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Moulds of this family are everywhere — in soil, compost and decaying leaves — and almost everyone breathes in their spores harmlessly every day. In people whose immune system is severely weakened, or whose diabetes is badly out of control, the spores can take hold and grow. The infection invades blood vessels, cuts off the blood supply to the tissue it is growing in, and spreads quickly. It is rare, it is serious, and treatment is urgent: the difference between starting antifungal treatment early and starting it several days later is measurable in survival.
Definition
Zygomycosis is an invasive fungal infection caused by moulds of the order Mucorales. The preferred modern term is mucormycosis, because the older taxonomic grouping "Zygomycetes" has been revised and no longer reflects the organisms responsible.1,3 Both names describe the same disease.
It is defined by angioinvasion — the fungus grows into blood vessels, causing thrombosis and death of the surrounding tissue.6 That single property explains its speed, the black necrotic appearance of affected tissue, and why antifungal drugs alone are frequently insufficient: the drug cannot reach tissue that no longer has a blood supply.1,6
Who is at risk
Mucormycosis is overwhelmingly a disease of compromised host defence, and healthy people are not meaningfully at risk.2,4
- Poorly controlled diabetes, particularly with ketoacidosis — the commonest risk factor worldwide.2,4
- Haematological malignancy, and prolonged neutropenia.2,7
- Stem cell or solid organ transplantation.2
- Prolonged corticosteroid therapy or other immunosuppression.4,5
- Iron overload and treatment with deferoxamine.6
- Major trauma or burns, where spores are introduced directly.4
A large increase in cases was reported during the COVID-19 pandemic, particularly in India, driven by the combination of corticosteroid treatment, diabetes and severe viral illness.5,9
Forms of the disease
- Rhino-orbito-cerebral — beginning in the sinuses and spreading towards the eye and brain. Most strongly associated with diabetic ketoacidosis.4,9
- Pulmonary — affecting the lungs, most often in haematology and transplant patients, and the form most relevant to a respiratory service.2,4
- Cutaneous — following trauma or burns, and the form with the best outcome.2
- Gastrointestinal — mainly in very low birthweight infants and severely malnourished patients.2
- Disseminated — spread through the bloodstream, carrying the worst prognosis.2
Symptoms
Early features are non-specific, which is a large part of the diagnostic difficulty.3,4
- Pulmonary disease — fever unresponsive to antibiotics, cough, chest pain, and coughing blood. Fever that persists despite broad antibiotics in a neutropenic patient is the classic trigger for investigation.2,4
- Sinus disease — facial pain or numbness, nasal congestion, dark nasal discharge, and a black lesion on the palate or inside the nose. Eye swelling, protrusion or visual loss indicate spread.4,9
- Skin disease — a painful, hardened area that darkens and forms a black eschar.2
In a person with poorly controlled diabetes or a weakened immune system, facial pain with a dark nasal lesion, or persistent fever with a new lung shadow, requires urgent hospital assessment the same day.1,7
Diagnosis
- CT imaging — of the sinuses or chest. The reversed halo sign on chest CT is suggestive in the right clinical setting, though not specific.1,3
- Tissue biopsy with histopathology, the diagnostic standard, showing broad non-septate hyphae invading vessels.1,3
- Culture, which is insensitive — the organism frequently fails to grow, and a negative culture does not exclude the diagnosis.3
- Molecular testing (PCR), increasingly used and recommended alongside conventional methods.1,3
- Note what does not help: galactomannan and beta-D-glucan, used for other invasive fungal infections, are negative in mucormycosis. A negative result is sometimes misread as excluding fungal infection.1,3
Management
Treatment rests on three simultaneous actions, and delay in any of them worsens outcome.1,7
- Antifungal therapy — liposomal amphotericin B first-line, with isavuconazole and posaconazole as alternatives or step-down.1,8
- Surgical debridement of all necrotic tissue, often extensive and sometimes repeated, because devascularised tissue cannot be reached by drugs.1,6
- Reversing the underlying predisposition — correcting ketoacidosis, controlling glucose, reducing immunosuppression where possible, and supporting neutrophil recovery.1,6
Speed is itself a treatment. In haematology patients, delaying amphotericin-based therapy by six days or more approximately doubled mortality compared with early initiation — which is why treatment is usually begun on suspicion, before biopsy confirmation.7
Living with it and afterwards
Survivors are frequently left with substantial consequences: the effects of extensive surgery, prolonged hospitalisation and critical illness, and in sinus disease the loss of an eye or of facial structures.2,4
Prolonged antifungal treatment continues for months after discharge, and the underlying condition — diabetes, malignancy, transplantation — still requires management. Recovery is measured in months.
Role of the physiotherapist
Acute mucormycosis is treated by infectious diseases physicians, surgeons and intensive care teams. We have no role in the acute illness, and this page exists partly so people can recognise urgency and partly for those recovering afterwards.
Where cardiorespiratory physiotherapy contributes is rehabilitation, and there the need is considerable:
- Pulmonary rehabilitation after lung involvement or resection. Structured exercise and education improve exercise capacity and quality of life across chronic respiratory disease; the evidence in post-infectious lung disease specifically is thinner, and we say so.10
- Recovery after critical illness — muscle weakness, deconditioning and reduced exercise tolerance after a long intensive care stay, which respond to graded, supervised exercise.10
- Airway clearance where surgery or lung damage has left secretion retention.10
- Breathlessness management and pacing during a recovery measured in months.
Rehabilitation starts once the infectious diseases team confirms the infection is controlled. We work from their advice and from the surgical team's, not ahead of it.
We have no part in the acute illness — that belongs to infectious diseases, surgery and intensive care. We see people afterwards, when the infection is controlled and recovery from extensive surgery and a long hospital stay is measured in months. Graded exercise, airway clearance where secretions are hard to shift, and pacing through a slow recovery.
Part 1 · References
- Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the ECMM in cooperation with the MSG ERC. Lancet Infect Dis 2019;19(12):e405–e421.
- Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41(5):634–653.
- Skiada A, Pavleas I, Drogari-Apiranthitou M. Epidemiology and diagnosis of mucormycosis: an update. J Fungi 2020;6(4):265.
- Petrikkos G, Skiada A, Lortholary O, et al. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012;54(Suppl 1):S23–S34.
- Patel A, Agarwal R, Rudramurthy SM, et al. Multicenter epidemiologic study of coronavirus disease-associated mucormycosis, India. Emerg Infect Dis 2021;27(9):2349–2359.
- Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18(3):556–569.
- Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008;47(4):503–509.
- Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 2016;16(7):828–837.
- Jose A, Singh S, Roychoudhury A, et al. Current understanding in the pathophysiology of SARS-CoV-2-associated rhino-orbito-cerebral mucormycosis. J Maxillofac Oral Surg 2021;20(3):373–380.
- Spruit MA, Singh SJ, Garvey C, et al. An official ATS/ERS statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013;188(8):e13–e64.
Clinical evidence
Part 1 covers the same condition without the technical detail. What follows is the evidence base behind it, written for clinicians — the literature, the reasoning and the gaps.
For clinicians: this summary supports clinical reasoning and is not a protocol. Check current guidelines and local policy before applying it, and read it alongside the key references and guidelines directory.
Framing. Mucormycosis — the preferred term, the older "zygomycosis" reflecting a superseded taxonomy — is an angioinvasive mould infection of the immunocompromised host, with mortality historically reported around 50% and considerably higher in disseminated and cerebral disease.2,3 The 2019 ECMM/MSG ERC global guideline is the reference document, and it is explicit that most of its recommendations rest on low-quality evidence.1
Angioinvasion drives everything, including why drugs alone fail
Vascular invasion with thrombosis and infarction is the defining pathological feature and accounts for necrosis, rapid progression, and poor antifungal penetration into devascularised tissue.6 This is the mechanistic reason surgery is not adjunctive but central, and combined medical–surgical management is consistently associated with better survival across series.1,2,6
Time to treatment is among the strongest modifiable predictors
In haematological malignancy, initiation of amphotericin-based therapy six or more days after diagnosis was associated with approximately double the mortality of early treatment.7 Guideline practice is therefore to treat on clinical suspicion rather than await histological confirmation.1,7 Liposomal amphotericin B is first-line; isavuconazole has been evaluated in a single-arm open-label trial with case-control comparison and is an alternative, particularly for step-down.1,8
Diagnostic pitfalls are systematic rather than incidental
Culture is insensitive because hyphae are frequently damaged during tissue processing, and negative culture is common in proven disease.3 Galactomannan and beta-D-glucan are negative in mucormycosis, and their use as a general "fungal screen" is a recognised route to missed diagnosis in patients already receiving mould-active prophylaxis that lacks Mucorales cover.1,3 Molecular methods are recommended as adjuncts.1,3
Epidemiology has shifted, twice
The 929-case review established the historical distribution by risk group and clinical form.2 Subsequent series document rising incidence with expanding transplantation and immunosuppression.4 The COVID-19-associated surge, concentrated in India, reflected the convergence of corticosteroid exposure, hyperglycaemia and severe viral illness, and is best read as an amplification of known risk factors rather than a new disease.5,9
Rehabilitation: no condition-specific evidence
Survivors frequently carry the combined burden of extensive surgical resection, prolonged critical illness and months of antifungal therapy. There is no rehabilitation literature in mucormycosis. ATS/ERS pulmonary rehabilitation principles provide the applicable framework, with benefits established in chronic respiratory disease and increasingly in post-acute respiratory illness.10 A physiotherapy service should present this as extrapolation and should not begin before the infectious diseases team confirms disease control, since ongoing active infection, not deconditioning, is the governing problem.1,10
What we do not know
- Whether combination antifungal therapy improves survival. Repeatedly proposed, never established in a randomised trial.1,8
- The optimal extent and timing of surgery, where practice is guided by necrosis and by what is anatomically feasible rather than by trial data.1,6
- How to shorten time to diagnosis, the strongest modifiable determinant of outcome.3,7
- Whether the COVID-associated surge represents a durable epidemiological change or a time-limited event.5,9
- What rehabilitation should look like for survivors, an entirely unstudied question in a population with unusually complex deficits.10
References for the clinical evidence summary
- Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the ECMM in cooperation with the MSG ERC. Lancet Infect Dis 2019;19(12):e405–e421.
- Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41(5):634–653.
- Skiada A, Pavleas I, Drogari-Apiranthitou M. Epidemiology and diagnosis of mucormycosis: an update. J Fungi 2020;6(4):265.
- Petrikkos G, Skiada A, Lortholary O, et al. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012;54(Suppl 1):S23–S34.
- Patel A, Agarwal R, Rudramurthy SM, et al. Multicenter epidemiologic study of coronavirus disease-associated mucormycosis, India. Emerg Infect Dis 2021;27(9):2349–2359.
- Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18(3):556–569.
- Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008;47(4):503–509.
- Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 2016;16(7):828–837.
- Jose A, Singh S, Roychoudhury A, et al. Current understanding in the pathophysiology of SARS-CoV-2-associated rhino-orbito-cerebral mucormycosis. J Maxillofac Oral Surg 2021;20(3):373–380.
- Spruit MA, Singh SJ, Garvey C, et al. An official ATS/ERS statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013;188(8):e13–e64.
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