Fusariosis
Also known as: Fusarium Infection, Fusarium Keratitis, Disseminated Fusariosis
Fusarium is a genus of ubiquitous hyaline filamentous fungi in soil, water, air, and plants (a major plant pathogen and a source of mycotoxins such as fumonisins, trichothecenes, and zearalenone). It causes the third commonest invasive mould infection in haematological patients after aspergillosis and mucormycosis, and it is the leading cause of mould keratitis in warm climates.
Fusariosis covers three groups of disease: superficial and local (keratitis, onychomycosis, skin and soft tissue infection), invasive and disseminated disease in the immunocompromised, and allergic or toxin related disease (mycotoxicosis from contaminated grain). Disseminated disease with positive blood cultures and skin lesions in a neutropenic patient is characteristic.
| Species complex | Examples | Clinical notes |
|---|---|---|
| Fusarium solani species complex | Fusarium solani, Fusarium keratoplasticum, Fusarium petroliphilum | Commonest in keratitis, onychomycosis, and disseminated disease; reduced susceptibility to amphotericin B and azoles; colonises water systems and hospital plumbing |
| Fusarium oxysporum species complex | Fusarium oxysporum | Disseminated disease, keratitis, and onychomycosis; variable susceptibility |
| Fusarium fujikuroi species complex | Fusarium verticillioides, Fusarium proliferatum, Fusarium sacchari | Disseminated disease; produces fumonisins; amphotericin B and voriconazole often active |
| Fusarium incarnatum equiseti species complex | Fusarium incarnatum, Fusarium equiseti | Keratitis and disseminated disease |
| Fusarium dimerum species complex | Fusarium dimerum | Rare; low virulence |
| Fusarium chlamydosporum species complex | Fusarium chlamydosporum | Rare; skin and invasive disease |
Species identification uses sequencing of translation elongation factor 1 alpha, and RNA polymerase subunit genes, because the internal transcribed spacer region does not separate species, and mass spectrometry needs an extended mould database.
| Aspect | Details |
|---|---|
| Colony | Fast growing (3 to 5 days) on Sabouraud dextrose agar at 25 to 37 degrees Celsius; woolly or cottony, white, then pink, violet, cream, or yellow, with a pigmented reverse in many species. Grows on media with cycloheximide at reduced rates |
| Hyphae | Hyaline, septate, 3 to 8 micrometres wide, with acute angle (about 45 degree) and dichotomous branching, similar to Aspergillus in tissue |
| Conidia | Macroconidia that are sickle or banana shaped, multiseptate, with a foot cell, produced in sporodochia on specialised media (carnation leaf agar); microconidia, single or two celled, in false heads (Fusarium solani) or chains (Fusarium verticillioides, Fusarium proliferatum) on long or short monophialides |
| Adventitious sporulation | Formation of conidia, yeast like cells, and phialides in tissue and in blood, which explains positive blood cultures in about 40 to 60 percent of disseminated cases and distinguishes Fusarium (and Scedosporium) from Aspergillus |
| Direct microscopy | Calcofluor white or potassium hydroxide shows hyaline septate hyphae, which cannot be separated from Aspergillus |
| Histology | Angioinvasion with thrombosis and infarction; hyphae and adventitious yeast like forms; neutrophilic or granulomatous inflammation |
| Biomarkers | Beta D glucan is often positive; serum galactomannan is positive in a proportion of cases through cross reactivity, so a positive test does not identify Aspergillus |
| Molecular detection | Panfungal polymerase chain reaction with sequencing; real time polymerase chain reaction on blood is used in some centres |
| Susceptibility testing | Reference broth microdilution; no clinical breakpoints; minimal inhibitory concentration values guide therapy, because resistance is common and species dependent |
| Setting | Details |
|---|---|
| Haematological malignancy | Acute leukaemia with prolonged neutropenia (most invasive cases), and allogeneic stem cell transplant with graft versus host disease |
| Other immunosuppression | Solid organ transplant, corticosteroid treatment, T cell depleting agents, and inherited immune defects |
| Skin and nail breach | Onychomycosis and tinea pedis in neutropenic patients are the commonest portal of entry for disseminated disease |
| Trauma and inoculation | Penetrating injury with plant material or soil, burns, and surgical wounds |
| Contact lens wear and ocular injury | Keratitis; outbreaks were linked to a contact lens solution in 2005 to 2006 |
| Hospital water | Contaminated plumbing, showers, and taps are a reservoir in haematology units |
| Geography | More frequent in tropical and subtropical regions, including Brazil, where it is the second commonest invasive mould infection in leukaemia |
Disseminated and invasive disease
- Persistent fever in a neutropenic patient unresponsive to broad spectrum antibacterials.
- Skin lesions in about 60 to 70 percent: multiple painful erythematous macules, papules, or nodules, often with a central necrotic area and a halo (target like or ecthyma gangrenosum like lesions), on the trunk and limbs, and metastatic lesions throughout the body.
- Myalgia and bone pain.
- Pulmonary disease: nodules, cavities, consolidation, halo sign, pleural effusion, and haemoptysis.
- Sinus disease: sinusitis with facial pain, necrosis, and extension to the orbit and brain.
- Fungaemia with positive blood cultures in many.
- Endophthalmitis, osteomyelitis, central nervous system disease, and endocarditis occur less often.
- Mortality is 50 to 80 percent, and higher than 90 percent in persistent neutropenia.
Localised disease
| Site | Features |
|---|---|
| Keratitis | Painful, red eye after trauma with plant material or contact lens wear; corneal ulcer with feathery margins, satellite lesions, hypopyon, and ring infiltrate; can progress to perforation and endophthalmitis |
| Endophthalmitis | After intraocular surgery or haematogenous spread |
| Onychomycosis | Proximal subungual and white superficial patterns, with periungual infection and paronychia; common in diabetic patients |
| Skin and soft tissue | Wound infection, cellulitis, and cutaneous nodules after trauma; burns |
| Mycetoma | Rare, with pale grains |
| Peritonitis, arthritis, and osteomyelitis | Peritoneal dialysis, injection, or after trauma |
| Mycotoxicosis | Alimentary toxic aleukia and other syndromes after ingestion of contaminated grain |
| Condition | Points that separate it |
|---|---|
| Invasive aspergillosis | Positive galactomannan, rarely positive blood cultures, rarely skin lesions |
| Mucormycosis | Aseptate broad hyphae, negative biomarkers, culture without cycloheximide |
| Scedosporiosis and lomentosporiosis | Annellides on culture, resistance pattern, fungaemia in prolificans |
| Ecthyma gangrenosum from Pseudomonas aeruginosa | Positive bacterial cultures, response to antibacterials |
| Disseminated candidiasis | Yeasts in blood culture, different histology |
| Bacterial sepsis with skin emboli | Cultures and biopsy |
| Sweet syndrome and leukaemia cutis | Biopsy and cytogenetics |
Culture of blood (positive in 40 to 60 percent of disseminated cases), skin biopsy of a new lesion for histology and culture (the fastest route in a neutropenic patient), and sputum, bronchoalveolar lavage, and tissue for microscopy and culture. Corneal scrapings (with calcofluor white and culture) for keratitis, and confocal microscopy in vivo where available. Biopsy of a skin lesion in a neutropenic patient with fever is done early.
| Drug | Activity |
|---|---|
| Amphotericin B | Active, but minimal inhibitory concentrations are higher in Fusarium solani complex and Fusarium oxysporum complex, with values of 2 micrograms per mL or higher in many isolates; Fusarium verticillioides and Fusarium proliferatum are often lower |
| Voriconazole | Active in about half of isolates, with a minimal inhibitory concentration of 1 to 8 micrograms per mL and higher in some; no clinical breakpoints |
| Posaconazole | Variable; usually higher values than voriconazole |
| Itraconazole and fluconazole | Poor or inactive |
| Isavuconazole | Variable, with limited data |
| Echinocandins | Inactive, and not used as monotherapy |
| Flucytosine | Inactive |
| Terbinafine | In vitro activity but limited clinical data |
| Natamycin | Active against Fusarium and the reference topical agent for keratitis |
Because of the unpredictable pattern, therapy is guided by isolate level susceptibility data and by the host and site.
Principles
Recovery from neutropenia is the strongest determinant of outcome, so management combines antifungal therapy, reversal of immune defects, removal of infected foci, and treatment of the portal of entry.
Invasive and disseminated disease
| Element | Details |
|---|---|
| First line | Voriconazole (loading 6 mg per kg intravenously every 12 hours for 2 doses, then 4 mg per kg every 12 hours; oral 200 mg every 12 hours, increased to 300 mg every 12 hours by trough, with 100 mg in people under 40 kg), or liposomal amphotericin B 5 to 10 mg per kg once daily in guidelines that favour higher doses (3 to 5 mg per kg is also used) |
| Combination | Liposomal amphotericin B with voriconazole, favoured in severe disease and in persistent neutropenia, where observational data suggest a lower mortality; evidence is limited to cohort studies |
| Salvage | Posaconazole delayed release tablets 300 mg every 12 hours on day 1, then 300 mg daily (with trough above 1 microgram per mL), or isavuconazonium sulphate 372 mg every 8 hours for 6 doses, then 372 mg daily, with limited data |
| Drug levels | Voriconazole trough 1 to 5.5 micrograms per mL (above 2 for severe disease), and posaconazole trough above 1 microgram per mL |
| Neutrophil support | Granulocyte colony stimulating factor, and granulocyte transfusions for refractory neutropenia (limited evidence) |
| Surgery | Debridement of necrotic skin, sinus, and pulmonary lesions, and removal of infected catheters |
| Reduction of immunosuppression | Reduce or stop corticosteroids where possible |
| Duration | Several weeks to months, until neutrophil recovery and resolution of lesions, and secondary prophylaxis during further neutropenia or transplant (voriconazole or posaconazole) |
| Monitoring | Blood cultures every 24 to 48 hours until clearance, skin lesion examination, imaging, and drug monitoring |
Keratitis
| Element | Details |
|---|---|
| Topical | Natamycin 5 percent suspension, one drop every hour while awake for the first 1 to 2 days, then every 2 hours, tapered over 2 to 3 weeks; superior to topical voriconazole 1 percent in a randomised trial for Fusarium keratitis |
| Alternatives | Voriconazole 1 percent drops, and amphotericin B 0.15 percent drops where natamycin is not available |
| Adjunctive systemic | Oral voriconazole (200 mg every 12 hours) in deep or severe disease, though oral voriconazole did not improve the outcome in the trial of oral voriconazole added to topical therapy |
| Intrastromal or intracameral | Voriconazole 50 micrograms per 0.1 mL (intrastromal) for deep infiltrates, with limited evidence |
| Surgery | Debridement of the epithelium, therapeutic keratoplasty for perforation or progressive infection, and cross linking has been tried with limited evidence |
| Follow up | Daily review in the first days and prolonged therapy until re-epithelialisation and resolution of infiltrate |
Onychomycosis and skin infection
Terbinafine 250 mg daily or itraconazole in nail disease, though response is poor in Fusarium onychomycosis, and treatment of the nail in an immunocompromised patient is done before chemotherapy. Wounds are debrided and treated with an oral azole according to susceptibility.
Prognosis depends on neutrophil recovery. Survival is higher than 60 percent in patients whose neutrophils recover, and below 10 percent in persistent neutropenia. Localised cutaneous disease and onychomycosis have a good outcome. Keratitis can result in loss of vision in up to 40 percent despite treatment.
- Treat onychomycosis and tinea pedis before chemotherapy and transplant.
- Protect haematology units with filtered air and water filters, or point of use filtration at taps and showers.
- Avoid contact lens misuse and corneal trauma. Contact lens hygiene is advised.
- Use mould active prophylaxis with posaconazole in high risk patients, with limited efficacy against Fusarium.
