Prediction of Disease Severity in Young Children Presenting With Acute Febrile Illness in Resource-limited Settings
Condition: Sepsis
MeSH terms: Hyperthermia; Fever
Study type: Observational

Summary: 
      Note that this is a study that is co-sponsored by Medecins Sans Frontieres, Spain, and the
      University of Oxford.

      The primary objective is to develop a risk prediction algorithm, combining measurements of
      host biomarkers and clinical features at the point-of-triage, for children with an acute
      febrile illness in resource-limited settings.

      The secondary objectives are to determine which host biomarkers, feasible for measurement at
      the point-of-care, are predictive of disease severity. Additionally to determine the optimal
      combination of clinical features (including demographics, anthropometric data, historical
      variables, vital signs, clinical signs and clinical symptoms), feasible for assessment by
      limited-skill health workers, that is predictive of disease severity.

      The tertiary objectives are to explore the impact of different methods of outcome
      classification on development of the risk prediction algorithm, and to explore the
      performance of the algorithm to predict disease severity in key presenting clinical syndromes
      and aetiologies.
    

Detailed description: 
      Background

      Febrile illnesses are amongst the most common reasons that parents seek non-routine
      healthcare for their children and a proportion progress to severe disease with substantial
      risk of mortality. Sepsis, defined as acute life-threatening organ dysfunction caused by a
      dysregulated host response to infection, carries significant morbidity. Incidence is highest
      in the paediatric age-range, with an estimated over four million children developing sepsis
      each year. This estimate is necessarily conservative, as the burden of sepsis is greatest in
      low- and middle-income countries (LMICs) where population-level data are not readily
      available.

      Distinguishing febrile children that require referral or admission to hospital, from those
      who can safely be cared for in the community, is challenging. In many tropical settings
      rational triage is especially difficult: healthcare providers receive limited training, and
      many acute febrile syndromes are clinically indistinguishable yet have different disease
      trajectories and require different interventions. Particularly in conflict settings, referral
      decisions involve complex mechanisms, costs and risks to both patient and provider.
      Consequently, patient outcomes are compromised: children with severe disease go unrecognised,
      whilst those with milder illnesses are unnecessarily hospitalised.

      Healthcare providers are trained to perform systematic clinical assessments, which focus on
      eliciting symptoms and signs that predict poor outcomes. Whilst tools such as the World
      Health Organization's Integrated Management of Childhood Illness (IMCI) aim to support this,
      results are inconsistent and adherence is poor. Integration of several syndrome-specific
      algorithms is impractical for many limited-skill health workers. A recent systematic review
      concluded that validity of existing paediatric triage tools is uncertain and that none are
      likely to be reliable in resource-constrained environments.

      Numerous clinical severity scoring systems predict deterioration in hospitalised patients and
      recent attempts have been made to adapt these to the paediatric population.

      However, many require physiological variables that are only routinely measured in the
      intensive care unit (ICU) and simplified versions perform inconsistently. In addition, the
      generalisability of these tools to LMICs is uncertain and further work is required to explore
      their utility at the point-of-triage.

      Rationale

      Spot Sepsis will collect the necessary data to permit a multi-country evaluation of existing
      severity scoring systems at the point-of-triage, and determine whether a combinatorial
      approach, utilising simple-to-elicit clinical features and measurement of host biomarkers,
      holds potential for widespread public health impact.

      Context-appropriate tools that enable reliable disease severity assessment in febrile
      children have great potential to improve patient outcomes and ensure optimal allocation of
      scarce resources. Pathogen-specific diagnostics alone are not sufficient to improve clinical
      management of febrile illness: the majority of children in LMICs present to facilities with
      limited diagnostic support and even well-resourced research studies often only ascertain a
      microbiological cause in a minority of febrile patients. Furthermore, in many circumstances,
      even when a pathogen is identified a child's illness trajectory can remain unpredictable.

      Characterising the host response represents an alternative strategy, which has potential to
      be robust to heterogeneity in fever aetiology and applicable to all febrile children
      irrespective of whether a microbiological cause of their illness can be identified. Given
      wide-ranging pathogen (aetiology and/or inoculum) and host (genetic and/or immunological)
      diversity, tools that combine multiple parameters are likely to be most effective: a uniform
      pathophysiological disturbance is unlikely.

      The Sequential Organ Failure Assessment (SOFA) score is proposed as a parsimonious tool to
      risk stratify adults admitted to the intensive care unit (ICU) with suspected infection.
      Recent work has adapted SOFA for paediatric use (pSOFA), with encouraging results. However
      both SOFA and pSOFA are validated for patients admitted to the ICU. Whilst quick-SOFA
      (qSOFA), a simplified version of SOFA consisting of three simple clinical variables (mental
      status, respiratory rate and systolic blood pressure), performs well in hospitalised adults
      outside of the ICU, it appears less useful in LMICs, when adapted for use in children and
      outside the hospital setting. Of note, abnormal systolic blood pressure is known to be a late
      sign in unwell children and sphygmomanometers are often not present outside of hospital
      settings in LMICs. Recognising that different clinical parameters may be relevant for febrile
      children at the point-of-triage in LMICs, a recent modified-Delphi process identified 45
      possible predictors of paediatric sepsis feasible for collection in resource-limited
      settings. Which of these might be most important is yet to be determined.

      Simple clinical assessments (for example, the Lambaréné Organ Dysfunction Score [LODS])
      predict in-hospital mortality in children with febrile illnesses in sub-Saharan Africa (SSA).
      In children with severe malaria performance of these assessments improves when combined with
      measurement of certain host biomarkers, such as those reflecting endothelial and immune
      activation, including angiopoietin-2 (Ang-2) and soluble triggering receptor expressed on
      myeloid cells-1 (sTREM-1). Importantly, this contrasts with laboratory indicators such as
      venous lactate, which although predictive of mortality in children with febrile illness, does
      not improve discrimination of clinical assessment.30,31 This suggests that whilst
      conventional laboratory indicators may be crude biochemical surrogates for clinical
      assessment, certain biomarkers may reflect sub-clinical endothelial and immune activation,
      and have potential to improve identification of children at risk of severe febrile illness.

      Most studies to date have focused on malaria in African children. Limited data exists from
      Asia, and non-malarial febrile illnesses are comparatively understudied. However, recent work
      suggests endothelial and immune activation play a central role in the pathophysiology of
      severe infection across a spectrum of microbial aetiologies, including dengue, bacterial
      sepsis and influenza. Furthermore, whilst most studies have enrolled hospitalised children, a
      recent study recruiting adults attending Tanzanian outpatient clinics, suggests that this
      approach could aid triage when patients first present to care from the community.

      Assumptions, limitations and generalisability

      The fundamental assumption underlying this approach is that there are final common pathways
      to severe febrile illness and that markers of these pathways will be elevated and measurable
      at a sufficiently early point in the course of an illness, to meaningfully contribute to
      patient assessment and triage. Whilst this is known for clinical parameters such as vital
      signs, a growing body of evidence supports this thesis: endothelial and immune activation
      appear to be part of a final common pathway to severe illness. Furthermore, alterations in
      microvascular physiology occur early in the disease course of common childhood febrile
      illnesses.

      This study will recruit children aged > 28 days and < 5 years presenting with an acute
      febrile illness. Hence, the major limitations are the exclusion of neonates and older
      children, and the decision to base the eligibility criteria around fever. This will limit the
      ability to develop a parsimonious tool for all children presenting with suspected infection
      in the community.

      The decision to limit recruitment to children aged > 28 days and < 5 years reflects the fact
      that, (a) all febrile neonates require further assessment, (b) outside the neonatal range,
      the biggest burden of disease affects children under the age of five, and (c) including older
      children would require substantially greater resources to ensure power to examine interaction
      of predictive performance with age.

      The decision to limit the study to children with an abnormal temperature or short history of
      fever reflects the fact that, (a) these inclusion criteria are expected to capture the
      majority of children with suspected sepsis (TuNDRA study, Angkor Hospital for Children
      [OxTREC 512-17; 287 NECHR], unpublished data), and (b) limiting this initial study to the
      febrile population will constrain heterogeneity, increasing likelihood of success whilst
      still addressing an important public health problem.

      This study aims to develop a risk prediction algorithm to improve disease severity assessment
      of febrile children in rural and/or remote community settings and decentralised models of
      care. However, derivation of a prediction algorithm requires a certain number of 'outcome
      events' (episodes of severe illness), and hence recruiting febrile children presenting at
      peripheral levels of the health system would be logistically and financially challenging.

      To overcome this challenge, Spot Sepsis will recruit patients presenting to mid-level health
      facilities, for example, district and/or provincial hospitals, where severe illness occurs
      more frequently. However, the investigators recognise that this compromise risks a potential
      loss of generalisability to community settings (the ultimate intended-use setting for the
      algorithm).

      To mitigate this risk, the sites selected for Spot Sepsis serve as a primary point of
      healthcare access for a predominantly rural and/or underserved population, the demographics
      of which are representative of patients presenting to lower levels of care. Hence the primary
      difference between the Spot Sepsis sites and eventual intended-use sites, is the frequency
      with which children at risk of severe illness attend, rather than systematic differences in
      their demographic characteristics (acknowledging that there can be differences in patients
      presenting to hospital outpatient departments compared to community care settings). This will
      maximise the chance of successful out-of-sample validation and generalisability of the tool
      to community settings.

      NOTE

      In addition, a greater understanding of biomarker kinetics is crucial. To investigate this
      further the investigators will perform an exploratory nested case-control sub-study at the
      Cambodia site to investigate whether the kinetics of the biomarker response differs between
      hospitalised children who develop severe illness and hospitalised controls. Furthermore,
      findings that the angiopoietin axis can remain activated beyond apparent clinical resolution,
      and conveys excess post-discharge mortality risk, is concordant with high post-discharge
      mortality observed in adults with bacterial sepsis and in hospitalised children in LMICs. If
      confirmed, measuring biomarkers of endothelial and immune activation at discharge could help
      prioritise at-risk children for follow-up. At the Cambodia site biomarker levels will be
      measured at discharge and patient follow-up extended to six months to determine if children
      at risk of poor outcomes can be readily identified prior to discharge and prioritised for
      outpatient or community-based follow-up.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Children aged > 28 days and < 5 years presenting to the study site with an acute febrile
        illness
      
Biospecimen description: 
      Blood will be taken for biomarker assessment from all children, which may include pathogenic
      identification.
    
Keywords: Febrile illness; Biomarker; Clinical Severity Scale; Disease severity; Resource-limited setting