Mucorales: Biology
The Mucorales are an order of fast growing, ubiquitous filamentous fungi (subphylum Mucoromycotina) that live on decaying organic matter, soil, dung, bread, and fruit. Disease is called mucormycosis (formerly zygomycosis). Infection is acquired by inhalation of sporangiospores, by inoculation of skin, and by ingestion, and it is angioinvasive, causing thrombosis and tissue necrosis.
Mucormycosis is rare in people with normal immunity and is dominated by a few host conditions: uncontrolled diabetes with ketoacidosis, haematological malignancy with neutropenia, transplantation, corticosteroid treatment, trauma and burns, and iron overload and iron chelation with deferoxamine.
It is the second commonest invasive mould infection in haematological patients after aspergillosis, and it is the commonest invasive mould infection in people with diabetes in many low and middle income countries.
| Family and genus | Species | Typical disease and setting |
|---|---|---|
| Mucoraceae: Rhizopus | Rhizopus arrhizus (Rhizopus oryzae), Rhizopus microsporus | The commonest cause worldwide (about 50 to 70 percent of cases); rhino-orbital-cerebral disease in diabetes, pulmonary and disseminated disease; also contaminated bandages and wooden devices |
| Mucoraceae: Mucor | Mucor circinelloides, Mucor indicus, Mucor racemosus | Sinus and pulmonary disease, cutaneous disease; azole prophylaxis breakthrough; Mucor circinelloides is commonly less susceptible to amphotericin B |
| Mucoraceae: Rhizomucor | Rhizomucor pusillus | Pulmonary and disseminated disease in neutropenia; thermophilic |
| Lichtheimiaceae: Lichtheimia (Absidia) | Lichtheimia corymbifera, Lichtheimia ramosa | Pulmonary, cutaneous, and burn wound disease; common in Europe |
| Cunninghamellaceae: Cunninghamella | Cunninghamella bertholletiae | Pulmonary and disseminated disease in stem cell transplant and leukaemia; high mortality; reduced amphotericin B susceptibility |
| Saksenaeaceae: Apophysomyces, Saksenaea, Saksenaea related genera | Apophysomyces variabilis, Apophysomyces elegans, Saksenaea vasiformis | Traumatic wound and soft tissue infection in immunocompetent hosts, tropical regions, natural disasters |
| Syncephalastraceae: Syncephalastrum | Syncephalastrum racemosum | Rare cutaneous and sinus disease |
| Cokeromyces, Actinomucor, and others | Cokeromyces recurvatus, Actinomucor elegans | Rare |
Taxonomy is under revision, and many species names have changed. Species level identification matters because of differences in amphotericin B susceptibility, thermotolerance, and clinical association.
| Feature | Description |
|---|---|
| Hyphae in tissue | Broad (6 to 25 micrometres), ribbon like, thin walled, with few or no septa (pauciseptate or aseptate), irregular and non dichotomous branching at about 90 degrees; often twisted or collapsed |
| Asexual structures | Sporangiophores bearing sporangia that contain sporangiospores; a columella inside the sporangium, an apophysis (a funnel shaped swelling below the columella in Lichtheimia and Apophysomyces) |
| Rhizoids | Root like structures at the base of sporangiophores, present in Rhizopus (at nodes, opposite the sporangiophores) and in Lichtheimia (between nodes); absent in Mucor and Cunninghamella |
| Rhizopus | Unbranched sporangiophores in groups, with rhizoids at their base and a hemispherical columella |
| Mucor | Branched sporangiophores, no rhizoids, globose sporangia and columella |
| Lichtheimia | Pyriform apophysis, rhizoids between nodes, small sporangia |
| Rhizomucor | Branched sporangiophores with rhizoids; grows at up to 54 degrees Celsius |
| Cunninghamella | Vesicles bearing single spored sporangiola |
| Apophysomyces | Pyriform sporangia with a funnel shaped apophysis, in a bell shape; growth at 37 to 42 degrees Celsius |
| Saksenaea | Flask shaped sporangia with a long neck, formed on specialised media |
| Sexual reproduction | Thick walled zygospores after fusion of compatible hyphae, seen only in some cultures |
Aseptate hyphae with right angle branching distinguish Mucorales from Aspergillus (septate, 3 to 6 micrometres, acute angle branching) in tissue, but morphology alone is unreliable and cultures and molecular identification confirm.
| Aspect | Details |
|---|---|
| Growth | Colonies are very fast growing: white, cottony, filling the plate in 24 to 72 hours at 25 to 37 degrees Celsius, then grey or brown as spores develop; "lid lifting" growth. Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor, and Lichtheimia grow at 37 to 45 degrees Celsius or higher; Mucor species grow poorly above 37 degrees Celsius; Saksenaea grows slowly |
| Media | Sabouraud dextrose agar and potato dextrose agar at 30 and 37 degrees Celsius, without cycloheximide (which inhibits Mucorales) |
| Specimen handling | Tissue is minced, not ground or homogenised, because hyphae are fragile and are damaged by homogenisation, and specimens are not refrigerated; fluids are centrifuged |
| Direct microscopy | Potassium hydroxide with calcofluor white shows broad aseptate hyphae within minutes, and is the fastest test |
| Histology | Haematoxylin and eosin shows hyphae well, and Grocott methenamine silver and periodic acid Schiff are also used; angioinvasion, thrombosis, infarct necrosis, neutrophilic or granulomatous inflammation, and perineural invasion are typical |
| Culture | Positive in only about 50 percent of cases, and tissue is preferred to swabs; blood cultures are almost always negative |
| Identification | Colony and microscopic features, sequencing of the internal transcribed spacer region (the reference method), and matrix assisted laser desorption ionisation time of flight mass spectrometry with an extended mould database |
| Molecular detection | Quantitative polymerase chain reaction for Mucorales DNA in blood (serum or plasma), bronchoalveolar lavage, and tissue; sensitivity about 85 to 90 percent in blood, with positive results often 3 to 9 days before imaging confirms disease |
| Biomarkers | Galactomannan and beta D glucan are negative in mucormycosis, so a negative result in a patient with a suggestive picture does not exclude it, and a positive beta D glucan or galactomannan in a patient on mould active therapy suggests a coexisting infection or aspergillosis |
| Susceptibility testing | Reference broth microdilution, with no clinical breakpoints; epidemiological cutoff values are used for amphotericin B, posaconazole, and isavuconazole |
Spores are found in soil, compost, rotting wood and vegetation, dung, bread, and fruit. Hospital sources include contaminated bandages, adhesive tape, wooden tongue depressors, air conditioning and ventilation, linen, and water damaged building materials. Natural disasters (tornado, tsunami, earthquake, and flooding) and military trauma cause cutaneous outbreaks.
Incidence varies by region. In Europe and the United States it is about 0.1 to 0.3 cases per 100 000 people per year and has risen. In India it is estimated to be about 80 times higher (140 per million population).
India and Pakistan have large numbers in people with diabetes. The COVID-19 pandemic produced a large epidemic of COVID-19 associated mucormycosis in India in 2021 (tens of thousands of cases). It was driven by uncontrolled diabetes, corticosteroids, and, in some analyses, contaminated humidification and iron or zinc supplementation.
| Risk factor | Notes |
|---|---|
| Diabetes mellitus, especially with ketoacidosis | The commonest in many regions; rhino-orbital-cerebral disease |
| Haematological malignancy, neutropenia, and stem cell transplant | Pulmonary and disseminated disease; graft versus host disease treated with corticosteroids |
| Solid organ transplant | Kidney, lung, heart, liver; immunosuppression and diabetes |
| Corticosteroids | Prolonged or high dose, including in COVID-19 |
| Iron overload and deferoxamine chelation | Deferoxamine acts as a siderophore for Mucorales (feroxamine) |
| Injection drug use | Cerebral and cutaneous disease |
| Burns, trauma, surgery, and contaminated dressings | Cutaneous and soft tissue disease |
| Prematurity, malnutrition, and low birth weight | Gastrointestinal and cutaneous disease in neonates |
| COVID-19 | Corticosteroids, diabetes, and prolonged intensive care |
| Voriconazole exposure | Selects Mucorales as breakthrough infection in transplant and leukaemia |
| Renal failure, acidosis, and malnutrition | Defective phagocyte function and iron availability |
| Mould active prophylaxis and healthy hosts | Rare cases in apparently normal hosts (isolated renal infection in Asia, trauma) |
| Mechanism | Details |
|---|---|
| Spore germination and host defence | Spores that reach the alveoli or sinuses are killed by macrophages (which inhibit germination) and neutrophils (which damage hyphae). Neutropenia, corticosteroids, and hyperglycaemia with acidosis impair these defences |
| Hyperglycaemia and acidosis | Impair neutrophil chemotaxis and killing, and acidic pH frees iron from transferrin. Ketone bodies are used as substrates by Rhizopus through ketone reductase |
| Iron acquisition | Free iron promotes growth. Mucorales have a high affinity iron permease (FTR1), take iron through the siderophore rhizoferrin, and use deferoxamine as a xenosiderophore. Deferoxamine therapy and iron overload thus raise risk |
| Endothelial invasion | Rhizopus expresses the spore coat homologue protein CotH3, which binds glucose regulated protein 78 on endothelial cells; this receptor is upregulated by high glucose, iron, and ketones, mediating endothelial damage and angioinvasion. This explains the susceptibility in diabetic ketoacidosis |
| Angioinvasion | Vessel invasion causes thrombosis, ischaemia, necrosis, and haematogenous spread. Antifungal drugs reach necrotic tissue poorly, so surgery is needed |
| Mycotoxin | Rhizoxin and ricin like toxins in some species; their role is unclear |
| Thermotolerance | Growth at 37 degrees Celsius and above in clinical species |
| Immune response | Th1 and Th17 responses, interferon gamma, and neutrophil function; a Mucorales specific T cell response occurs in patients |
| Class | Activity |
|---|---|
| Amphotericin B | Active, with MICs 0.06 to 2 micrograms per mL; Cunninghamella bertholletiae and Mucor circinelloides often higher |
| Posaconazole | Active in vitro for most species (MIC 0.25 to 4), and the usual oral step down and salvage agent |
| Isavuconazole | Active in vitro for most species, but with higher MICs in Mucor and Rhizopus in some series |
| Itraconazole | Variable, and not recommended for primary therapy |
| Voriconazole and fluconazole | Intrinsically resistant |
| Echinocandins | Little activity against Mucorales, though Rhizopus produces a target and synergy has been proposed |
| Flucytosine and terbinafine | Not active alone |
| New agents | Fosmanogepix shows in vitro activity and is in clinical development; olorofim has no activity against Mucorales |
A patient on voriconazole prophylaxis who develops a fungal infection has a higher probability of mucormycosis, and Mucorales should be sought in tissue.
