Impaired interferon response in plasmacytoid dendritic cells from children with persistent wheeze.

BACKGROUND: Impaired interferon response and allergic sensitization may contribute to virus-induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity as critical producers of type I interferons. pDCs also express the high-affinity IgE receptor through which type I interferon production may be negatively regulated. Whether antiviral function of pDCs is associated with recurrent episodes of wheeze in young children is not well understood. OBJECTIVE: We sought to evaluate the phenotype and function of circulating pDCs in children with a longitudinally defined wheezing phenotype. METHODS: We performed multiparameter flow cytometry on PBMCs from 38 children presenting to the emergency department with an acute episode of respiratory wheeze and 19 controls. RNA sequencing on isolated pDCs from the same individuals was also performed. For each subject, their longitudinal exacerbation phenotype was determined using the Western Australia public hospital database. RESULTS: We observed a significant depletion of circulating pDCs in young children with a persistent phenotype of wheeze. The same individuals also displayed upregulation of the FcεRI on their pDCs. Based on transcriptomic analysis, pDCs from these individuals did not mount a robust systemic antiviral response as observed in children who displayed a nonrecurrent wheezing phenotype. CONCLUSIONS: Our data suggest that circulating pDC phenotype and function are altered in young children with a persistent longitudinal exacerbation phenotype. Expression of high-affinity IgE receptor is increased and their function as major interferon producers is impaired during acute exacerbations of wheeze.

Rhinoviruses A and C elicit long-lasting antibody responses with limited cross-neutralization.

Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types.

Enhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection.

Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P < 0.001, χ2) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.

The impact of cytokine levels in young South African children with and without HIV-associated acute lower respiratory infections.

Altered host immune responses are considered to play a key role in the pathogenesis of acute lower respiratory infections (ALRI). The existing literature on cytokine responses in ALRI is largely focussed on adults from developed countries and there are few reports describing the role of cytokines in childhood ALRI, particularly in African or human immunodeficiency virus (HIV)-infected populations. To measure systemic cytokine levels in blood plasma from young South African children with and without ALRI and with and without HIV to determine associations between cytokine responses and disease status and respiratory viral identification. Blood plasma samples were collected from 106 hospitalized ALRI cases and 54 non-ALRI controls less than 2 years of age. HIV status was determined. Blood plasma concentrations of 19 cytokines, 7 chemokines, and 4 growth factors (epidermal growth factor, fibroblast growth factor-basic, hepatocyte growth factor, and vascular endothelial) were measured using The Human Cytokine 30-Plex Panel. Common respiratory viruses were identified by PCR. Mean cytokine concentrations for G-CSF, interferon (IFN)-γ, interleukin (IL)-5, and MCP-1 were significantly higher in ALRI cases than in nonrespiratory controls. Within the ALRI cases, several cytokines were higher in children with a virus compared with children without a virus. Mean cytokine concentrations for IFN-α, IFN-γ, IL-4, IL-5, IL-13, tumour necrosis factor-α, and MIP-1α were significantly lower in HIV-infected cases than in HIV-uninfected cases, while IP-10 and monokine induced by interferon-γ were significantly higher in HIV-infected cases than in HIV-uninfected cases. Certain cytokines are likely to play an important role in the host immune response to ALRI. HIV-infected children have impaired inflammatory responses to respiratory infections compared with HIV-uninfected children.

Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing.

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hi versus IRF7lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes.

Spatially explicit analyses of environmental and health data to determine past, emerging and future threats to child health.

BACKGROUND: Dire forecasts predict that an increasingly hostile environment globally will increase the threats to human health. Infants and young children are especially at risk because children are particularly vulnerable to climate-related stressors. The childhood diseases most affected, the breadth and magnitude of future health problems and the time frame over which these problems will manifest remain largely unknown. OBJECTIVES: To review the possibility that spacially explicit analyses can be used to determine how climate change has affected children's health to date and whether these analyses can be used for future projections. METHODS: As an example of whether these objectives can be achieved, all available Australian environmental and health databases were reviewed. RESULTS: Environmental and health data in Australia have been collected for up to 30 years for the same spatial areas at 'Statistical Area level 1' (SA1) scale. SA1s are defined as having a population of between 200 and 800 people and collectively they cover the whole of Australia without gaps or overlap. Although the SA1 environmental and health data have been collected separately, they can be merged to allow detailed statistical analyses that can determine how climate change has affected the health of children. CONCLUSIONS: The availability of environmental and health datasets that share the same precise spatial coordinates provides a pathway whereby past and emerging effects on child health can be measured and predicted into the future. Given that the future health and well-being of children is one of society's greatest concerns, this information is urgently needed.

Glutathione S-Transferase Genotype Protects against In Utero Tobacco-linked Lung Function Deficits.

Rationale:In utero tobacco exposure is associated with reduced lung function from infancy. Antioxidant enzymes from the glutathione S-transferase (GST) family may protect against these lung function deficits.Objectives: To assess the long-term effect of in utero smoke exposure on lung function into adulthood, and to assess whether GSTT1 and GSTM1 active genotypes have long-term protective effects on lung function.Methods: In this longitudinal study based on a general population (n = 253), lung function was measured during infancy and at 6, 11, 18, and 24 years. GSTM1 and GSTT1 genotype was analyzed in a subgroup (n = 179). Lung function was assessed longitudinally from 6 to 24 years (n = 199).Measurements and Main Results: Exposure to maternal in utero tobacco was associated with lower FEV1 and FVC longitudinally from 6 to 24 years (mean difference, -3.87% predicted, P = 0.021; -3.35% predicted, P = 0.035, respectively). Among those homozygous for the GSTM1-null genotype, in utero tobacco exposure was associated with lower FEV1 and FVC compared with those with no in utero tobacco exposure (mean difference, -6.2% predicted, P = 0.01; -4.7% predicted, P = 0.043, respectively). For those with GSTM1 active genotype, there was no difference in lung function whether exposed to maternal in utero tobacco or not. In utero tobacco exposure was associated with deficits in lung function among those with both GSTT1-null and GSTT1-active genotypes.Conclusions: Certain GST genotypes may have protective effects against the long-term deficits in lung function associated with in utero tobacco exposure. This offers potential preventative targets in antioxidant pathways for at-risk infants of smoking mothers.

Progressive increase of FcεRI expression across several PBMC subsets is associated with atopy and atopic asthma within school-aged children.

BACKGROUND: Antigen-specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non-atopic/non-asthmatic age-matched healthy controls. METHODS: We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. RESULTS: We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non-atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non-asthmatic children also after adjusting for serum IgE levels. CONCLUSION: Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non-asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children.

Immunodominant T-Cell Epitopes in the VP1 Capsid Protein of Rhinovirus Species A and C.

Rhinovirus (RV) species A and C are the most frequent cause of respiratory viral illness worldwide, and RV-C has been linked to more severe exacerbations of asthma in young children. Little is known about the immune responses to the different RV species, although studies comparing IgG1 antibody titers found impaired antibody responses to RV-C. Therefore, the aim of this study was to assess whether T-cell immunity to RV-C is similarly impaired. We measured T-cell proliferation to overlapping synthetic peptides covering the entire VP1 capsid protein of an RV-A and RV-C genotype for 20 healthy adult donors. Human leukocyte antigen (HLA) was typed in all the donors in order to investigate possible associations between the HLA type and RV peptide recognition. Total and specific IgG1 antibody titers to the VP1 proteins of both RV-A and RV-C were also measured to examine associations between the antibody and T-cell responses. We identified T-cell epitopes that are specific to and representative of each RV-A and RV-C species. These epitopes stimulated CD4+-specific T-cell proliferation, with similar magnitudes of response for both RV species. All the donors, independent of their HLA-DR or -DQ type, were able to recognize the immunodominant RV-A and -C regions of VP1. Furthermore, the presence or absence of specific antibody titers was not related to changes in T-cell recognition. Our results indicate a dissociation between the antibody and T-cell responses to rhinoviruses. The species-representative T-cell epitopes identified in this study are valuable tools for future studies investigating T-cell responses to the different RV species. IMPORTANCE: Rhinoviruses (RVs) are mostly associated with the common cold and asthma exacerbations, although their contributions to most upper and lower respiratory tract diseases have increasingly been reported. Species C (RV-C) has been associated with more frequent and severe asthma exacerbations in young children and, along with RV-A, is the most clinically relevant species. Little is known about how our immune system responds to rhinoviruses, and there are limited tools to study specific adaptive immunity against each rhinovirus species. In this study, we identified immunodominant T-cell epitopes of the VP1 proteins of RV-A and RV-C, which are representative of each species. The study found that T-cell responses to RV-A and RV-C were of similar magnitudes, in contrast with previous findings showing RV-C-specific antibody responses were low. These findings will provide the basis for future studies on the immune response to rhinoviruses and can help elucidate the mechanisms of severity of rhinovirus-induced infections.

Infant lung function predicts asthma persistence and remission in young adults.

BACKGROUND AND OBJECTIVE: Asthma in adults is associated with a persistent reduction in lung function from childhood, but this link has not been assessed back to infancy. Reduced infant lung function (ILF), a measure of antenatal and infant lung growth, is associated with asthma into adolescence. Our aim was to assess whether this link persists into adulthood and whether ILF can predict the remission of asthma symptoms in young adults. METHODS: The study cohort was an unselected full-term birth cohort of 253 subjects enrolled antenatally with lung function assessments at 1, 6 and 12 months (maximum expiratory flow at functional residual capacity, V'maxFRC), and 6, 11, 18 and 24 years (spirometry) of age. RESULTS: Infants with V'maxFRC in the lowest quartile at 1 month had an OR of 5.1 (95% CI: 2-13, P = 0.001) for asthma at 24 years. Subjects with asthma at 24 years had a mean V'maxFRC at 1 month of 69% predicted (95% CI: 48-90%) versus 110% (95% CI: 101-119%) in non-asthmatic patients (P = 0.001). Subjects with current versus resolved asthma symptoms at 24 years had a mean V'maxFRC at 1 month of 69% predicted (95% CI: 53-84%) versus 105% (88-123%), respectively (P = 0.003). Subjects with current asthma at 24 years had persistently lower lung function from infancy with a mean reduction of 16.2% (95% CI: 8.1-24.3%, P < 0.0001). CONCLUSION: Reduced lung function in early infancy is predictive of persistent asthma in young adults and a persistent reduction in lung function, suggesting abnormal lung development and growth in utero or very early in life.

Rhinovirus-C detection in children presenting with acute respiratory infection to hospital in Brazil.

Human rhinovirus (RV) is a common cause of acute respiratory infection (ARI) in children. We aimed to characterize the clinical and demographic features associated with different RV species detected in children attending hospital with ARI, from low-income families in North-east Brazil. Nasopharyngeal aspirates were collected from 630 children <5 years with ARI. Clinical diagnosis and disease severity were also recorded. Samples were analyzed by multiplex PCR for 18 viral and atypical bacterial pathogens; RV positive samples underwent partial sequencing to determine species and type. RV was the fourth commonest pathogen accounting for 18.7% of pathogens detected. RV was commonly detected in children with bronchiolitis, pneumonia, and asthma/episodic viral wheeze (EVW). Species and type were assigned in 112 cases (73% RV-A; 27% RV-C; 0% RV-B). Generally, there were no differences in clinical or demographic characteristics between those infected with RV-A and RV-C. However, in children with asthma/EVW, RV-C was detected relatively more frequently than RV-A (23% vs. 5%; P = 0.04). Our findings highlight RV as a potentially important pathogen in this setting. Generally, clinical and demographic features were similar in children in whom RV-A and C species were detected. However, RV-C was more frequently found in children with asthma/EVW than RV-A.

Rhinovirus species and clinical features in children hospitalised with pneumonia from Mozambique.

OBJECTIVES: To describe the prevalence of human rhinovirus (RV) species in children hospitalised with pneumonia in Manhiça, Mozambique, and the associations between RV species and demographic, clinical and laboratory features. METHODS: Nasopharyngeal aspirates were collected from children 0 to 10 years of age (n = 277) presenting to Manhiça District Hospital with clinical pneumonia. Blood samples were collected for HIV and malaria testing, blood culture and full blood counts, and a chest X-ray was performed. A panel of common respiratory viruses was investigated using two independent multiplex RT-PCR assays with primers specific for each virus and viral type. RV species and genotypes were identified by seminested PCR assays, sequencing and phylogenetic tree analyses. RESULTS: At least one respiratory virus was identified in 206 (74.4%) children hospitalised with clinical pneumonia. RV was the most common virus identified in both HIV-infected (17 of 38, 44.7%) and HIV-uninfected (74 of 237, 31.2%; P = 0.100) children. RV-A was the most common RV species identified (47 of 275, 17.0%), followed by RV-C (35/275, 12.6%) and RV-B (8/275, 2.9%). Clinical presentation of the different RV species was similar and overlapping, with no particular species being associated with specific clinical features. CONCLUSIONS: RV-A and RV-C were the most common respiratory viruses identified in children hospitalised with clinical pneumonia in Manhiça. Clinical presentation of RV-A and RV-C was similar and overlapping.

Longitudinal assessment of airway responsiveness from 1 month to 18 years in the PIAF birth cohort.

The Perth Infant Asthma Follow-up (PIAF) study involves a birth cohort of unselected subjects who have undergone longitudinal assessments of airway responsiveness at 1, 6 and 12 months and 6, 11 and 18 years of age. The aim of this study was to determine the relationship between increased airway responsiveness throughout childhood and asthma in early adult life.Airway responsiveness to histamine, assessed as a dose-response slope (DRS), and a respiratory questionnaire were completed at 1, 6 and 12 months and 6, 11 and 18 years of age.253 children were initially recruited and studied. Airway responsiveness was assessed in 203, 174, 147, 103, 176 and 137 children at the above-mentioned time points, respectively (39 participants being assessed on all test occasions). Asthma at 18 years was associated with increased airway responsiveness at 6, 12 and 18 years, but not during infancy (slope 0.24, 95% CI 0.06-0.42; p=0.01; slope 0.25, 95% CI 0.08-0.49; p=0.006; and slope 0.56, 95% CI 0.29-0.83; p<0.001, respectively).Increased airway responsiveness and its association with asthma at age 18 years is established between infancy and 6 years. We propose that airway responsiveness in early life reflects the initial airway geometry and airway responsiveness later in childhood increasingly reflects immunological responses to environmental influences.

Comparison of rhinovirus antibody titers in children with asthma exacerbations and species-specific rhinovirus infection.

BACKGROUND: Asthma exacerbations are associated with human rhinovirus (HRV) infections, and more severe exacerbations are associated with HRV-C. We have previously shown that the HRV-C-specific antibody response is low in healthy adult sera and that most of the antibody to HRV-C is cross-reactive with HRV-A. OBJECTIVES: To compare the antibody response to each HRV species in asthmatic and nonasthmatic children in whom the type of HRV infection was known. METHODS: Total and specific IgG1 binding to HRV viral capsid protein antigens of HRV-A, -B, and -C were tested in the plasma from nonasthmatic children (n = 47) and children presenting to the emergency department with asthma exacerbations (n = 96). HRV, found in most of the children at the time of their exacerbation (72%), was analyzed using molecular typing. RESULTS: Asthmatic children had higher antibody responses to HRV. The titers specific to HRV-A, and to a lesser extent HRV-B, were higher than in nonasthmatic controls. The species-specific responses to HRV-C were markedly lower than titers to HRV-A and HRV-B in both asthmatic and nonasthmatic children (P < .001). The titers both at presentation and after convalescence were not associated with the HRV genotype detected during the exacerbation. CONCLUSIONS: The higher total anti-HRV antibody titers of asthmatic children and their higher anti-HRV-A and -B titers show their development of a heightened antiviral immune response. The low species-specific HRV-C titers found in all groups, even when the virus was found, point to a different and possibly less efficacious immune response to this species.

Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop.

Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.

Human rhinovirus species C infection in young children with acute wheeze is associated with increased acute respiratory hospital admissions.

RATIONALE: Human rhinovirus species C (HRV-C) is the most common cause of acute wheezing exacerbations in young children presenting to hospital, but its impact on subsequent respiratory illnesses has not been defined. OBJECTIVES: To determine whether acute wheezing exacerbations due to HRV-C are associated with increased hospital attendances due to acute respiratory illnesses (ARIs). METHODS: Clinical information and nasal samples were collected prospectively from 197 children less than 5 years of age, presenting to hospital with an acute wheezing episode. Information on hospital attendances with an ARI before and after recruitment was subsequently obtained. MEASUREMENTS AND MAIN RESULTS: HRV was the most common virus identified at recruitment (n = 135 [68.5%]). From the 120 (88.9%) samples that underwent typing, HRV-C was the most common HRV species identified, present in 81 (67.5%) samples. Children with an HRV-related wheezing illness had an increased risk of readmission with an ARI (relative risk, 3.44; 95% confidence interval, 1.17-10.17; P = 0.03) compared with those infected with any other virus. HRV-C, compared with any other virus, was associated with an increased risk of a respiratory hospital admission before (49.4% vs. 27.3%, respectively; P = 0.004) and within 12 months (34.6% vs. 17.0%; P = 0.01) of recruitment. Risk for subsequent ARI admissions was further increased in atopic subjects (relative risk, 6.82; 95% confidence interval, 2.16-21.55; P = 0.001). Admission risks were not increased for other HRV species. CONCLUSIONS: HRV-C-related wheezing illnesses were associated with an increased risk of prior and subsequent hospital respiratory admissions. These associations are consistent with HRV-C causing recurrent severe wheezing illnesses in children who are more susceptible to ARIs.

How climate change degrades child health: A systematic review and meta-analysis.

BACKGROUND: Children are more vulnerable than adults to climate-related health threats, but reviews examining how climate change affects human health have been mainly descriptive and lack an assessment of the magnitude of health effects children face. This is the first systematic review and meta-analysis that identifies which climate-health relationships pose the greatest threats to children. OBJECTIVES: We reviewed epidemiologic studies to analyse various child health outcomes due to climate change and identify the relationships with the largest effect size. We identify population-specific risks and provide recommendations for future research. METHODS: We searched four large online databases for observational studies published up to 5 January 2023 following PRISMA (systematic review) guidelines. We evaluated each included study individually and aggregated relevant quantitative data. We used quantitative data in our meta-analysis, where we standardised effect sizes and compared them among different groupings of climate variables and health outcomes. RESULTS: Of 1301 articles we identified, 163 studies were eligible for analysis. We identified many relationships between climate change and child health, the strongest of which was increasing risk (60 % on average) of preterm birth from exposure to temperature extremes. Respiratory disease, mortality, and morbidity, among others, were also influenced by climate changes. The effects of different air pollutants on health outcomes were considerably smaller compared to temperature effects, but with most (16/20 = 80 %) pollutant studies indicating at least a weak effect. Most studies occurred in high-income regions, but we found no geographical clustering according to health outcome, climate variable, or magnitude of risk. The following factors were protective of climate-related child-health threats: (i) economic stability and strength, (ii) access to quality healthcare, (iii) adequate infrastructure, and (iv) food security. Threats to these services vary by local geographical, climate, and socio-economic conditions. Children will have increased prevalence of disease due to anthropogenic climate change, and our quantification of the impact of various aspects of climate change on child health can contribute to the planning of mitigation that will improve the health of current and future generations.