Development of a Febrile Neutropenia Guideline for South African Children with Cancer

David Moore^1, Sheena Mukkada^2, Ambuj Kumar^3, Andrew Whitelaw^4,5, Anel Van Zyl^6, Azraa Paruk⁷ Bernard Goodwin⁸ Beverley Neethling^9, Fathima Naby¹⁰ Fareed Omar¹¹ Helder de Quintal¹² Helena Rabie^6, Joelle Mukendi¹³ Kamalina Coopsamy⁹ Karla Thomas¹⁴ Liezl du Plessis¹⁵ Mampoi Jonas¹⁵ Nickhill Bhakta² Sarah-Anne Falcon¹⁶ Tea Reljic³ Vutshilo Netushini¹⁷ Yasmin Goga⁹ Gita Naidu^1,

¹ Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg; South Africa
² Department of Global Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, Tennessee; USA
³ Research Methodology and Biostatistics Core, University of South Florida, Tampa, Florida; USA
⁴ Division of Medical Microbiology, Stellenbosch University, Cape Town; South Africa
⁵ National Health Laboratory Service, Tygerberg Hospital, Cape Town; South Africa
⁶ Department of Paediatrics and Child Health, Tygerberg Hospital, Stellenbosch University, Cape Town; South Africa
⁷ Department of Pharmacology, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg; South Africa
⁸ Department of Paediatrics and Child Health, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg; South Africa
⁹ Department of Paediatrics and Child Health, Inkosi Albert Luthuli Hospital, University of KwaZulu-Natal, Durban; South Africa
¹⁰ Department of Paediatrics and Child Health, Grey’s Hospital, Pietermaritzburg; South Africa
¹¹ Department of Paediatrics and Child Health, Steve Biko Academic Hospital, University of Pretoria, Pretoria; South Africa
¹² Department of Paediatrics and Child Health, Red Cross War Memorial Childrens Hospital, University of Cape Town, Cape Town; South Africa
¹³ Department of Paediatric Nursing, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg; South Africa
¹⁴ Department of Paediatrics and Child Health, Frere Hospital, East London; South Africa
¹⁵ Department of Paediatrics and Child Health, Universitas Hospital, University of the Free State, Bloemfontein; South Africa
¹⁶ Childhood Cancer Foundation South Africa (CHOC), Rivonia; South Africa
¹⁷ Department of Paediatrics and Child Health, Pietersburg Hospital, University of Limpopo, Polokwane; South Africa

Introduction

Febrile neutropenia (FN) is a common cause of interruptions to childhood cancer treatment. Lack of guidance and inconsistent management of FN may contribute to poor patient outcomes.

In South Africa, a low-middle income country with a high burden of malnutrition, human immunodeficiency virus type-1 (HIV) and tuberculosis, many children with cancer have co-morbidities which converge to contribute to poorer outcomes.^1–3 Furthermore, in children and adolescents with cancer, antimicrobial agents are among the most commonly prescribed drugs utilised during the course of cancer treatment.⁴

The presence of indwelling catheters independently predicts microbiologically-confirmed severe bacterial sepsis episodes, and pneumonia, tuberculosis, profound or prolonged neutropenia, profound lymphopenia and prolonged monocytopenia are independently associated with death in South African children with cancer.²

Critical care bed availability is scarce, and infection-associated diagnoses as an indication for intensive care admission is an independent predictor of mortality.⁵ Mortality rates are higher than those described from a multicentre, prospective study of FN in African children (40.4% vs 11.0%).^2,6

We hypothesize that creating an evidence-based guideline for FN management across South African institutions is feasible and may optimize patient outcomes across centres.

Objectives

Convene a guideline development panel.
Disseminate a Guideline Prioritisation Survey to relevant stakeholders, to identify topics for inclusion in the guideline.
Select key topics, as identified through the Guideline Prioritisation Survey, for systematic review and guideline development.

Methods

A multi-centre, cross-disciplinary guideline development panel was convened. South African panellists are based in six of the country’s nine provinces, and overall, there is a favourable female-to-male ratio (2.3:1). Most (13/23, 56.5%) of the panellists are practising paediatric Haematology-Oncology sub-specialists, Figure 1.

The panel designed a guideline prioritisation survey to identify topics that should be considered for development of a guideline tailored to the South African context. The survey, which consisted of 51 questions inclusive of 37 practice points, was distributed to colleagues working in child health disciplines across South Africa in December 2021 through February 2022.

Figure 1: Characteristics of the Guideline Development Panel Members.

Results

Fifty-two (74.3%) complete responses were obtained from 70 clinicians who responded to the on-line survey. Twenty-eight (53.9%) of the respondents were paediatric haematologists or oncologists and 12 (23.1%) were general paediatricians, mostly (48/52, 92.3%) based at tertiary/academic centres. Eight of the nine South African provinces were represented, Figure 2.

Figure 2: Prioritisation survey responses.

Topics for inclusion in the guideline

Topics deemed “very important” (according to >75% of respondents) included:

To define fever;
To define neutropenia;
To describe how to modify antimicrobial therapy in unstable patients;
To define patients at high risk for invasive fungal disease; and
To define when to remove indwelling lines in paediatric patients with FN.

A further 19 questions were considered either “important” or “very important” for inclusion in the guidelines, according to >90% (47/52) of respondents.

The guideline development panel classified the identified topics into “Diagnostics” and “Management” categories (Table).

Topic	Classification
Case definitions
To define fever	Case definitions
To define neutropenia	Case definitions
Microbiology
Blood cultures	Diagnostics
Urinalysis and culture	Diagnostics
Stool diagnostics in diarrhoea	Diagnostics
Tuberculosis diagnostics	Diagnostics
PCP diagnostics	Diagnostics
Virology
Resp virus testing	Diagnostics
SARS-CoV-2 testing	Diagnostics
Biomarkers
Fungal biomarkers	Diagnostics
Bacterial biomarkers	Diagnostics
Radiology
Routine CXR	Diagnostics
Radiology for persistent fever	Diagnostics
Radiology for fungal infection	Diagnostics
Risk stratification
Risk stratification	Management
High risk criteria	Management
Low risk criteria	Management
Low-risk outpatient management	Management
Fungal at-risk	Management
Antimicrobials
High-risk empiric antibiotics	Management
Double Gram negative cover	Management
Gram positive cover	Management
Low-risk empiric antibiotics	Management
Low-risk oral antibiotics	Management
Empirical antifungal therapy	Management
Prophylactic antimicrobials	Management
Modifications to therapy
Modification to therapy - afebrile	Management
Modification to therapy - febrile	Management
Modification to therapy - unstable	Management
Immunomodulation
Corticosteroids	Management
G-CSF	Management
Treatment duration
Antibiotic stop - high-risk	Management
Antibiotic stop - low-risk	Management
Line care
Antibiotic lock therapy	Management
Removal of indwelling lines	Management
Discharge
Discharge - high-risk	Management
Discharge - low-risk	Management
Note:
CXR = Chest X-ray; G-CSF = granulocyte colony stimulating factor; PCP = Pneumocystis pneumonia; Resp = respiratory.

Training in GRADE methodology

Six on-line training sessions which educated panellists on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to clinical practice guideline development⁷ were led by the Methodology Team (AK and TR) from 10 February to 01 September 2022, Figure 3.

Figure 3: Timeline of guideline trainings in 2022, and topics covered.

Next steps

The South African FN Guideline for children with cancer is soon to move towards the phase of active review of the literature, based on a review of the literature highlighted by topics covered in the prioritisation survey responses.

Once the systematic review process has been finalised, the guidelines will be compiled by the writing team, and all panellists will have a role in contributing to the manuscript. Final submission will be based on the approval of all key stake holders.

The peer review process will highlight areas which may need improvement or clarification, ahead of publication and wide dissemination of the guideline document.

Once the guideline has been formally adopted by clinicians caring for children with cancer in South Africa, their impact will be appraised through a series of studies aimed at evaluating patient outcomes pre- and post-implementation of the guidelines.

Conclusions

Twenty-four topics were considered important for inclusion in a South African FN guideline. Future steps will be to apply the GRADE approach to develop recommendations for the prioritized questions. This work will facilitate research to evaluate the use and impact of the completed guidelines on outcomes of FN in South African children with cancer.

References

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Israels T, Afungchwi GM, Klootwijk L, et al. Fever and neutropenia outcomes and areas for intervention: A report from SUCCOUR - Supportive Care for Children with Cancer in Africa. Pediatr Blood Cancer 2021; 68: e29224.

Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383–94.

“We hypothesize that up-to-date clinical guidelines will impact favourably on clinical outcomes in children with febrile neutropenia.”