Immune biomarkers in the spectrum of childhood noncommunicable diseases

doi:10.1016/j.jaci.2016.03.012

Journal of Allergy and Clinical Immunology

Volume 137, Issue 5, May 2016, Pages 1302-1316

https://doi.org/10.1016/j.jaci.2016.03.012 Get rights and content

A biomarker is an accurately and reproducibly quantifiable biological characteristic that provides an objective measure of health status or disease. Benefits of biomarkers include identification of therapeutic targets, monitoring of clinical interventions, and development of personalized (or precision) medicine. Challenges to the use of biomarkers include optimizing sample collection, processing and storage, validation, and often the need for sophisticated laboratory and bioinformatics approaches. Biomarkers offer better understanding of disease processes and should benefit the early detection, treatment, and management of multiple noncommunicable diseases (NCDs). This review will consider the utility of biomarkers in patients with allergic and other immune-mediated diseases in childhood. Typically, biomarkers are used currently to provide mechanistic insight or an objective measure of disease severity, with their future role in risk stratification/disease prediction speculative at best. There are many lessons to be learned from the biomarker strategies used for cancer in which biomarkers are in routine clinical use and industry-wide standardized approaches have been developed. Biomarker discovery and validation in children with disease lag behind those in adults; given the early onset and therefore potential lifelong effect of many NCDs, there should be more studies incorporating cohorts of children. Many pediatric biomarkers are at the discovery stage, with a long path to evaluation and clinical implementation. The ultimate challenge will be optimization of prevention strategies that can be implemented in children identified as being at risk of an NCD through the use of biomarkers.

Section snippets

What are biomarkers?

A biomarker (biological marker) is a quantifiable biological characteristic that provides an objective measure of health status or disease. For disease, biomarkers have the potential for use in risk stratification, early detection, identification of the treatment of choice and monitoring response to treatment, surveillance, and drug monitoring and development. Biomarkers are also used in other clinical scenarios, such as microbial identification and diagnostics. A biomarker can be a gene,

Allergy

Allergic disorders, including atopic dermatitis, food allergy, allergic rhinitis, and asthma, affect more than 1 billion persons across the globe, and their prevalence is expected to quadruple by the 2050s.²⁴ Atopic dermatitis, which is typically accompanied by IgE sensitization to food, and food allergy are the earliest-onset NCDs and the most common chronic NCDs of childhood worldwide.25, 26 They are considered the first steps on the allergic march, whereby atopic dermatitis and food allergy

Benefits and challenges of biomarkers

Biomarkers must consistently and accurately predict a biological process or clinical outcome of interest. Most biomarkers in clinical use today have come about through the traditional experimental route outlined above. Today, these and untargeted (typically omics) approaches are used for biomarker discovery. It is very easy to speculate about the longer-term clinical utility of a novel potential biomarker, but the reality is a lengthy, painful, and expensive path from an exploratory to a

Summary

The utility of biomarkers is 2-fold: to identify mechanistic pathways enabling better understanding of disease processes and revealing novel therapeutic targets and to generate diagnostic or prognostic biomarkers that have clinical effect. The goal for the latter is an objective, accurate, and reproducible measurement that relates to the clinical scenario of interest. Such a biomarker must be accurate, sensitive, and specific; it helps if it is physiologically relevant to the disease or

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Cited by (18)

Cord blood soluble Fas ligand linked to allergic rhinitis and lung function in seven-year-old children
2022, Journal of Microbiology, Immunology and Infection
Citation Excerpt :
These genetic and epigenetic factors can leave long-term influences on a patient's immunological, cardiovascular, and other systemic functioning and can lead to diseases later in life.4,5 Many birth cohort studies have investigated the link between perinatal exposure and the outcomes of atopic diseases in an attempt to identify possible predictive biomarkers.6,7 Fas and Fas ligand (FasL) interaction is an important pathway in inducing apoptosis.
Serum or cord blood soluble Fas ligand (FasL) has been related to asthma, allergic rhinitis, and atopic dermatitis in cross-sectional and short-term follow-up studies. However, the association of cord blood soluble FasL with long-term allergic outcomes has seldom been investigated.
The Prediction of Allergies in Taiwanese Children birth cohort study recruited healthy newborns upon delivery. At birth, blood was collected from the umbilical cords of these children, and the cord blood soluble Fas ligand levels were measured. At the age of seven years, the allergic outcome of each child was diagnosed by pediatric allergists and pulmonologists. Tests were conducted to measure the specific immunoglobulin E, fractional exhaled nitric oxide (FeNO), and pulmonary function levels of each child.
Cord blood soluble FasL levels were higher in seven-year-old children with allergic rhinitis (Odds ratio [OR] = 2.41, p = 0.012) and expiratory airway obstruction (the highest forced expiratory volume in 1 second/forced vital capacity < 90%, OR = 2.11, p = 0.022). The FeNO and Dermatophagoides pteronyssinus-specific immunoglobulin E levels of seven-year-old children were positively correlated with cord blood soluble FasL levels (p = 0.006 and 0.02, respectively).
In this birth cohort, the cord blood soluble FasL levels were associated with allergic rhinitis, obstructive-type lung function, FeNO, and house dust mite sensitization in 7-year-old children. The cord blood soluble FasL level might be used as a predictor for allergic diseases in children who are 7 years old.
Overexpression of YKL-40 (CHI3L1 gene) in patient fluids may be a potential predictive marker for early detection of comorbidity in non-communicable disease
2020, Medical Hypotheses
Citation Excerpt :
Proliferative cells such as macrophages in the circulation, synovial cells in joints, vascular smooth muscle cells and endothelial cells in arthritic chondrocytes and solid carcinomas actively express YKL-40 [4,10,11]. NCDs are closely associated with chronic low-grade inflammation and express specific biomarkers at different stages of disease onset [12]. Biomarkers are used clinically to diagnose and/or prognose a condition of the patients for referral of a specific treatment.
Predictive biomarkers which can diagnose the onset of non-communicable diseases and the associated comorbid conditions are lacking for clinical utility. Highly sensitive and specific biomarkers for early disease detection and risk stratification may provide timely intervention to patients and prevent secondary complications. However, till the time patients are diagnosed, cellular events and biomolecules get active effecting multiple organs at the same time. This series of events lead to disruption in normal functioning of the organs and their coordinative crosstalk, hence, increase in mortality rate of patients. The primary functional molecules of inflammatory pathways are active in NCDs. YKL-40, an anti-apoptotic molecule in inflammatory pathways, is overexpressed in patient fluids in different organs under diseased conditions. We performed a preliminary network analysis to study YKL-40 co-expression with diagnostic markers: TNNT2/I3 (Cardiac Troponin T/I) for cardiovascular diseases, LCN2 (NGAL) and CKM (Creatinine kinase M-type) in acute kidney injury and HbA1c in type-2-diabetes. It is observed that YKL-40 is actively co-expressed and linked with standard diagnostic markers and may be influencing the pathways active in organ crosstalk. The pathways may be regulating the signaling events in patients with non-communicable diseases leading to comorbidities. We, hence, postulate that if YKL-40 and disease specific pathways influenced are clinically utilized, this will provide the foundation of establishing tailored and specific approach in diagnosis and monitoring non-communicable diseases and predict the onset of comorbid conditions due to phenomenon influencing organ cross talks.
42 - The Epidemiology of Asthma
2019, Kendig's Disorders of the Respiratory Tract in Children
Epidemiology is the study of populations to discover modifiable factors that contribute to disease occurrence and natural history with a view to reducing disease burden through prevention. Asthma is a complex, polygenic disease with heterogeneous manifestations making it difficult to define precisely in population studies. Despite this, global efforts to harmonize outcome definitions have led to detailed understanding of the temporal and spatial variations of asthma prevalence in children. Asthma prevalence notably increased in high-income countries during the final three decades of the 20th century, but the cause for this has never been fully established.
Early life has been implicated as a critical period for the development of asthma. Many environmental influences have been considered as potential risk factors for asthma, but few have been associated with more than modest increases in risk. One barrier to identifying causal risk factors is the clustering of environmental factors with consequent confounding of relationships between environment and disease. Thus even strong and reproducible associations can seldom be regarded as causal without experimental evidence, which is generally lacking.
Despite these difficulties, new approaches to asthma classification, meticulous observations in birth cohorts, technological advances that enable assignment or genetic risk and identification of biomarkers for disease pathways, and analytical advances have contributed to real advances in understanding asthma pathogenesis. The interaction of allergic sensitization with respiratory viral infections offers a promising target for the development of preventative interventions.
Children as Biomarker Orphans: Progress in the Field of Pediatric Biomarkers
2018, Journal of Pediatrics
Key points for moving the endotypes field forward
2018, Implementing Precision Medicine in Best Practices of Chronic Airway Diseases
Asthma, rhinitis, atopic dermatitis, and other allergic diseases are complex and heterogeneous diseases in clinical outcomes and pathophysiology. Pre-existing genetic, epigenetic, metabolic and immunologic factors as well as age-dependent nutrition, microbiome, virome, allergen exposure, and other environmental influences all shape the disease characteristics and response to treatment. Therefore, together with the clinical observable characteristics of the disease, called phenotypes, distinct underlying molecular pathomechanisms of the disease, called endotypes, have been proposed. We describe here the taxonomy and the current state of the art on various endotypes and phenotypes of different allergic diseases. Moreover, we present the range of currently existing and emerging measurable indicators of different disease characteristics, called biomarkers. Finally, discussing the technological advances, such as next generation sequencing, other omics technologies, and big data handling in research and clinical aspects, we propose further steps and directions in the field of precision and personalized medicine in allergy and clinical immunology. All those aspects are crucial in further development of an individual patient-oriented concept of precision health.
Immune monitoring for precision medicine in allergy and asthma
2017, Current Opinion in Immunology
Citation Excerpt :
Diagnostic methods and classification schemes are of greatest value if they guide selection of effective therapies, and decrease rates of serious side effects. Even if there are reproducible biological differences between subcategories of a disease, unless there are meaningful therapeutic options for each subcategory, or other advantages such as improved prognostication of the disease course, the clinical relevance of the classification will be questionable [4,37•,38]. Validation of new classification schemes via testing of different therapies, such as monoclonal antibody drugs, will have major clinical and financial consequences for patients, and for companies developing novel therapies and ‘companion diagnostics’ intended to evaluate whether a therapy would be effective in an individual patient.
‘Precision Medicine’ embodies the analyses of extensive data collected from patients and their environments to identify and apply patient-specific prophylactic strategies and medical treatments to improve clinical outcomes and healthcare cost-effectiveness. Many new methods have been developed for evaluating the activity of the human immune system. Such ‘immune monitoring’ approaches are now being used in studies of allergy and asthma in the hope of identifying better correlates of disease status, predictors of therapeutic outcomes, and potential side-effects of treatment. Together with analyses of family histories, genetic and other biometric data, and measurements of exposures to environmental and other risk factors for developing or exacerbating disease, immune monitoring approaches promise to enable ‘Precision Medicine’ for allergic diseases and asthma.

View all citing articles on Scopus

: Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

: C.L.S. and H.R. are supported by the Deutsche Forschungsgemeinschaft–funded SFB 1021.

: Disclosure of potential conflict of interest: C. Skevaki has received grants from the German Research Foundation and the German Center for Lung Research. J. Garssen has been a member of medical ethical committee boards for Utrecht University and Free University Amsterdam and has received grants from the European Union, NWO Netherlands, STW Netherlands, TIP Netherlands, and CCC Netherlands. A. Landay has consultant arrangements with Merck and has received payment from Gilead grant review and EMD Serono grant review. H. Renz has received grants from the German Research Foundation. The rest of the authors declare that they have no relevant conflicts of interest.

: Terms in boldface and italics are defined in the glossary on page 1303.

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Reviews and feature articleImmune biomarkers in the spectrum of childhood noncommunicable diseases

Section snippets

What are biomarkers?

Allergy

Benefits and challenges of biomarkers

Summary

Strategies to prevent or reduce allergic disease

Ann Nutr Metab

Facing a “slow-motion disaster”—the UN meeting on noncommunicable diseases

N Engl J Med

Priority actions for the non-communicable disease crisis

Lancet

Early-life environmental determinants of allergic diseases and the wider pandemic of inflammatory noncommunicable diseases

J Allergy Clin Immunol

Raising the priority of preventing chronic diseases: a political process

Lancet

Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study

Lancet

Monitoring and surveillance of chronic non-communicable diseases: progress and capacity in high-burden countries

Lancet

Asthma and pregnancy: emerging evidence of epigenetic interactions in utero

Curr Opin Allergy Clin Immunol

Origin and physiological roles of inflammation

Nature

Inflammatory mechanisms in obesity

Annu Rev Immunol

The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies

J Allergy Clin Immunol

The hygiene hypothesis revised: is the rising frequency of allergy due to changes in the intestinal flora?

Allergy

Fecal microbiota composition differs between children with beta-cell autoimmunity and those without

Diabetes

Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood

J Allergy Clin Immunol

Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases

Proc Natl Acad Sci U S A

Developmental origins of metabolic disease: life course and intergenerational perspectives

Trends Endocrinol Metab

What are biomarkers?

Curr Opin HIV AIDS

Biomarkers of immunity and inflammation for use in nutrition interventions: International Life Sciences Institute European Branch work on selection criteria and interpretation

Endocr Metab Immune Disord Drug Targets

Biomarker discovery and validation

Clin Chem

The human plasma proteome: history, character, and diagnostic prospects

Mol Cell Proteomics

MicroRNAs: target recognition and regulatory functions

Cell

Current state of circulating microRNAs as cancer biomarkers

Clin Chem

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

Nat Med

Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three

J Allergy Clin Immunol

A global survey of changing patterns of food allergy burden in children

World Allergy Org J

The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies

Allergy

Epidemiology and natural history of atopic diseases

Eur Clin Respir J

Monitoring of disease activity by measurement of inflammatory markers in atopic dermatitis in childhood

Allergy

Circulating LL-37 is a biomarker for eczema severity in children

J Eur Acad Dermatol Venereol

Serum measurement of interleukin-31 (IL-31) in paediatric atopic dermatitis: elevated levels correlate with severity scoring

J Eur Acad Dermatol Venereol

Serum concentration of IL-18 correlates with disease extent in young children with atopic dermatitis

Pediatr Dermatol

Serum mucosa-associated epithelial chemokine (MEC/CCL28) in atopic dermatitis: a specific marker for severity

Int J Dermatol

Serum measurement of thymus and activation-regulated chemokine/CCL17 in children with atopic dermatitis: elevated normal levels in infancy and age-specific analysis in atopic dermatitis

Pediatr Allergy Immunol

Serum levels of cutaneous T-cell attracting chemokine (CTACK) as a laboratory marker of the severity of atopic dermatitis in children

Clin Exp Dermatol

Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis

J Dermatol

Profiling of serum and urinary microRNAs in children with atopic dermatitis

PLoS One

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers

J Allergy Clin Immunol

Reviews and feature article
Immune biomarkers in the spectrum of childhood noncommunicable diseases