Describe aspergillosis and mucormycosis with their clinical forms, diagnosis and treatment.

Aspergillus

• A ubiquitous environmental mould with septate hyphae branching at acute (about 45 degree) angles, and characteristic conidiophores bearing a swollen vesicle with radiating phialides — the appearance that gives it its name (from the aspergillum, a holy water sprinkler)
• Species — A. Fumigatus (the commonest invasive pathogen), A. Flavus (commoner in India, and the producer of aflatoxin), A. Niger (otomycosis) and A. Terreus (intrinsically amphotericin-resistant)
• Acquired by inhalation of spores, which are everywhere in air, soil, dust, decaying vegetation and damp buildings; hospital construction and renovation are a recognised cause of outbreaks in haematology units
• It is angioinvasive in the immunosuppressed, invading blood vessels to cause thrombosis, infarction and haemorrhage — which explains the wedge-shaped infarcts, the haemoptysis and the dissemination

The Mucorales — Mucormycosis

• Caused by Rhizopus, Mucor, Rhizomucor, Lichtheimia and related genera
• Broad, ribbon-like, aseptate (or sparsely septate) hyphae branching at wide, roughly 90-degree angles — the microscopic appearance that distinguishes it from Aspergillus and that must be recognised immediately, because the treatments differ
• The classical predisposing factor is diabetic ketoacidosis. The organisms require free iron, and acidosis releases iron from transferrin; they also possess a ketone reductase allowing them to thrive in a high-glucose acidotic environment
• Other risk factors — neutropenia, haematological malignancy, transplantation, corticosteroids, iron overload and desferrioxamine (which acts as a siderophore for the fungus), malnutrition, burns and penetrating trauma
• Rhino-orbito-cerebral is the commonest form — beginning in the nose and paranasal sinuses with facial pain and nasal congestion, then a black necrotic eschar on the palate or nasal turbinate, orbital involvement with proptosis and ophthalmoplegia, and finally cerebral extension. It is angioinvasive, causing thrombosis and infarction, which is why the tissue turns black
• Other forms — pulmonary (in neutropenia), cutaneous (after trauma or contaminated dressings), gastrointestinal (in malnourished infants) and disseminated
• India has the highest burden of mucormycosis in the world, driven by the prevalence of uncontrolled diabetes; a very large surge occurred during the COVID-19 pandemic, attributed to the combination of diabetes, corticosteroids and COVID-19 itself

Diagnosis

• Direct microscopy is the most important immediate test — KOH or calcofluor white on tissue, showing either septate acute-angle hyphae (Aspergillus) or broad aseptate wide-angle hyphae (Mucorales). This distinction can be made within minutes and dictates treatment
• Histopathology with silver or PAS stains, demonstrating tissue invasion and angioinvasion — the definitive proof of invasive disease
• Culture on Sabouraud agar without cycloheximide, which inhibits these moulds; but culture is frequently negative in mucormycosis because grinding the tissue destroys the aseptate hyphae — so the tissue should be minced, not ground
• Galactomannan antigen in serum or bronchoalveolar lavage for Aspergillus; and beta-D-glucan, which is raised in many fungal infections but is negative in mucormycosis and in cryptococcosis
• Imaging — the halo sign and air crescent in invasive aspergillosis; the reverse halo sign and bone erosion in mucormycosis; magnetic resonance imaging for orbital and cerebral extension
• PCR and MALDI-TOF where available

Distinguishing the Two on Microscopy

Treatment and Applied Aspects

• Invasive aspergillosis — voriconazole is first-line, with isavuconazole and liposomal amphotericin B as alternatives; echinocandins are only adjunctive, since Aspergillus is not reliably killed by them
• Mucormycosis — requires three things together: (1) urgent and repeated surgical debridement of all necrotic tissue, which is the decisive intervention; (2) liposomal amphotericin B in high dose, with posaconazole or isavuconazole as step-down; and (3) correction of the underlying condition — reversing ketoacidosis, controlling glucose, stopping steroids and stopping desferrioxamine
• The mucorales are intrinsically resistant to voriconazole, fluconazole and the echinocandins. This is the single most important therapeutic fact: a patient treated for presumed aspergillosis with voriconazole who actually has mucormycosis will deteriorate, and voriconazole prophylaxis has itself been associated with breakthrough mucormycosis
• Suspect mucormycosis in a diabetic with facial pain, nasal blockage or a black nasal or palatal lesion, and examine the nose and palate directly; delay of days changes the outcome
• Prevention in hospital — HEPA filtration and positive-pressure rooms for neutropenic patients, barriers during construction work, and avoiding damp and dust
• Glycaemic control and rational steroid use are the practical preventive measures in India; the COVID-19-associated surge in mucormycosis followed directly from steroid use in patients whose diabetes was then poorly controlled
• Examine the nose and palate in any diabetic with facial pain or periorbital swelling; a black eschar is a surgical emergency and the examination takes seconds
• Aspergilloma is common in India because tuberculosis is; an old tuberculous cavity is the usual substrate, and haemoptysis in a treated tuberculosis patient should raise it before assuming relapse
• Galactomannan may be falsely positive with piperacillin-tazobactam and other beta-lactams, and falsely negative in patients already on antifungal prophylaxis — both worth knowing before acting on a single result
• Never treat presumed aspergillosis with voriconazole in a ketoacidotic diabetic without excluding mucormycosis, since the Mucorales are intrinsically resistant to it and the patient will deteriorate
• Surgery is the decisive treatment in mucormycosis, and repeated debridement is usually necessary; antifungals alone rarely succeed because the tissue is already infarcted and no drug reaches it
• Stop desferrioxamine immediately in a patient who develops mucormycosis, since it acts as a siderophore delivering iron to the fungus
• Reverse the ketoacidosis as urgently as the infection; the acidosis releases iron from transferrin and is what permits the fungus to grow at all
• ABPA is treated with steroids, which is counterintuitive in a fungal disease and is the point most often misunderstood; itraconazole is adjunctive and steroid-sparing
• Massive haemoptysis from an aspergilloma is a surgical or radiological emergency; bronchial artery embolisation buys time where resection is not immediately possible
• Ask about hospital construction work in a cluster of invasive aspergillosis on a haematology unit; renovation is a documented cause of outbreaks and the remedy is engineering rather than antifungal
• Steroids in invasive aspergillosis are catastrophic and in ABPA are the treatment — which is why the distinction between the three pulmonary forms must be made before anything is prescribed
• Mince the tissue, do not grind it, when mucormycosis is suspected; this single instruction to the laboratory determines whether the culture grows anything