How are the major systemic fungal infections grouped?
Systemic (deep) mycoses fall into two exam-friendly groups. Opportunistic moulds such as Aspergillus and the Mucorales are everywhere in the environment and cause serious disease mainly when host defences are weak. Endemic dimorphic fungi such as Histoplasma capsulatum and Coccidioides live in particular soils and regions, are inhaled as spores, and then convert into a tissue form in the lung.
| Fungus | Type | Tissue form | Usual host or setting |
|---|---|---|---|
| Aspergillus | Opportunistic mould | Septate hyphae, acute-angle (dichotomous) branching, 3 to 6 micron wide | Neutropenia, haematological malignancy, transplant, long-term steroids; asthma and cystic fibrosis (ABPA); pre-existing lung cavity (aspergilloma) |
| Mucorales (Rhizopus, Mucor) | Opportunistic mould | Broad, ribbon-like, non-septate or pauciseptate hyphae, right-angle branching, 5 to 10 micron | Poorly controlled diabetes, ketoacidosis, iron overload, severe COVID-19, transplant |
| Histoplasma capsulatum | Endemic dimorphic | Small narrow-based budding yeast, 2 to 4 micron, inside macrophages | Soil with bird or bat droppings; river valleys; HIV and immunosuppression for dissemination |
| Coccidioides | Endemic dimorphic | Spherules filled with endospores (2 to 5 micron) | Arid regions of the Western Hemisphere; 'Valley fever' |
What are the types of aspergillosis and how is each diagnosed?
Aspergillosis is a spectrum that depends on the host's immune status. The same genus can cause an asymptomatic aspergilloma, an allergic disease (ABPA), a chronic pulmonary infection, or invasive disease in the severely immunocompromised. Aspergillus is ubiquitous, with spores (conidia) measured per cubic metre of air, and is higher in places with soil disruption.
| Form | Who | Key points |
|---|---|---|
| Invasive pulmonary aspergillosis | Neutropenia, haematological malignancy, stem-cell or solid-organ transplant, advanced HIV, prolonged corticosteroids, ICU | Angioinvasive; halo sign on CT (central nodule with ground-glass change from haemorrhage and thrombosis); air-crescent sign later, after neutropenia recovers; serum galactomannan useful in haematological malignancy and transplant patients |
| ABPA (allergic bronchopulmonary aspergillosis) | Asthma (about 2-3%) and cystic fibrosis (about 9%) | Recurrent asthma exacerbations, wheeze, brown mucus plugs; diagnosis needs positive Aspergillus skin test or specific IgE plus at least two of: total IgE above 1000 IU/mL, raised Aspergillus IgG or precipitins, eosinophilia, characteristic imaging |
| Aspergilloma (fungal ball) | Pre-existing cavity: old TB cavity, bronchiectasis, tumour, lung abscess | Often asymptomatic or haemoptysis; mass within a cavity with a surrounding air shadow; surgery considered for haemoptysis |
| Invasive rhinosinusitis | Severely immunocompromised; chronic granulomatous form in immunocompetent people (A. flavus predominant) | See also fungal sinusitis |
Histology and stains: Aspergillus is seen on H&E, and better with PAS and Gomori methenamine silver (GMS); fluorescent dyes such as calcofluor white are used. The morphology is narrow (3 to 6 micron) septate hyphae with dichotomous, acute-angle branching, but Scedosporium and Fusarium can look similar, so culture or molecular confirmation matters.
What is the treatment of aspergillosis?
- Invasive aspergillosis: voriconazole or isavuconazole is recommended in most instances. Isavuconazole is non-inferior to voriconazole with a more predictable pharmacokinetic profile.
- Voriconazole needs trough monitoring around days 4 to 7; adverse effects include photosensitivity, and in transplant patients prolonged use has been linked to cutaneous squamous cell carcinoma.
- Landmark trial (2002): survival at 12 weeks 70.8% with voriconazole versus 57.9% with amphotericin B deoxycholate.
- Breakthrough on voriconazole prophylaxis: liposomal amphotericin B until susceptibility is known.
- Echinocandin monotherapy is not recommended for Aspergillus because it is fungistatic against it.
- ABPA: systemic glucocorticoids are the primary treatment of acute exacerbations; the goals are symptom control, preventing exacerbations and preserving lung function.
- Aspergilloma: goal is clinical stability and preventing haemoptysis; a thoracic surgeon is consulted for haemoptysis or poor response, and outcomes after surgery for simple aspergilloma are generally excellent.
What is mucormycosis, and who gets it?
Mucormycosis is a severe opportunistic infection caused by fungi of the order Mucorales (genera include Rhizopus, Mucor, Rhizomucor, Lichtheimia, Cunninghamella and Apophysomyces). The moulds are ubiquitous, and infection follows inhalation of sporangiospores. They are rapidly angioinvasive, causing infarction, necrosis and thrombosis.
| Risk factor | Point to remember |
|---|---|
| Poorly controlled diabetes, especially ketoacidosis | The most significant predisposing factor: high glucose and free iron favour rapid filamentous growth; acidosis impairs neutrophil chemotaxis and phagocytosis. Diabetes was a risk factor in more than half of cases in Indian series |
| Haematological malignancy, neutropenia, transplant | Common underlying conditions; rhino-orbital-cerebral disease also follows renal transplant |
| Iron overload | Free iron supports fungal growth |
| Severe COVID-19 | Listed as a risk factor |
| Burns and trauma | Primary cutaneous disease by direct inoculation |
India and Sri Lanka stand out: the global incidence is estimated at 2.7 per 100,000 people, with about 2 per million in most countries but 14 per 100,000 in India and Sri Lanka.
How is mucormycosis diagnosed and treated?
Histology is the gold standard. The hallmark is broad, ribbon-like, non-septate or pauciseptate hyphae, 5 to 10 micron wide, with right-angle (90 degree) branching and invasion of blood-vessel walls. H&E may show only the outline of the wall; GMS shows the walls black or brown and PAS shows detail. The most common presentation in diabetic patients and renal-transplant recipients is rhino-orbital-cerebral disease, following inhalation into the paranasal sinuses. In pulmonary and sinus disease, CT and mucosal necrosis prompt a biopsy.
| Step | Detail |
|---|---|
| 1. Reverse the cause | Correct hyperglycaemia and acidosis, reduce immunosuppression, treat the underlying condition |
| 2. Surgery | Urgent, aggressive debridement (may mean facial resection, lobectomy or bowel resection); often repeated |
| 3. Antifungal | Start as soon as suspected. Liposomal amphotericin B is the preferred first-line agent, typically 5 mg/kg daily, and 10 mg/kg for CNS involvement or transplant recipients |
| 4. Maintenance and add-ons | After clinical improvement, isavuconazole or posaconazole (posaconazole trough at least 1 microgram/mL); combination with amphotericin B is considered if not responding. Hyperbaric oxygen with debridement has been associated with lower mortality |
What is histoplasmosis?
Histoplasma capsulatum is a dimorphic fungus found worldwide, mainly in soil enriched with bird or bat droppings (guano) in humid river-valley environments. Most infections occur in the Americas, and the Ohio, Mississippi and Missouri river valleys of the United States are the classic endemic areas, but it is also endemic across parts of Africa and Asia. Outbreaks follow construction, demolition or exposure to chicken coops, caves and bat or bird droppings.
- Pathogenesis: conidia are inhaled, reach the alveoli and change from mould to budding yeast, which alveolar macrophages ingest but cannot kill; the yeast survives by blocking phagosome acidification and spreads with infected macrophages.
- Histology: caseating or non-caseating granulomas; in severe immunosuppression, diffuse sheets of macrophages packed with yeast. Yeast is small, ovoid, 2 to 4 micron, narrow-based budding, often inside macrophages.
- Spectrum: most exposures are asymptomatic or mild; disseminated disease (fever, weight loss, hepatosplenomegaly) occurs mainly in the immunocompromised. Incubation is typically 3 to 17 days.
- Diagnosis: urine Histoplasma antigen EIA is the preferred initial test in severe or disseminated disease (sensitivity falls to about 30% in subacute pulmonary disease). Antigen and antibody tests cross-react with Blastomyces and Coccidioides. Histopathology has a low sensitivity (9 to 50%).
- Treatment: mild-to-moderate acute pulmonary disease often needs none; itraconazole is preferred when treatment is needed. Severe disease: liposomal amphotericin B 3 mg/kg/day for 1 to 2 weeks, then itraconazole for at least 12 weeks. Chronic cavitary disease: itraconazole for at least 12 months.
What is coccidioidomycosis (Valley fever)?
Coccidioidomycosis, or San Joaquin Valley fever, is caused by the dimorphic fungus Coccidioides, endemic to the arid regions of the Western Hemisphere (California, Arizona, Utah, Nevada and New Mexico in the United States). In the environment it exists as mycelia that fragment into barrel-shaped arthroconidia, the infectious particles. Inhaled arthroconidia transform in the lung into spherules, which are filled with endospores (2 to 5 micron); when a spherule bursts, the endospores spread infection.
- Presentation: about 60% asymptomatic; symptoms begin 7 to 21 days after exposure with fever, cough, dyspnoea and chest pain that can mimic community-acquired pneumonia.
- Dissemination is frequent in the immunocompromised, pregnant patients and people of African or Filipino ancestry; skin lesions and vertebral osteomyelitis (mimicking staphylococcal infection) are common, and meningitis can occur.
- Diagnosis: serology (tube precipitin or IgM antibody detected in about 90% in the first 3 weeks; complement-fixing IgG; immunodiffusion; EIA); culture and histology of spherules.
- Treatment: an oral azole such as fluconazole is recommended for fibrocavitary disease; liposomal amphotericin B 3 to 5 mg/kg daily is started in all transplant recipients, then switched to an oral azole for at least 12 months if the response is durable.
- Meningitis: intravenous amphotericin B does not work well because of poor penetration across the blood-brain barrier; fluconazole is used, and hydrocephalus is a common complication.
What are the drugs of choice and common traps?
| Infection | First-line | Notes |
|---|---|---|
| Invasive aspergillosis | Voriconazole or isavuconazole | Echinocandin alone not recommended; L-AmB if on voriconazole prophylaxis |
| ABPA | Glucocorticoids (acute exacerbation) | Antifungal not the primary therapy for exacerbation |
| Mucormycosis | Liposomal amphotericin B + urgent surgery | 5 mg/kg; 10 mg/kg for CNS; maintenance with isavuconazole or posaconazole |
| Histoplasmosis (needing treatment) | Itraconazole; severe: liposomal amphotericin B then itraconazole | Itraconazole at least 12 weeks; chronic cavitary at least 12 months |
| Coccidioidomycosis | Oral azole (fluconazole) for fibrocavitary disease; L-AmB in transplant recipients | Meningitis: fluconazole, because IV amphotericin penetrates poorly |
- Mucor is not septate: a 'septate hyphae with acute branching' option points to Aspergillus.
- Echinocandins are fungistatic against Aspergillus and are not used alone for invasive disease.
- Galactomannan can be falsely positive with piperacillin-tazobactam or amoxicillin-clavulanate.
- Histoplasma and Coccidioides tests cross-react with other endemic fungi.
- ABPA needs IgE above 1000 IU/mL plus two other criteria; it is a disease of asthma and cystic fibrosis.
For related exam topics, see stains and culture media in microbiology, fungal sinusitis and primary immunodeficiency disorders.