Pulmonary, Cutaneous, Gastrointestinal and Disseminated Mucormycosis
Also known as: Pulmonary Mucormycosis, Cutaneous Mucormycosis, Gastrointestinal Mucormycosis, Disseminated Mucormycosis
Beyond the head, mucormycosis presents as pulmonary, cutaneous and soft tissue, gastrointestinal, and disseminated disease, with a few less common forms. The portal of entry (inhalation, skin inoculation, or ingestion) and the host determine presentation.
| Form | Typical host | Common organisms | Mortality |
|---|---|---|---|
| Pulmonary | Neutropenia, stem cell transplant, haematological malignancy, solid organ transplant, diabetes | Rhizopus, Mucor, Lichtheimia, Rhizomucor, Cunninghamella | 50 to 70 percent or higher |
| Cutaneous and soft tissue | Trauma, burns, surgery, disasters, contaminated dressings, neonates | Apophysomyces, Saksenaea, Lichtheimia, Rhizopus, Mucor | 10 to 30 percent (superficial), 50 to 80 percent (deep or disseminated) |
| Gastrointestinal | Premature neonates, malnutrition, diabetes, neutropenia | Rhizopus, Mucor, Lichtheimia | 50 to 85 percent |
| Disseminated | Neutropenia, transplant, iron chelation | Rhizopus, Cunninghamella, Lichtheimia | 80 to 100 percent |
| Isolated renal | Apparently healthy adults in Asia (and some immunosuppressed) | Rhizopus, Mucor | 30 to 60 percent |
| Isolated cerebral | Injection drug users (basal ganglia) | Rhizopus | High |
| Others | Endocarditis, osteomyelitis, peritonitis, mediastinitis | Variable | High |
Hosts
Neutropenia from leukaemia or chemotherapy, allogeneic stem cell transplant (graft versus host disease), solid organ transplant (lung and kidney), diabetes mellitus, corticosteroids, and iron overload. It is also an important complication after voriconazole prophylaxis and in COVID-19.
Clinical features
- Persistent fever unresponsive to broad spectrum antibacterials, cough, pleuritic chest pain, dyspnoea, and haemoptysis, which can be massive when the process invades the hilum and major vessels (pulmonary artery or its branches, with pseudoaneurysm or arteriovenous fistula).
- Hilar and mediastinal invasion, bronchial obstruction, and extension through the chest wall or diaphragm.
- Dissemination to brain, skin, and other organs.
- Symptoms can be minimal in neutropenic patients, and it is easily mistaken for aspergillosis or bacterial pneumonia.
Imaging
| Finding | Notes |
|---|---|
| Reverse halo sign (atoll sign: a central area of ground glass attenuation surrounded by a ring of consolidation) | Present in up to about 20 to 50 percent, more suggestive of mucormycosis than aspergillosis early in neutropenia |
| Multiple (10 or more) nodules, pleural effusion, and concomitant sinusitis | More often in mucormycosis; a halo sign is more often in aspergillosis |
| Large consolidation, thick walled cavities, and air crescent | Occur in both |
| Vascular invasion, lobar destruction, and "pulmonary artery pseudoaneurysm" | Risk of fatal haemoptysis; computed tomography angiography |
| Mediastinal and hilar mass | Direct extension |
Diagnosis
- Bronchoscopy with bronchoalveolar lavage for direct microscopy (calcofluor white), culture, and Mucorales polymerase chain reaction; culture sensitivity is low (about 25 to 50 percent), and transbronchial biopsy and computed tomography guided biopsy have a better yield where safe.
- Tissue histology showing broad aseptate hyphae with angioinvasion.
- Serum or plasma Mucorales polymerase chain reaction.
- Galactomannan and beta D glucan are negative.
- A positive respiratory culture for Mucorales in a high risk patient is regarded as significant, in contrast to Aspergillus.
Treatment
- First line: liposomal amphotericin B 5 to 10 mg per kg intravenously once daily, with step down to posaconazole delayed release tablets 300 mg twice daily on day 1 then 300 mg once daily (trough above 1 microgram per mL) or isavuconazonium sulphate 372 mg every 8 hours for 6 doses then 372 mg daily, after clinical stabilisation.
- Surgery: resection (lobectomy or pneumonectomy) of localised disease combined with antifungal therapy is associated with better survival, and is considered early, particularly for lesions abutting vessels, cavities, and haemoptysis. Mediastinal disease needs surgical debridement.
- Reverse underlying defects: granulocyte colony stimulating factor, reduction of immunosuppression, and glycaemic control.
- Combination therapy: liposomal amphotericin B with an echinocandin or posaconazole is used in refractory disease, with limited evidence.
- Duration: at least 6 to 12 weeks, until radiological resolution and immune recovery, with secondary prophylaxis (posaconazole 300 mg daily or isavuconazole 372 mg daily) during further chemotherapy or transplant.
- Massive haemoptysis: bronchial or pulmonary artery embolisation and emergency surgery.
Setting
Primary cutaneous mucormycosis follows direct inoculation of spores into skin: traumatic injuries with soil contamination (road traffic accidents, falls, and combat wounds), tornado and tsunami injuries, burns, surgical wounds, intravenous catheter and injection sites, insect bites, adhesive tape and bandages, and in neonates. Apophysomyces and Saksenaea are associated with trauma in healthy hosts in tropical regions, Lichtheimia with burns and wounds, and Rhizopus with contaminated dressings. Secondary disease is by haematogenous spread.
Clinical features
- Superficial: plaques, pustules, and papules with erythema and scaling, and a wound that fails to heal; usually slowly progressive.
- Deep: rapidly progressive necrotic ulcers with a black eschar, surrounded by erythema and induration, with infarction, haemorrhagic bullae, and spread to fascia and muscle (necrotising fasciitis like picture), tendons, and bone.
- Disseminated: multiple skin lesions and organ involvement.
- Pain, fever in some, and rapid expansion over hours to days despite antibacterial therapy.
Diagnosis
Punch or surgical biopsy from the edge of the lesion (not a swab), with direct microscopy, histology (broad aseptate hyphae with vascular invasion and necrosis), culture, and polymerase chain reaction; imaging (computed tomography or magnetic resonance imaging) for depth, bone, and fascia involvement; and a search for dissemination.
Treatment
- Surgery: early and wide debridement of all necrotic and infected tissue to healthy bleeding margins, repeated every 24 to 48 hours as needed, often with fasciotomy and sometimes amputation. Early excision is the principal determinant of survival.
- Antifungal therapy: liposomal amphotericin B 5 to 10 mg per kg intravenously once daily, with step down to posaconazole 300 mg daily after the first dose of 300 mg twice daily (delayed release tablets) or isavuconazonium sulphate 372 mg once daily after loading.
- Topical: topical amphotericin B or local irrigation have been used as adjuncts, with limited evidence.
- Adjuncts: negative pressure wound therapy after debridement, hyperbaric oxygen in some centres (limited evidence), control of diabetes, and reduction of immunosuppression.
- Duration: until wounds heal and a granulating bed is clear of fungus on repeated biopsy, commonly 4 to 8 weeks or more, and longer in deep disease.
- Burns: early excision of infected eschar, biopsy of burn wounds that deteriorate or fail to heal, and removal of contaminated dressings.
Gastrointestinal mucormycosis is uncommon and is difficult to diagnose, and it is often found at laparotomy or autopsy. The stomach is the commonest site (about 60 percent), followed by colon and ileum.
Setting
- Premature and low birth weight neonates with necrotising enterocolitis, antibacterial exposure, and corticosteroids, and contamination of enteral feed and equipment.
- Malnourished children and adults, in low income settings, with amoebiasis, typhoid, and diarrhoeal diseases.
- Diabetes, haematological malignancy, transplant, and corticosteroid treatment.
- Ingestion of contaminated fermented foods, herbal preparations, and traditional medicines (reported in India, Africa, and the Middle East).
- Gastric catheters, peritoneal dialysis, and abdominal surgery.
Clinical features
Abdominal pain and distension, nausea and vomiting, haematemesis or melaena, diarrhoea, fever, and non resolving necrosis. Complications are perforation, peritonitis, massive bleeding, and mesenteric thrombosis with infarction. Neonates present like necrotising enterocolitis that fails to respond to treatment.
Diagnosis
Endoscopic biopsy (ulcerated or necrotic mucosa), histology, and culture; imaging by computed tomography shows bowel thickening, necrosis, and perforation. Diagnosis is often by laparotomy or at autopsy, so a high index of suspicion is required.
Treatment
Surgical resection of necrotic bowel and debridement of the peritoneum is combined with liposomal amphotericin B 5 to 10 mg per kg once daily (neonates 5 mg per kg once daily), followed by posaconazole or isavuconazole step down. Duration is at least 6 weeks and until resolution. Mortality is 50 to 85 percent, and early surgery lowers it.
Dissemination follows pulmonary, sinus, cutaneous, or gastrointestinal infection and affects mainly neutropenic and iron overloaded patients, and those on deferoxamine. The brain is the commonest site, followed by the skin, spleen, heart, and kidney. Cunninghamella bertholletiae and Rhizopus are the usual agents. Signs are fever, sepsis, multiple organ failure, skin lesions, and neurological deficits.
Diagnosis is by biopsy of skin or involved organs, polymerase chain reaction on blood, and imaging. Treatment is liposomal amphotericin B 10 mg per kg once daily (with attention to nephrotoxicity), combination therapy in refractory disease, surgical debridement of accessible foci, reversal of immune deficits (neutrophil recovery with granulocyte colony stimulating factor), and secondary prophylaxis. Mortality is 80 to 100 percent, and survival depends on recovery of neutrophils.
- Isolated renal mucormycosis: presents in apparently healthy adults in Asia (and in some immunocompromised patients) with flank pain, fever, and haematuria; bilateral renal involvement can cause kidney failure. Nephrectomy for unilateral disease and liposomal amphotericin B, with posaconazole step down, give survival of about 50 to 70 percent.
- Isolated cerebral mucormycosis: injection drug users (basal ganglia abscess and infarction); surgery plus liposomal amphotericin B 10 mg per kg daily.
- Endocarditis: prosthetic valves and drug use; valve replacement and liposomal amphotericin B 5 to 10 mg per kg daily.
- Osteomyelitis: post traumatic or surgical; debridement and prolonged therapy.
- Peritonitis: peritoneal dialysis; catheter removal and antifungal therapy.
- Mediastinitis and tracheobronchial disease: after cardiac surgery or in diabetes.
- Otomycosis and external otitis, and ocular and orbital infection: local debridement and antifungal therapy.
| Condition | Points that separate it |
|---|---|
| Invasive aspergillosis | Septate hyphae, galactomannan positive, halo sign more than reverse halo; both may coexist |
| Fusariosis and scedosporiosis | Septate hyaline hyphae, positive blood culture in fusariosis, skin lesions |
| Bacterial necrotising fasciitis and ecthyma gangrenosum | Rapid response to antibacterial therapy and surgery; bacterial cultures |
| Necrotising pneumonia, lung abscess, and tuberculosis | Culture and molecular testing |
| Pyoderma gangrenosum | Biopsy and response to immunosuppression |
| Mesenteric ischaemia, necrotising enterocolitis, and Crohn disease | Clinical context and histology |
| Neoplasm and vasculitis | Histology |
| Agent | Detail |
|---|---|
| Liposomal amphotericin B | 5 mg per kg once daily is standard, and 10 mg per kg once daily is used in central nervous system and some severe disease; check creatinine, potassium, magnesium, and use saline loading; infusion reactions are less than with the conventional form |
| Posaconazole | Delayed release tablet 300 mg twice daily on day 1, then 300 mg daily, with food; intravenous form (via central line) at equivalent doses; trough above 1 microgram per mL; interactions with calcineurin inhibitors, sirolimus, and vinca alkaloids; QT prolongation |
| Isavuconazole | 372 mg every 8 hours for 6 doses, then 372 mg daily, orally or intravenously; no QT prolongation (shortening); fewer interactions; liver tests |
| Duration | At least 6 weeks and until imaging, culture, and immune defect resolve; many patients need months |
| Salvage | Combination of liposomal amphotericin B with posaconazole or an echinocandin, or posaconazole with isavuconazole, with limited data |
| Factor | Effect |
|---|---|
| Delay in diagnosis and treatment beyond 5 to 6 days | Higher mortality (about 80 percent against 50 percent in one series) |
| Site | Cerebral and disseminated disease worst; sinus disease best |
| Surgery | Early surgical debridement improves survival |
| Underlying defect | Persistent neutropenia and corticosteroids worsen; diabetes control improves |
| Amphotericin B dose and formulation | Lipid formulation at 5 mg per kg or higher |
| Cunninghamella and renal failure | Poor prognosis |
Glycaemic control, minimising corticosteroids, avoiding deferoxamine in at risk patients, wound care and early debridement of contaminated trauma and burns, protective environments for neutropenic and transplant patients (high efficiency particulate air filtration, avoiding construction and flooding), sterile water for humidifiers and oxygen, avoidance of contaminated adhesive tapes, wooden depressors, and linen, and posaconazole or isavuconazole prophylaxis for selected high risk haematology patients.
