David Burgner

HLA and Infectious Diseases

SUMMARY Following their discovery in the early 1970s, classical human leukocyte antigen (HLA) loci have been the prototypical candidates for genetic susceptibility to infectious disease. Indeed, the original hypothesis for the extreme variability observed at HLA loci (H-2 in mice) was the major selective pressure from infectious diseases. Now that both the human genome and the molecular basis of innate and acquired immunity are understood in greater detail, do the classical HLA loci still stand out as major genes that determine susceptibility to infectious disease? This review looks afresh at the evidence supporting a role for classical HLA loci in susceptibility to infectious disease, examines the limitations of data reported to date, and discusses current advances in methodology and technology that will potentially lead to greater understanding of their role in infectious diseases in the future.

A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease

Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, p combined = 1.13×10−6) and ZFHX3 (rs7199343, p combined = 2.37×10−6) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p = 10−13) containing five fine-mapped genes—LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1—with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment. This is one of the first GWAS in an infectious disease. We have identified novel, plausible, and functionally related variants associated with KD susceptibility that may also be relevant to other cardiovascular diseases.

Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research.

This article proposes a clinical guideline for the diagnosis and treatment of Kawasaki disease in the UK based on the best available evidence to date, and highlights areas of practice where evidence is anecdotal or based on retrospective data. Future research as proposed by the London Kawasaki Disease Research Group is outlined, and clinicians are invited to prospectively enrol their suspected cases into this collaborative research project.

Genetic susceptibility to infectious diseases: big is beautiful, but will bigger be even better?

Summary Genetic epidemiology, including twin studies, provides robust evidence that genetic variation in human populations contributes to susceptibility to infectious disease. One of the major limitations of studies that attempt to identify the genes and mechanisms that underlie this susceptibility has been lack of power caused by small sample size. With the development of novel technologies, burgeoning information on the human genome, the HapMap project, and human genetic diversity, we are at the beginning of a new era in the study of the genetics of complex diseases. This review looks afresh at the epidemiological evidence that supports a role for genetics in susceptibility to infectious disease, examines the somewhat limited achievements to date, and discusses current advances in methodology and technology that will potentially lead to translational data in the future.

Innate immunity in human newborn infants: prematurity means more than immaturity

Neonates, particularly those born prematurely, are exquisitely vulnerable to life-threatening infections. This increased susceptibility to infection is maintained into childhood. Despite the considerable human and economic cost of infection-related neonatal morbidity and mortality, the mechanisms underlying this heightened susceptibility are only partly understood. It is increasingly recognised that innate immune responses are key to the protection against infection early in life, and emerging data suggest that such responses are deficient in the newborn and especially in preterm infants. Here we review the current understanding of the maturation of the innate immune response in human neonates highlighting the clinical relevance and possible avenues for therapeutic intervention.

Kawasaki disease: What is the epidemiology telling us about the etiology?

Summary Kawasaki disease (KD) is an important and common inflammatory vasculitis of early childhood with a striking predilection for the coronary arteries. It is the predominant cause of paediatric acquired heart disease in developed countries. Despite 40 years of research, the aetiology of KD remains unknown and consequently there is no diagnostic test and treatment is non-specific and sub-optimal. The consensus is that KD is due to one or more widely distributed infectious agent(s), which evoke an abnormal immunological response in genetically susceptible individuals. The epidemiology of KD has been extensively investigated in many populations and provides much of the supporting evidence for the consensus regarding etiology. These epidemiological data are reviewed here, in the context of the etiopathogenesis. It is suggested that these data provide additional clues regarding the cause of KD and may account for some of the continuing controversies in the field.

Infection-induced Inflammation and Cerebral Injury in Preterm Infants

Preterm birth and infectious diseases are the most common causes of neonatal and early childhood deaths worldwide. The rates of preterm birth have increased over recent decades and account for 11% of all births worldwide. Preterm infants are at significant risk of severe infection in early life and throughout childhood. Bacteraemia, inflammation, or both during the neonatal period in preterm infants is associated with adverse outcomes, including death, chronic lung disease, and neurodevelopmental impairment. Recent studies suggest that bacteraemia could trigger cerebral injury even without penetration of viable bacteria into the CNS. Here we review available evidence that supports the concept of a strong association between bacteraemia, inflammation, and cerebral injury in preterm infants, with an emphasis on the underlying biological mechanisms, clinical correlates, and translational opportunities.

Transforming Growth Factor-β Signaling Pathway in Patients With Kawasaki Disease

Background—Transforming growth factor (TGF)-&bgr; is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-&bgr; signaling might be important in KD susceptibility and disease outcome. Methods and Results—We investigated genetic variation in 15 genes belonging to the TGF-&bgr; pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase–polymerase chain reaction for these same genes, and measured TGF-&bgr;2 protein levels in plasma. Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A SMAD3 haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (P=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-&bgr; pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-&bgr;2 plasma protein levels changed dynamically over the course of the illness. Conclusions—These studies suggest that genetic variation in the TGF-&bgr; pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery Z scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis.

An issue of access: Delivering equitable health care for newly arrived refugee children in Australia

Abstract:  Newly arrived refugees and asylum seekers are faced with many difficulties in accessing effective health care when settling in Australia. Cultural, language and financial constraints, lack of awareness of available services, and lack of health provider understanding of the complex health concerns of refugees can all contribute to limiting access to health care. Understanding the complexities of a new health care system under these circumstances and finding a regular health provider may be difficult. In some cases there may be a fundamental distrust of government services. The different levels of health entitlements by visa category and (for some) detention on arrival in Australia may further complicate the provision and use of health services for providers and patients. Children are particularly at risk of suboptimal health care due to the impact of these factors combined with the effect of resettlement stresses on parents’ ability to care for their children. Unaccompanied and separated children, and those in detention experience additional challenges in accessing care. This article aims to increase awareness among health professionals caring for refugee children of the challenges faced by this group in accessing and receiving effective health care in Australia. Particular consideration is given to the issues of equity, rights of asylum seekers, communication and cultural sensitivities in health care provision, and addressing barriers to health care. The aim of the paper is to alert practitioners to the complex issues surrounding the delivery of health care to refugee children and provide realistic recommendations to guide practice.

Infection is the major component of the disease burden in aboriginal and non-aboriginal Australian children: a population-based study.

Background: Infection accounts for the majority of pediatric mortality and morbidity in developing countries, but there are limited data on the infectious diseases burden in children from developed countries. We investigated reasons for hospitalization before age 2 years in a birth cohort of Western Australian Aboriginal and non-Aboriginal children. Methods: Data on live births between January 1990 and December 2000, and corresponding deaths and hospitalizations in the first 2 years of life, were obtained through linked population-based data. Results: Almost half the cohort of 270,068 children were hospitalized at least once. Aboriginal children had significantly higher admission rates (2196 vs. 779 per 1000 live births), stayed longer and were more likely to die in hospital than non-Aboriginal children. Infections (mainly respiratory and gastrointestinal) were the most common reason for hospitalization, accounting for 34% of all admissions, with higher rates in Aboriginal (1114 per 1000 live births) than non-Aboriginal children (242 per 1000) (P < 0.001). Over time, admission rates for infections declined in Aboriginal children but increased in non-Aboriginal children. Aboriginal children were admitted 14 times more often for pneumonia than non-Aboriginal children. Conclusions: Infections are the leading cause of hospitalization in children under 2 years of age. The continuing heavy burden of serious infections, borne disproportionately by Aboriginal children, needs to be alleviated. Public health interventions such as the development and universal implementation of vaccines for respiratory syncytial virus, rotavirus and influenza are needed, while adequate funding must be committed to Indigenous health services and training.