmonary haemorrhage, drug toxicity, and radiation pneumonitis | Clinical context and bronchoalveolar lavage |
| Lung cancer, lymphoma, and septic emboli | Histology |
First line therapy
| Agent | Dose | Notes |
|---|---|---|
| Voriconazole | 6 mg per kg intravenously every 12 hours for 2 doses, then 4 mg per kg every 12 hours; oral 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (adults 40 kg and above; 100 mg every 12 hours below 40 kg), titrated to levels | Standard first line; improved survival and fewer adverse events than amphotericin B deoxycholate in the pivotal trial; trough level monitoring (1 to 5.5 micrograms per mL), as exposure varies with CYP2C19 genotype |
| Isavuconazonium sulphate | 372 mg (isavuconazole 200 mg) intravenously or orally every 8 hours for 6 doses, then 372 mg once daily | Non inferior to voriconazole in a randomised trial, with fewer hepatic, visual, and skin adverse events; shortens the QT interval; preferred where QT prolongation or interactions limit voriconazole |
| Posaconazole | Delayed release tablets 300 mg twice daily on day 1, then 300 mg once daily; intravenous 300 mg every 12 hours on day 1, then 300 mg daily | Non inferior to voriconazole in a randomised trial; troughs above 1 microgram per mL |
| Liposomal amphotericin B | 3 mg per kg once daily (3 to 5 mg per kg in practice) | Alternative first line, and the choice with suspected azole resistance, or where azoles are contraindicated; a dose of 10 mg per kg gave more toxicity without benefit |
| Voriconazole with anidulafungin | Voriconazole 6 mg per kg every 12 hours for 2 doses then 4 mg per kg every 12 hours, with anidulafungin 200 mg on day 1 then 100 mg once daily, for 2 weeks | Improved 6 week survival in a post hoc analysis of patients with a positive galactomannan, though the primary endpoint at 6 weeks was not significant; used in severe disease and when resistance is possible |
Salvage therapy
- Liposomal amphotericin B 3 to 5 mg per kg daily, after azole failure or resistance.
- Echinocandins: caspofungin 70 mg on day 1 then 50 mg once daily, micafungin 100 to 150 mg once daily, or anidulafungin 200 mg then 100 mg once daily. Echinocandins are fungistatic against Aspergillus, and are used as salvage or with other agents, not alone as first line.
- Posaconazole or isavuconazole where the first azole failed or was not tolerated.
- Itraconazole 200 mg twice daily after loading (400 mg daily) is not preferred in invasive disease because of variable absorption.
- Investigational and new agents include olorofim and fosmanogepix, which have activity against resistant strains and are in late stage trials.
Management of resistance
For suspected or confirmed azole resistant Aspergillus fumigatus, first line therapy is liposomal amphotericin B 5 mg per kg once daily (with or without an echinocandin), and azoles are avoided unless susceptibility is documented. Combination therapy is used in severe disease in settings where azole resistance is frequent.
Duration and response assessment
Treatment lasts a minimum of 6 to 12 weeks, and continues throughout immunosuppression and until lesions have resolved or stabilised on imaging. Response is judged by clinical features, galactomannan trends, and imaging at about 2 weeks, and failure of response or deterioration leads to review of the diagnosis, drug levels, azole resistance, surgical options, and reduction of immunosuppression. Secondary prophylaxis is given in patients who need further chemotherapy or transplantation.
Adjunctive measures
- Reduction of immunosuppression: tapering of corticosteroids and other immunosuppressants where possible.
- Neutrophil recovery: granulocyte colony stimulating factor in neutropenia, and granulocyte transfusions in selected refractory cases, with limited evidence.
- Interferon gamma: in chronic granulomatous disease.
- Surgery: resection of localised lesions in life threatening haemoptysis, lesions abutting major vessels or the pericardium, residual cavitary disease before further chemotherapy or transplant, and chest wall invasion.
- Bronchial artery embolisation: for massive haemoptysis.
- Tracheobronchitis: bronchoscopic debridement may be needed, with nebulised amphotericin B reported as an adjunct.
Adverse effects and monitoring
Voriconazole: liver enzyme elevation, visual disturbance, hallucinations, photosensitivity and phototoxicity with skin cancer on prolonged use, periostitis from fluoride, and QT prolongation, with many interactions (calcineurin inhibitors, sirolimus, vinca alkaloids, and others).
Posaconazole: gastrointestinal upset, hepatotoxicity, QT prolongation.
Isavuconazole: hepatotoxicity, gastrointestinal upset, and shortened QT interval.
Amphotericin B: infusion reactions, nephrotoxicity, hypokalaemia, hypomagnesaemia.
Liver tests and renal function are monitored weekly, and drug levels checked.
Influenza associated pulmonary aspergillosis occurs in about 10 to 20 percent of patients with severe influenza in intensive care, and COVID-19 associated pulmonary aspergillosis in about 10 to 15 percent of ventilated patients with severe COVID-19, with crude mortality about 50 percent or higher.
Risk factors are mechanical ventilation, corticosteroids, interleukin 6 blockade (tocilizumab), chronic obstructive pulmonary disease, haematological malignancy, and liver disease. Presentation is a failure to improve or a deterioration after initial recovery, with tracheobronchitis common in influenza.
Diagnosis relies on bronchoalveolar lavage (galactomannan at 1.0 or above, culture, and polymerase chain reaction) and tracheal aspirate, and serum galactomannan is less sensitive. Treatment is voriconazole or isavuconazole (liposomal amphotericin B where azole resistance is possible), for at least 6 weeks and for the duration of intensive care, with drug monitoring and reduction of corticosteroids where possible.
| Strategy | Details |
|---|---|
| Mould active prophylaxis | Posaconazole delayed release tablets 300 mg twice daily on day 1, then 300 mg once daily, in acute myeloid leukaemia and myelodysplastic syndrome during induction, and in allogeneic transplant with graft versus host disease; alternatives are voriconazole 200 mg twice daily, isavuconazole 372 mg three times daily for 2 days then 372 mg daily, and liposomal amphotericin B |
| Lung transplant | Itraconazole, voriconazole, or posaconazole, with or without inhaled liposomal amphotericin B (for example 25 mg twice weekly), for months and then guided by bronchoscopic surveillance |
| Chronic granulomatous disease | Itraconazole 100 to 200 mg once daily (children 5 mg per kg daily), with interferon gamma 50 micrograms per square metre three times weekly in some protocols |
| Environmental control | High efficiency particulate air filtration and positive pressure rooms for allogeneic transplant, avoidance of construction exposure, protective masks outside protected rooms, and water and air quality surveillance |
| Screening strategy | Galactomannan twice weekly in high risk patients without mould active prophylaxis, with CT triggered pre-emptive therapy |
| Surveillance of azole resistance | Local susceptibility monitoring and cyp51A screening |
Patients are advised to avoid gardening, compost, and construction dust during periods of immunosuppression.
Twelve week survival in randomised trials of first line therapy is about 60 to 75 percent. Poor prognostic factors are persistent neutropenia, allogeneic transplant with graft versus host disease, high dose corticosteroids, central nervous system and disseminated disease, respiratory failure and ventilation, azole resistance, and delayed treatment. Early imaging triggered diagnosis and therapy (within 24 to 72 hours) improve survival.
