Fungal Infections in the oncology patient
The two most commonly diagnosed fungal infections are candidiasis and aspergillosis. Patients most at risk of systemic fungal infection are those with prolonged severe neutropenia on broad-spectrum antibiotics.
Risk factors
The two most commonly diagnosed fungal infections are candidiasis and aspergillosis. Patients most at risk of systemic fungal infection are those with prolonged severe neutropenia on broad-spectrum antibiotics.
Clinical features
These depend on the site of infection.
Fever (this may be the only clinical sign)
Cough, hypoxia
Sinus pain and/or discharge which may be clear or purulent
CNS signs (fungal space occupying lesion)
Hepatic transaminitis and/or abdominal pain
Renal dysfunction (renal fungal balls)
Patient risk stratification
Low risk
| PBSC autologous transplant |
| Childhood ALL |
Intermediate risk
| Low | Neuts 0.1-0.5 x 109/L for <3 weeks; lymphs <0.5 x 109/L on AB e.g., cotrimoxazole |
| CVC | |
| High | Colonised at >1 site or heavily at 1 site, neuts 0.1-0.5 x 109/L for 3-5 weeks |
| AML | |
| TBI | |
| Allogeneic matched sibling SCT | |
| Very High | Neuts <0.1 x 109/L for >3 weeks |
| Colonised by candida tropicalis | |
| Allogeneic MUD or mis-matched SCT | |
| GVHD | |
| Neuts < 0.5 x 109/L for >5 weeks | |
| Pred >1 mg/kg (or equivalent) and neuts <1 x 109/L for >1 week | |
| Pred >2 mg/kg (or equivalent) for >2 weeks | |
| High dose cytarabine (Ara-C) | |
| Fludarabine (uncertain) |
Investigations
This is generally done during investigations for persistent or recurrent PUO while on broad spectrum Abs:
CT scan - high resolution chest looking for specific (halo sign) or non specific (pneumonitis, nodules) features.
CT scan - head, sinuses, abdomen (hepatosplenic lesions) and pelvis.
Biopsies - if the patient is relatively well and BAL/biopsy (open or CT guided) can be arranged rapidly it is ideal to do this before starting antifungal therapy.
Non-culture based rapid diagnostic tests. There is some evidence for using Galactomannan as a screening test with reasonable specificity in adults. This section will be updated when there is further experience with these tests.
Aspergillus Species
Aspergillus is the most common mould causing invasive fungal infections. It is inherently resistant to fluconazole. The risk of infection is markedly reduced (but not entirely avoided) by nursing high-risk patients in filtered, positive pressure air. Rates of infection are increased in units where there are building works nearby.
Clinical features
pulmonary infiltration (best seen on CT scan)
sinus infiltration
occasionally focal CNS signs.
Investigations
As above
Management
There is insufficient data from paediatric trials to guide treatment of invasive aspergillus. Extrapolation from adult trials suggests that voriconazole may be superior to conventional amphotericin B but there were differences in treatment durations between the 2 arms of this trial and there are no head to head studies with liposomal amphotericin.
Treatment options are:
Voriconazole 6 mg/kg/dose bd with liposomal amphotericin 3 mg/kg/dose which can be stopped when therapeutic voriconazole levels are achieved. Therapeutic drug monitoring is required as some children may require up to 12 mg/kg/dose bd to achieve therapeutic levels.
Liposomal amphotericin 3 mg/kg daily
Caspofungin 50 mg/m2 daily as a second line agent.
Candida Albicans and Other Candida Species
There are several different types of Candida which have different susceptibility patterns⁽¹⁾. Currently:
Patterns of susceptibility to licensed antifungal agents among the major Candida species (*).
| - | Amphotericin B | Caspofungin | Fluconazole | Voriconazole |
| C. albicans | S | S | S | S |
| C. glabrata | S | S | S-DD to R | S to I |
| C. krusei | S | S | R | S to I |
| C. parapsilosis | S | S (**) | S | S |
| C. tropicalis | S | S | S | S |
Table adapted from Ostrosky-Zeichner and Pappas, 2006.
(*) Patterns of susceptibility are based on results of > 75% of clinical isolates.
(**) Intermediate susceptibility is rarely reported.
Clinical Features
These are variable and include:
skin and/or mucosal infection
severe oesophagitis
hepato-splenic syndrome with fever, mild jaundice and raised liver enzymes, and increasing hepatomegaly and sometimes splenomegaly.
systemic disease with fever, jaundice and pulmonary infiltrates.
Management⁽¹⁾⁽²⁾
Most of the trials in children have been done in predominantly non-neutropenic patients. There are no adequately powered studies in neutropenic children with invasive candida. There is no evidence that any one agent is more effective than another.
Previous therapy should be considered (prior use of fluconazole selects for fluconazole resistant organisms)
The antifungal used should be chosen depending on the candidal species isolated until sensitivities are available (if required)
Fluconazole (6 mg/kg PO or IV daily for non-invasive and superficial infection, and 12mg/kg IV or PO daily for invasive disease) remains the treatment of choice for proven candidal infection in non-neutropenic patients unless there is local epidemiological data suggesting high rates of resistant species.
In neutropenic patients with proven candida a fungicidal agent (an echinocandin or polyene) is suggested.
Caspofungin 70 mg/m² loading for the first dose, followed by 50 mg/m² daily
Ambisome 1-3 mg/kg/day
Therapy should continue for at least 14 days after the last positive culture, 4 weeks for meningitis and > 6 weeks for chronic disseminated candida, endocarditis, endopthalmitis and osteomyelitis⁽²⁾.
Other Fungi
While candida and aspergillus species are the commonest fungi that cause invasive infections, outbreaks of other fungi are not uncommon.
Yeasts: Cryptococcus
Zygomycetes (black mould): Mucor, rhizomucor
Hyphomycetes: Fusarium, Scedosporium
Investigations
As for other fungi except for Cryptococcus. This requires samples from:
Urine
Blood
Sputum
CSF
As well as CT head
Management
Discuss all these cases with Infectious Diseases as soon as possible.
Cryptococcus. Treatment with amphotercin is required but this should be discussed with oncology unit and infectious diseases.
Zygomycetes
Liposomal amphotericin 5 mg/kg/day (resistant to voriconazole but susceptible to posaconazole)
Aggressive surgical debridement
Scedosporium
Optimal treatment is unknown. Azoles are probably superior to polyenes (amphotericin) but some species are resistant to all antifungals
Fusarium
Amphotericin, voriconazole or posaconazole may all be effective but sensitivities vary so susceptibility testing is recommended.