Guideline for Prophylaxis and Management of Invasive Fungal Infection in the Paediatric Haematology and Oncology Department

• Aims
• Background
• Risk Assessment
• Antifungal Prophylaxis
• Empirical Therapy
• Directed Antimicrobial Treatment

Aims

To improve the prophylaxis and management of Invasive Fungal Infection in the Paediatric Haematology and Oncology Department.

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Background

Invasive fungal disease (IFD) describes tissue damage associated with clinical illness as a result of infection with yeast or mould. The incidence of IFD is rising, perhaps related to more intensive immunosuppression in the treatment of patients with a variety of conditions as well as improved survival of those with inherited immunodeficiencies. (1)Within paediatrics, the patients most commonly affected by IFD are those with haematological malignancy (particularly acute myeloid leukaemia (AML) and relapsed acute lymphoblastic leukaemia (ALL)), those undergoing allogeneic haematopoietic stem cell transplant (HSCT) and those receiving highly myelosuppressive chemotherapy for other malignancy. (2)The outcome of IFD with current therapies is poor. Yeast infections, including Candida, are associated with mortality of 10-50%. Invasive Aspergillus is even more challenging with 52.5-85% mortality. (3–5)

The available management strategies for IFD can be divided into three broad categories. Antifungal prophylaxis may be administered to high risk groups with a view to preventing the development of IFD, and have been reviewed in light of the most recent paediatric-specific international guidelines (6). Empirical treatment is that which is initiated when a physician suspects IFD in a high risk patient but has no diagnostic evidence for this. Directed therapy is that used once a definite mycological diagnosis is made.(7)

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Risk Assessment

1. All patients require a risk assessment for invasive fungal infection at diagnosis, at every phase of treatment (eg. induction, consolidation etc.) and on every presentation with febrile neutropenia.

Table 1: Risk assessment strata for invasive fungal infection in children under the care of paediatric haematology and oncology department

†Whilst still meeting criteria for receiving antifungal prophylaxis (as defined below). Any patient with severe or chronic graft versus host disease post allogeneic stem cell transplantation (SCT) that has required treatment with high dose steroid (>0.3mg/kg) or immunotherapy (for example basiliximab or etanercept) within the past year must be treated as per very high risk patient pathway irrespective of neutrophil count. Other non-neutropenic allogeneic SCT recipients should usually be managed as dictated by their clinical condition & discussed with a Consultant in Haematology/Oncology.

All high and very-high risk patients need a personal risk assessment for mould infections (this relates to their home/nearby environments, and includes any building works, poor state of housing, for example damp or obvious mould growth, or similar).  

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Antifungal Prophylaxis

All patients require education about the dietary and environmental aspects of protection from fungal disease by an appropriate healthcare professional.

Very high risk patients

Pharmaceutical antifungal antimould prophylaxis should be given to all very high risk patients.

Note: Antifungal prophylaxis does not remove all risk of fungal infection – patients CAN develop fungal infections and need to follow this guidance.

Choice of antifungal prophylaxis:

An echinocandin or mould-active azole are the antifungals of choice: caspofungin (IV only), or itraconazole / posaconazole.

Certain trial protocols may dictate specific prophylaxis regimes.

Intravenous antifungal prophylaxis:

1. If a patient is deemed to require prophylaxis and will be an in-patient, use caspofungin (70mg/m2 day 1, (capped at 70mg) subsequent days 50mg/m2 (capped at 50mg) ).
2. If caspofungin is not a suitable option, for example if there are concerns about hepatic toxicity, but IV prophylaxis is considered, use Ambisome. This should be prescribed via the ‘Protocols’ on EMeds, which has a test dose and then the complete dose; a Monday / Thursday system is considered acceptable.

Oral antifungal prophylaxis choices:

1. If a patient is considered to be at high risk for mould infection, consider anti-mould prophylaxis with itraconazole. The liquid preparation is thought to offer better bioavailability, though if taken appropriately, the capsules can achieve therapeutic levels. Formulation choice should be based on the individual and effects made to maximise the absorption for each different formulation. In the rare situation where neither product is tolerated, treatment options should be discussed with the consultant.
2. If the patient is on iron chelation therapy, consider posaconazole as the anti-fungal agent of choice.
3. Therapeutic drug monitoring for itraconazole is required - follow principles of adult guideline; test 7 days after commencing the drug, or after a change in situation (including any dose change or introduction of other drugs known to alter levels). Target level 0.5 - 4mg/L. If levels >2mg/L then be very cautious about other drug interactions and consider a lower target for this patient.

Stopping rules 

1.  For both standard antifungal prophylaxis and anti-mould prophylaxis, the stopping rules are as follows:
   • In patients with AML, stop if neutrophils >1 x10⁹/L and all chemotherapy completed.
   • In patients with severe aplastic anaemia or HLH, stop if neutrophils >0.5x10⁹/L for 2 weeks and off IST.
   • In patients following allogeneic HSCT, stop if: neuts >0.5 x 2 weeks, no chronic GVHD, no prednisolone >0.3mg/kg, off IST.

High risk patients

Note that this group will not usually be on prophylaxis.  However, if an environmental risk factor has been identified then prophylaxis should be considered.  It is also important to work to modify any environmental risk factors and the support of the social care team may be helpful.  

Standard risk patients

This group does not require anti-fungal prophylaxis.

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Empirical therapy

If a patient is admitted acutely with suspicion of an occult infection, most commonly febrile neutropenia, the following steps to consider and institute empirical therapy should be undertaken:

*Remember: Antifungal prophylaxis does not remove all risk of fungal infection – patients CAN develop fungal infections.

Note – at all points – if chest X-ray (CXR) clearly suggests a lower respiratory tract infection (LRTI) or other intra-thoracic problem, then discuss omission of high-resolution CT scan (HRCT) with on-call consultant and/or radiologist

Very high risk patients

1. Establish compliance with any pharmaceutical prophylaxis. It may be appropriate to check drug levels in some cases, on Consultant advice,
2. Assess for signs of fungal infection (including haemoptysis, chest pain, sinus pain, dental pain, skin lesions)
3. If there are lower respiratory tract signs – CXR +HRCT (including at weekends). If these are suggestive of fungal respiratory infection, discuss with the respiratory team and consider BAL for culture and Aspergillus antigen of fluid.
4. If there are sinus signs – request imaging (obtain radiology advice on most appropriate methods)
5. If any signs of fungal infection – commence treatment immediately with Ambisome 3mg/kg od.
6. In children who have a history of intravenous iron chelation with desferrioxamine, where probable IFI is present and not responding to first line therapy, consider an early change to posaconazole (if 8 years of age or older in line with current approvals; younger will need specific approval request). 
7. If there are no specific signs of fungal infection and still PERSISTENTLY febrile on day 5 of antibiotics, investigate with:
   • Repeat aspergillus antigen
   • CXR
   • Repeat blood cultures
   • HRCT chest (within a 48-72 hour window), if not already performed
     These investigations are used to find more evidence of infection in order to guide duration of treatment.
8. Start treatment with empiric Ambisome 1mg/kg od on day 5 (if not already commenced on 3mg/kg).
9. If infection is NOT confirmed, consider stopping antifungals when:
   • afebrile for at least 48 hours, and
   • there is no clinical/radiological/microbiological/serological evidence of invasive fungal infection

High risk patients

As above.  Note that this group will not usually be on prophylaxis.

Standard risk patients
Note: Standard risk patients are VERY UNLIKELY to have invasive fungal disease

Note that this group will not usually be on prophylaxis.

Please consider steps 1-4 above.

1. If there are any signs of fungal infection – commence treatment immediately with Ambisome 3mg/kg od.
2. If there are no specific signs of fungal infection and still PERSISTENTLY febrile and NOT RESPONDING to antibiotics, consider all possible other causes for infection, including bacteria and viruses, and refractory or progressive disease.
3. If strong concern remains that the cause of fever might be invasive fungal infection (see EORTC definitions of infection), then investigate on day 5 of illness with:
   • Aspergillus antigen
   • CXR
   • Repeat blood cultures
   • HRCT chest (within a 48-72 hour window)
     These investigations are used to find more evidence of infection in order to guide duration of treatment.
4. If these do not suggest fungal infection, do NOT routinely commence antifungal treatment.
5. If fungal infection is still being considered after the tests have been reviewed then consider starting empirical antifungal treatment (without investigations suggesting infection) is commenced.  Use Ambisome 1mg/kg od in this setting.
6. If treatment was empirical, consider stopping antifungals if there is no clinical/radiological/microbiological/serological evidence of invasive fungal infection, regardless of the presence of persistent fever.

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Directed antimicrobial treatment (when specific infection suspected and/or microbiology results are known)

Note: Proven and probable infections by EORTC criteria should be treated according to the appropriate specific recommendations.

Oral or genital candidiasis

1. Send swabs if suspected.
2. Start treatment with systemic fluconazole for 7 days, then review and consider further 7 days of treatment (14 days total).
3. STOP fluconazole if the swabs are negative
4. DO NOT routinely treat with topical agents alone (eg Nystatin)
5. If nappy rash with potential candidiasis, consider treatment with fluconazole, or topical clotrimazole if the rash is limited and the child is not unwell.

Invasive candida infection

1. At diagnosis, request Echo, abdominal USS, eye examination.
2. Do repeat blood cultures every 48-72 hours until negative.
3. Fast immediately and remove all central lines within 24 hours
4. Treatment principles - use IV caspofungin: discuss with on-call consultant & Microbiologist – step down to fluconazole when controlled
5. If evidence of endocarditis, treat on case by case basis following discussion with Microbiologist.
6. If no evidence of endocarditis, treat for two weeks following first negative blood culture.

Invasive aspergillosis

1. Immediate discussion with on-call consultant and Microbiologist.
2. Extra tests as determined by site of infection, and guided by consultants
3. Treatment principles - ambisome (3mg/kg od) or voriconazole (as per BNF-c) depending on site of infection and microbiology advice.
4. Standard treatment duration is a minimum of six weeks BUT this is highly dependent on site of infection, degree of future immunosuppression, and ongoing risk features in patient and environment. Discuss with appropriate consultant/microbiology.
5. Need for secondary prophylaxis depends on same features as above: site of infection, degree of future immunosuppression, and ongoing risk features in patient and environment. Discuss with appropriate consultant/microbiology.

Other invasive mould infections
As for Invasive Aspergillosis, but treatment with antifungal appropriate to identified organism.

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1. McNeil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD, et al. Trends in Mortality Due to Invasive Mycotic Diseases in the United States, 1980–1997. Clin Infect Dis. 2001 Sep 1;33(5):641–7.
2. Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, et al. Guideline for the Management of Fever and Neutropenia in Children With Cancer and/or Undergoing Hematopoietic Stem-Cell Transplantation. J Clin Oncol. 2012 Dec 10;30(35):4427–38.
3. Burgos A, Zaoutis TE, Dvorak CC, Hoffman JA, Knapp KM, Nania JJ, et al. Pediatric Invasive Aspergillosis: A Multicenter Retrospective Analysis of 139 Contemporary Cases. Pediatrics. 2008 May 1;121(5):e1286–94.
4. Groll AH, Kurz M, Schneider W, Witt V, Schmidt H, Schneider M, et al. Five-year-survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long-term survival. Mycoses. 1999;42(7-8):431–42.
5. Abbasi S, Shenep JL, Hughes WT, Flynn PM. Aspergillosis in Children with Cancer: A 34-Year Experience. Clin Infect Dis. 1999 Nov 1;29(5):1210–9.
6. Lehrnbecher T, Fisher BT, Phillips B, Beauchemin M, Carlesse F, Castagnola E et al. Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients. Journal of Clinical Oncology. 2020 May 27;JCO2000158. https://doi.org/10.1200/JCO.20.00158
7. Rüping MJGT, Vehreschild JJ, Cornely OA. Antifungal treatment strategies in high risk patients. Mycoses. 2008;51:46–51.
8. ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children. Warris A, Lehrnbecher T et al. Clin Microbiol Infect. 2019 25(9):1096-1113. doi: 10.1016/j.cmi.2019.05.019
9. Liposomal amphotericin B twice weekly as antifungal prophylaxis in paediatric haematological malignancy patients. Clinical Microbiology and Infection. 2011;17:1868-1874