Search

Background: Chronic granulomatous disease (CGD) is a rare disease in China, and very little large‐scale studies have been conducted to date. We aimed to investigate the clinical and genetic features of CGD in Chinese pediatric patients. Methods: Pediatric patients with CGD from Beijing Children's Hospital, Capital Medical University, China, were enrolled from January 2006 to December 2016. Results: A total of 159 pediatric patients with CGD were enrolled. The median age of clinical onset was 1.4 months, and 73% (116/159) had clinical onset symptoms before the 1 year of age. The most common site of invasion was the lungs. The lymph nodes, liver, and skin were more frequently invaded in X‐linked (XL) CGD patients than in autosomal recessive (AR) CGD patients (P < 0.05). Approximately 64% (92/144) of the pediatric patients suffered from abnormal response to BCG vaccination. The most frequent pathogens were Aspergillus and Mycobacterium tuberculosis. Gene analysis indicated that 132 cases (89%, 132/147) harbored CYBB pathogenic variants, 7 (5%, 7/147) carried CYBA pathogenic variants, 4 (3%, 4/147) had NCF1 pathogenic variants, and 4 (3%, 4/147) had NCF2 pathogenic variants. The overall mortality rate in this study was 43%, particularly the patients were males, with CYBB mutant and did not receive HSCT treatment. Conclusions: Chronic granulomatous disease is a rare disease affecting Chinese children; however, it is often diagnosed at a later age, and thus, the mortality rate is relatively high. The prevalence and the severity of disease in XL‐CGD are higher than AR‐CGD. [ABSTRACT FROM AUTHOR]

In 2008, more than 290,000 children suffered from urinary tract stones with a history of consuming melamine-contaminated powdered formula in China. Little was known about the long-term follow-up of outcomes of these patients in southwest China, so we conducted one-year follow-up investigation for further study. Thirty-six of 51 inpatients with melamine-induced urolithiasis were enrolled in this study. After 12 months follow-up, none of the children had vomiting, oliguria, gross hematuria, or fever. Twenty-seven patients were stone free, stones decreased in size in six patients and increased in three. Serum total protein, albumin, and pre-albumin increased significantly from baseline to 12 months, and renal function remained normal. Melamine-induced urolithiasis could not lead renal dysfunction at 12 months follow-up. The results of our study indicated that more attention should be paid to the prevention of protein malnutrition in children with a history of consuming melamine-contaminated food products. [ABSTRACT FROM PUBLISHER]

Summary: Objectives: To investigate the prevalence and molecular epidemiology of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) nasal carriage in children. Methods: We collected nasal and nasopharyngeal swabs from 2211 children aged 2–5 years attending 79 day care centers (DCCs) and 113 kindergartens (KGs) in all 18 geographical districts in Hong Kong. Results: The overall carriage rates of S. aureus and MRSA were 27.6% (95% confidence interval [CI], 24.8–28.5%) and 1.3% (95% CI, 0.8–1.8%), respectively. Molecular typing (staphylococcal cassette chromosome mec [SCCmec], sequence type [ST], clonal cluster [CC]) showed that all the 28 MRSA isolates had SCCmec IV (n = 13) or V (n = 15) including 12 isolates with community-associated-MRSA genotypes (ST59-IV/V, ST30-IV and ST88-V), 10 isolates with healthcare-associated-MRSA genotypes (ST45-IV/V, CC5-IV and ST630-V) and six isolates with novel genotypes (ST10-V and CC1-IV). Spa typing indicated that there was some within and between DCCs/KGs transmission of certain MRSA and methicillin-sensitive S. aureus strains but this was not extensive. Conclusion: Our findings indicate the potential for DCCs to be a reservoir for emerging MRSA genotypes and highlight the need to enhance education and infection control measures to reduce their cross-transmission in this population. [Copyright &y& Elsevier]

The hypothesis that protection of infants from exposure to infectious agents with delayed first exposure to one or more specific agents together contribute to the aetiology of childhood leukaemia, especially common acute lymphoblastic leukaemia (cALL), has substantial indirect support from descriptive epidemiology and case-control studies in developed Western countries. A case-control study of childhood leukaemia diagnosed at ages 2-14 years has now been conducted in Hong Kong. Cases (n=98) formed a consecutive series of Chinese children diagnosed with acute leukaemia; controls (n=228) were identified following a survey using random digit dialling and required to attend for medical examination by a paediatrician. Interviews with mothers were conducted in hospital by one trained interviewer using a structured questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) are reported for exposure variables capable of serving as proxies for exposure to infection in two critical time periods: first year of life, year before reference date (diagnosis for cases, corresponding date for controls). Analyses used logistic regression with adjustment for appropriate confounders. Change of area of residence reduced risk if during the first time period (OR = 0.47 [95% CI 0.23, 0.98]) and increased risk if during the second (OR=3.92, [95% CI 1.47, 10.46]). Reported roseola and/or fever and rash in the first year of life reduced risk (OR=0.33 [95% CI 0.16, 0.68]) whereas tonsillitis in the period 3-12 months before reference date increased risk (OR=2.56 [95% CI 1.22, 5.38]). Some other proxies for exposure to infection at the critical times were associated with predicted patterns of risk but day-care attendance failed to show predicted associations. These results provide support for the delayed exposure hypothesis in an affluent geographical setting in which population exposure to infectious agents is quite distinct from the settings of previous case-control studies. [ABSTRACT FROM AUTHOR]

Background: The thalassemias are common in southern China. We determined the prevalence of heterozygous carriers of these genetic disorders in Hong Kong and assessed the feasibility of a community-based screening program. Methods: An educational and screening program for the thalassemias was carried out in three high schools with a total of 2420 students. Seventy-five percent of the students agreed to undergo screening, which consisted of blood counts, hemoglobin electrophoresis, serum ferritin measurements, and DNA analyses. Results: Of the 1800 blood samples tested, 150 (8.3 percent) had microcytosis (mean corpuscular volume, <80 μm3). Ninety students (5.0 percent) were carriers of α-thalassemia, of whom 81 (4.5 percent) were carriers of the Southeast Asian type of deletion, in which both α-globin genes on the same chromosome 16 are deleted. Sixty-one students (3.4 percent) were carriers of either β-thalassemia or the mutation coding for hemoglobin E. Six students were carriers of both α- and β-thalassemias. On the basis of these figures, the estimated numbers of pregnancies in Hong Kong in which the fetus is at risk for homozygous α-thalassemia and β-thalassemia major or intermedia are 145 and 80 per year, respectively. In Hong Kong the actual numbers of women referred for prenatal diagnoses of these disorders are approximately 95 and 40 per year, respectively. Conclusions: Despite the availability of hospital-based screening and prenatal diagnosis for many years in Hong Kong, many women carrying fetuses at risk for thalassemia are not referred for genetic counseling. A community-based program of education, screening, and counseling is needed in Hong Kong and southern China. (N Engl J Med 1997;336:1298-301.) [ABSTRACT FROM AUTHOR]

Abstract: This study assessed the changes in serotype distribution and antibiotic resistance of Streptococcus pneumoniae isolates in children before and after introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Hong Kong. Nasopharyngeal specimens were collected from 1978 and 2211 children (ages, 2 to 6 years) attending day care centers or kindergartens in period 1 (1999–2000) and period 2 (2009–2010), respectively. Carriage of PCV7 serotypes decreased from 12.8% to 8.6% (P < 0.01). The relative contribution of PCV7 serotypes 14 and 18C had decreased, whereas that for non-PCV7 serotypes 19A, 6A, 6C, 23A, and 15B had increased. In period 2, PCV7 penetration rate (at least 1 dose) for children aged 2, 3, 4, and 5 years was 43%, 35.7%, 26.7%, and 20.4%, respectively. In multivariate analysis, PCV7 use was the only independent variable associated with fewer PCV7 serotype carriages (odds ratio 0.5; P = 0.001). In period 2, high rates of dual penicillin/erythromycin nonsusceptibility were found in serotypes 6B (77.3%), 14 (100%), 19F (100%), 23F (78%), 19A (75%), 6A (87.8%), 6C (59.3%), and 23A (78.9%). [Copyright &y& Elsevier]

Abstract: This study analyzed 828 isolates causing invasive pneumococcal disease (IPD) before (1995–2001, n =265) and after (2007–2009, n =563) the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Hong Kong. In children <5 years, serotype 14 had declined (36–15.7%, P <0.01) while 19A had increased (0–12.9%, P <0.01) in the before and after periods, respectively. In children aged <5 years, the proportion of PCV7 serotypes declined from 89.5% to 65.7% (72.8% if included cross protection against 6A) with time but that of PCV13 serotypes remained stable (91.4–93.2%). In elderly ≥65 years, 9V and 23F decreased from 3.8% to 0.3% (P =0.01) and from 18.9% to 7.4% (P <0.01), respectively while 7F increased significantly from 0% to 4.1% (P =0.04) over the same periods. Among isolates from aged <5 years, dual penicillin/erythromycin resistance increased from 44.1% to 64.2% (P =0.01). The types that often had dual penicillin/erythromycin resistance were 6B, 14, 19F, 23F, 6A and 19A. The emergence of serotype 19A was associated with expansion of sequence type 320. [Copyright &y& Elsevier]

Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses., (© 2024 Al Qureshah et al.)

Cryopyrin-associated periodic syndrome (CAPS) comprises a group of disorders characterized by recurrent bouts of systemic inflammation related to overactivation of inflammasome. So far, neither large cases of the correlation between genotype and phenotype nor treatment strategies have been clearly stated in China. Here, we studied the clinical and genetic characteristics and their correlation from 30 CAPS patients in China. We identified the pathogenesis for novel mutations by activating NLRP3 inflammasome for peripheral cells with ATP plus LPS, compared characteristics with other case series, and analyzed treatment outcomes of these patients. The patients harbored 19 substitutions in NLRP3 , and 8 of them were novel mutations. Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials. The correlation of phenotypes and their variants seemed different in our cases, such as T350M, S333G/I/R, and F311V (somatic mosaicism). Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up. Patients treated with prednisolone or prednisolone plus thalidomide or methotrexate, tocilizumab, TNF inhibiting agents, and sirolimus achieved only partial remission. Importantly, we firstly identified somatic mosaicism mutation of F311V, which was severe. Our study extended the spectrum of genotype and phenotype and characteristics of their correlations and provided detailed responses to different treatment strategies. These data provide guidance for future diagnosis and management for CAPS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shu, Zhang, Han, Li, Piao, Sun, Ma, Mo, Sun, Chan, Yang, Lau and Mao.)

Objectives: To identify novel genetic loci associated with systemic lupus erythematosus (SLE) and to evaluate potential genetic differences between ethnic Chinese and European populations in SLE susceptibility., Methods: A new genome-wide association study (GWAS) was conducted from Jining, North China, on 1506 individuals (512 SLE cases and 994 matched healthy controls). The association results were meta-analysed with existing data on Chinese populations from Hong Kong, Guangzhou and Central China, as well as GWAS results from four cohorts of European ancestry. A total of 26 774 individuals (9310 SLE cases and 17 464 controls) were included in this study., Results: Meta-analysis on four Chinese cohorts identifies KLF2 as a novel locus associated with SLE [rs2362475; odds ratio (OR) = 0.85, P=2.00E-09]. KLF2 is likely an Asian-specific locus as no evidence of association was detected in the four European cohorts (OR = 0.98, P =0.58), with evidence of heterogeneity (P=0.0019) between the two ancestral groups. Meta-analyses of results from both Chinese and Europeans identify STAB2 (rs10082873; OR= 0.89, P=4.08E-08) and DOT1L (rs4807205; OR= 1.12, P=8.17E-09) as trans-ancestral association loci, surpassing the genome-wide significance., Conclusions: We identified three loci associated with SLE, with KLF2 a likely Chinese-specific locus, highlighting the importance of studying diverse populations in SLE genetics. We hypothesize that DOT1L and KLF2 are plausible SLE treatment targets, with inhibitors of DOT1L and inducers of KLF2 already available clinically., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r 2  ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

The use of exome and genome sequencing has increased rapidly nowadays. After primary analysis, further analysis can be performed to identify secondary findings that offer medical benefit for patient care. Multiple studies have been performed to evaluate secondary findings in different ethnicities. However, relevant data are limited in Chinese. Here, with the use of a cohort consisted of 1116 Hong Kong Chinese exome sequencing data, we evaluated the secondary findings in the 59 genes recommended by the American College of Medical Genetics and Genomics. Fifteen unique pathogenic or likely pathogenic variants in 17 individuals were identified, representing a frequency of 1.52% in our cohort. Although 20 individuals harboured pathogenic or likely pathogenic variants in recessive conditions, none carried bi-allelic mutations in the same gene. Our finding was in accordance with the estimation from the American College of Medical Genetics and Genomics that about 1% individuals harbour secondary findings.

ABSTRACT As another wave of COVID-19 outbreak has approached in July 2020, a larger scale COVID-19 pediatric Asian cohort summarizing the clinical observations is warranted. Children confirmed with COVID-19 infection from the Republic of Korea, the Hong Kong Special Administrative Region (HKSAR) and Wuhan, China, during their first waves of local outbreaks were included. Their clinical characteristics and the temporal sequences of the first waves of local paediatric outbreaks were compared. Four hundred and twenty three children with COVID-19 were analyzed. Wuhan had the earliest peak, followed by Korea and HKSAR. Compared with Korea and Wuhan, patients in HKSAR were significantly older (mean age: 12.9 vs. 10.8 vs. 6.6 years, p  < 0.001, respectively) and had more imported cases (87.5% vs. 16.5% vs. 0%, p  < 0.001, respectively). The imported cases were also older (13.4 vs. 7.6 years, p  < 0.001). More cases in HKSAR were asymptomatic compared to Korea and Wuhan (45.5% vs. 22.0% vs. 20.9%, p  < 0.001, respectively), and significantly more patients from Wuhan developed fever (40.6% vs. 29.7% vs. 21.6%, p =0.003, respectively). There were significantly less imported cases than domestic cases developing fever after adjusting for age and region of origin ( p  = 0.046). 5.4% to 10.8% of patients reported anosmia and ageusia. None developed pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PMIS-TS). In general, adolescents were more likely to be asymptomatic and less likely to develop fever, but required longer hospital stays. In conclusion, majority patients in this pediatric Asian cohort had a mild disease. None developed PIMS-TS. Their clinical characteristics were influenced by travel history and age.

Background: Drug allergy, or drug hypersensitivity, is a potentially fatal disorder, and patients labeled with drug allergies have restricted access to first-line treatments. Full knowledge of the characteristics associated with drug allergies and severe reactions during allergy evaluation is beneficial for appropriate risk stratification., Objective: We sought to determine whether certain clinical characteristics are associated with drug allergies in Chinese children., Methods: Charts were reviewed for ethnic Chinese patients less than 18 years old referred to our tertiary allergy center for suspected drug allergies and completed skin and drug provocative testing between 2005 to 2017. Univariate and multivariate analyses were performed on the age of onset of drug allergies, gender, and other atopy versus drug allergies., Results: Out of 75 children, 18 (24%) had IgE-mediated drug allergies, while 8 (10.7%) had delayed drug hypersensitivities, with a cumulative 26 subjects (34.7%) with any drug hypersensitivity. There were positive independent associations between drug hypersensitivities onset age vs IgE-mediated drug allergies (odds ratio (OR) = 14.9, 95% confidence intervals (CIs) = 1.5-148.3, P = 0.017) and between male gender and IgE-mediated drug allergies (OR = 4.4, CIs = 1.2-16.4, P = 0.019). Age 13 years was the best cut-off for IgE-mediated drug allergies according to the receiver operating characteristic curve (P = 0.026). Older age group (OR = 24.0, CIs = 1.4-417.8, P = 0.024) and atopic dermatitis (OR = 8.2, CIs = 1.4-49.8, P = 0.015) were correlated with delayed drug hypersensitivities., Conclusions: While several previous studies suggested a higher prevalence of IgE-mediated drug allergies in younger adult females, older boys were more likely to have drug allergies for Chinese children.

Objectives: To compare the clinical and laboratory features of severe acute respiratory syndrome 2003 (SARS) and coronavirus disease 2019 (COVID-19) in 2 Chinese pediatric cohorts, given that the causative pathogens and are biologically similar., Study Design: This is a cross-sectional study reviewing pediatric patients with SARS (n = 43) and COVID-19 (n = 244) who were admitted to the Princess Margaret Hospital in Hong Kong and Wuhan Children's Hospital in Wuhan, respectively. Demographics, hospital length of stay, and clinical and laboratory features were compared., Results: Overall, 97.7% of patients with SARS and 85.2% of patients with COVID-19 had epidemiologic associations with known cases. Significantly more patients with SARS developed fever, chills, myalgia, malaise, coryza, sore throat, sputum production, nausea, headache, and dizziness than patients with COVID-19. No patients with SARS were asymptomatic at the time of admission, whereas 29.1% and 20.9% of patients with COVID-19 were asymptomatic on admission and throughout their hospital stay, respectively. More patients with SARS required oxygen supplementation than patients with COVID-19 (18.6 vs 4.7%; P = .004). Only 1.6% of patients with COVID-19 and 2.3% of patients with SARS required mechanical ventilation. Leukopenia (37.2% vs 18.6%; P = .008), lymphopenia (95.4% vs 32.6%; P < .01), and thrombocytopenia (41.9% vs 3.8%; P < .001) were significantly more common in patients with SARS than in patients with COVID-19. The duration between positive and negative nasopharyngeal aspirate and the length in hospital stay were similar in patients with COVID-19, regardless of whether they were asymptomatic or symptomatic, suggesting a similar duration of viral shedding., Conclusions: Children with COVID-19 were less symptomatic and had more favorable hematologic findings than children with SARS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The field of primary immunodeficiencies (PIDs) is marked by continuous discoveries in the mechanisms of disease, genetic etiologies, and treatments. A widening gap between cutting-edge scientific research and its translation to clinical practice is noticeable. To narrow this gap, collaborative networks must be made that bring together a critical mass of specialists to share the knowledge required for the next innovations. In this paper, we describe the current status of the Asian primary immunodeficiency network, which links 40 hospitals in China and Southeast Asia. Over the past 10 years, genetic studies performed on more than 500 patients have led to genetic confirmation of primary immunodeficiency in 272 patients, as well as generating cohort studies that have provided unique phenotypic observations. The network has a dynamic capacity to accommodate priorities and interests of collaborating units, from consultations and genetic testing to scientific research involving next-generation sequencing technologies., (© 2011 New York Academy of Sciences.)

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic involvement. The susceptibility genes identified so far can only explain a small proportion of disease heritability. Through a genome-wide association in a Hong Kong Chinese cohort and subsequent replication in two other Asian populations, with a total of 3164 patients and 4482 matched controls, we identified association of ELF1 (E74-like factor 1) with SLE (rs7329174, OR = 1.26, joint P= 1.47 × 10(-8)). ELF1 belongs to the ETS family of transcription factors and is known to be involved in T cell development and function. Database analysis revealed transcripts making use of three alternative exon1s for this gene. Near equivalent expression levels of distinct transcripts initiated from alternative exon1s were detected in peripheral blood mononuclear cells from both SLE patients and healthy controls. Although a direct association of rs7329174 with the three forms of transcripts for this gene was not detected, these findings support an important role of ELF1 in SLE susceptibility and suggest a potentially tight regulation for the expression of this gene.

The response of a leukocyte to immune complexes (ICs) is modulated by receptors for the Fc region of IgG (FcgammaRs), and alterations in their affinity or function have been associated with risk of autoimmune diseases, including systemic lupus erythematosus (SLE). The low-affinity FcgammaR genomic locus is complex, containing regions of copy number variation (CNV) which can alter receptor expression and leukocyte responses to IgG. Combined paralogue ratio tests (PRTs) were used to distinguish three intervals within the FCGR locus which undergo CNV, and to determine FCGR gene copy number (CN). There were significant differences in FCGR3B and FCGR3A CNV profiles between Caucasian, East Asian and Kenyan populations. A previously noted association of low FCGR3B CN with SLE in Caucasians was supported [OR = 1.57 (1.08-2.27), P = 0.018], and replicated in Chinese [OR = 1.65 (1.25-2.18), P = 4 x 10(-4)]. There was no association of FCGR3B CNV with vasculitis, nor with malarial or bacterial infection. Linkage disequilibrium (LD) between multi-allelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus was defined for the first time. Despite LD between FCGR3B CNV and a variant in FcgammaRIIB (I232T) which abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FcgammaRIIB-232T allele were individually strongly associated with SLE risk. Thus CN of FCGR3B, which controls IC responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis. Further interpretations of contributions to pathogenesis by FcgammaRs must be made in the context of LD involving CNV regions.

Introduction: X-linked agammagobulinemia (XLA) is a primary immunodeficiency disorder caused by Bruton's tyrosine kinase (Btk) gene mutation. Recent studies suggested genotype-phenotype correlation in XLA, but a definitive association remains controversial., Patients and Methods: We examined the relationship between specific Btk gene mutations and severity of clinical presentation in 62 patients with XLA. Disease severity was assessed by the age of disease onset and the presence of severe infections, while mutations were classified into severe and mild based on structural and functional consequence by bioinformatics analysis., Results: Fifty-six Btk mutations were identified in 62 patients from 57 kindreds. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset as well as occurrence of severe infections., Conclusion: A critical analysis of the circumstances upon presentation also revealed that under-recognition of recurrent infections and relevant family history are important hurdles to timely diagnosis of XLA.

Viral shedding profile of infections caused by the pandemic H1N1 2009 influenza A virus has not been reported. The aim of this study was to determine the viral load in different body sites. Viral loads of pandemic H1N1 virus in respiratory specimens, stool, urine, and serum were determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Respiratory specimens from patients with seasonal influenza were used as historical controls. Initial pre-treatment viral load were compared between these two groups. Serial respiratory specimens from patients with pandemic H1N1 virus infection were obtained for analysis of viral dynamics. Twenty-two pandemic H1N1 cases and 44 seasonal influenza historical controls were included. The mean initial viral load before oseltamivir therapy was 1.84 x 10(8) copies/ml for pandemic H1N1 virus compared with 3.28 x 10(8) copies/ml in seasonal influenza historical controls (P = 0.085). Among patients with pandemic H1N1 virus infection, peak viral load occurred on the day of onset of symptoms, and declined gradually afterwards, with no virus being detectable in respiratory specimens by RT-PCR 8 days and by culture 5 days after the onset of symptoms respectively, except in one patient. Pandemic H1N1 virus was detected in stool and in urine from 4/9 and 1/14 patients, respectively. Viral culture was also positive from the stool sample with the highest viral load. Younger age was associated with prolonged shedding in the respiratory tract and higher viral load in the stool. Data from this quantitative analysis of viral shedding may have implications for formulating infection control measures., ((c) 2009 Wiley-Liss, Inc.)

Primary immunodeficiency disorders (PIDs) are rare inborn errors of the immune system. Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying infections, autoimmunity, lymphoproliferation, allergy and cancer. Over 150 PID syndromes were characterized in the past 60 years, with an ever growing list of new entities being discovered. Because of their rarity, multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights into the phenotypic and genetic diversities of PIDs. In this article, we summarize our research findings on PIDs in Chinese population in the past 20 years. Close collaboration among various immunology centers, cross-referrals and systematic data analysis constitute the foundation for research on PIDs. Future directions include establishment of a national PID registry, raising awareness of PIDs and securing sufficient resources for patient care and scientific research.

Background: Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency disease, with an incidence of 4/1,000,000 live male births. In China, an estimated number of 35 babies with WAS are born each year, but likely many remain undiagnosed., Objectives: The objectives of study were to review the clinical and molecular characteristics of a cohort of Chinese children with WAS and to describe the long-term outcome of those who underwent hematopoietic stem cell transplant (HSCT)., Materials and Method: Records of 35 patients diagnosed with WAS during 1991-2008 were reviewed. Genetic diagnosis was established by direct gene sequencing., Results: All patients had classical WAS phenotype. WASP mutations were identified in 33 patients from 29 families. Nine patients underwent HSCT at a mean age of 22.1 months (match-unrelated donor, n = 5; mismatched related donor, n = 2; matched-sibling donor, n = 2). Post-transplant immune hemolytic anemia and thrombocytopenia occurred in three patients with complete resolution. All patients survived without significant long-term complications and had full platelet, T and B lymphocyte recovery within 2 years post-transplant., Conclusion: In the past decade, there has been significant improvement in clinical and genetic diagnosis of WAS in Chinese. We demonstrated excellent long-term survival in patients who underwent HSCT. Early workup for transplant should be advocated for children with classical WAS before they suffer from major disease complications and morbidities.

Background: The SARS outbreak in 2003 provides a unique opportunity for the study of human responses to a novel virus. We have previously reported that dendritic cells (DCs) might be involved in the immune escape mechanisms for SARS-CoV. In this study, we focussed on the gene expression of toll-like receptors (TLRs), chemokine receptors (CCRs) and death receptor ligands in SARS-CoV infected DCs. We also compared adult and cord blood (CB) DCs to find a possible explanation for the age-dependent severity of SARS., Results: Our results demonstrates that SARS-CoV did not modulate TLR-1 to TLR-10 gene expression but significantly induced the expression of CCR-1, CCR-3, and CCR-5. There was also strong induction of TNF-related apoptosis-inducing ligand (TRAIL), but not Fas ligand gene expression in SARS-CoV infected DCs. Interestingly, the expressions of most genes studied were higher in CB DCs than adult DCs., Conclusion: The upregulation of chemokines and CCRs may facilitate DC migration from the infection site to the lymph nodes, whereas the increase of TRAIL may induce lymphocyte apoptosis. These findings may explain the increased lung infiltrations and lymphoid depletion in SARS patients. Further explorations of the biological significance of these findings are warranted.

Background: Chronic granulomatous disease (CGD) is a rare disorder of phagocytic oxidative bursts leading to recurrent pyogenic infections. Affected individuals are most prone to infections caused by staphylococci, Salmonella, Candida, and Aspergillus, but previously we observed a high incidence of Mycobacterium tuberculosis infection in Chinese children with CGD., Objective: To determine the spectrum of infections in patients with X-linked CGD, with an emphasis on mycobacterial infections, and to review all CYBB gene mutations identified in our center., Results: From 1988 to 2005, 17 Chinese male children were diagnosed to have X-linked CGD. Fifteen mutations were identified, including 3 splice site defects (IVS1-1G>C, 266G>A, IVS3-1G>A), 5 missense mutations (591T>C, 627T>A, 949T>A, 1039T>A, 1512G>C), 3 nonsense mutations (882C>T, 1451C>A, 1569G>T), 1 insertion (756&#95;757insA), and 3 deletions (660&#95;662delTTC, 727delT, 1341delT). Eight of these were novel mutations. Recurrent pneumonia, lymphadenitis, and bacterial skin abscess were the commonest types of infection. Seven patients had tuberculosis (TB). Seven patients had prolonged scarring or abscess formation at the Calmette-Guérin bacillus (BCG) injection site, and 1 had disseminated BCG infection. Three patients had pulmonary aspergillosis. Four patients underwent hemopoietic stem cell transplantation, but 2 died of complications., Conclusions: Patients with CGD are susceptible to TB and BCG complications. Our observation suggests that oxidative burst is probably important in host defense against mycobacterial infections. Because interferon-gamma is the key cytokine involved in mycobacterial immunity, there may be a stronger indication for its use in CGD patients living in areas endemic for TB.

Objective: To test the hypothesis that low serum mannose-binding lectin (MBL) levels, as a result of the single-nucleotide polymorphisms in the promoter region (-221 X/Y) and exon 1 (codon 54 A/B) of the MBL2 gene, predispose to infection in Chinese patients with systemic lupus erythematosus (SLE)., Methods: Two hundred forty-five patients with SLE were prospectively followed for the development of major infective episodes that required hospitalization and antibiotic treatment during 1992-2005. MBL genotypes were determined by polymerase chain reaction and serum MBL levels were measured by ELISA., Results: In total, 254 major infections developed in 130 patients. Serum MBL levels were shown to correlate inversely with the number of bacterial infections (r = -0.13, p = 0.03). The distribution of MBL genotypes was similar in patients with and without major infection (p = 0.84). Patients with major infection also had more major lupus exacerbations that required daily prednisolone dose > or = 15 mg. Logistic regression showed that log MBL level (odds ratio 0.516, 95% confidence interval 0.305-0.873; p = 0.01) and major lupus exacerbation (OR 1.382, 95% CI 1.154-1.654; p < 0.001) were independent risk factors to major bacterial infection after adjustment for age and disease duration. Multiple regression analysis showed an increase in risk of bacterial infection by 34.2% for every decrease in serum MBL level by one log, and by 22.8% for each increase in number of major lupus exacerbations., Conclusion: Low serum MBL level predisposes Chinese patients with SLE to more major infections, in particular bacterial ones.

Background: Chemokines play important roles in inflammation and antiviral action. We examined whether polymorphisms of RANTES, IP-10 and Mig affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS)., Methods: We tested the polymorphisms of RANTES, IP-10 and Mig for their associations with SARS in 495 Hong Kong Chinese SARS patients and 578 controls. Then we tried to confirm the results in 356 Beijing Chinese SARS patients and 367 controls., Results: RANTES -28 G allele was associated with SARS susceptibility in Hong Kong Chinese (P < 0.0001, OR = 2.80, 95%CI:2.11-3.71). Individuals with RANTES -28 CG and GG genotypes had a 3.28-fold (95%CI:2.32-4.64) and 3.06-fold (95%CI:1.47-6.39) increased risk of developing SARS respectively (P < 0.0001). This -28 G allele conferred risk of death in a gene-dosage dependent manner (P = 0.014) with CG and GG individuals having a 2.12-fold (95% CI: 1.11-4.06) and 4.01-fold (95% CI: 1.30-12.4) increased risk. For the replication of RANTES data in Beijing Chinese, the -28 G allele was not associated with susceptibility to SARS. However, -28 CG (OR = 4.27, 95%CI:1.64-11.1) and GG (OR = 3.34, 95%CI:0.37-30.7) were associated with admission to intensive care units or death due to SARS (P = 0.011)., Conclusion: RANTES -28 G allele plays a role in the pathogenesis of SARS.

Objective: The programmed death 1 (PD-1) molecule is a negative regulator of T cells, and a genetic association between PD-1 and systemic lupus erythematosus and rheumatoid arthritis (RA) in Caucasians has been reported. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with RA in the Chinese population., Methods: Three single-nucleotide polymorphisms (SNPs), PD-1.1 G/A, PD-1.3 G/A, and PD-1.5 C/T, were genotyped in 180 patients with RA and 647 healthy controls in a case-control association study. Analyses of the association of genotypes and alleles with disease, haplotype construction, and linkage disequilibrium (LD) were performed., Results: We constructed haplotypes with the alleles of markers PD-1.1 G/A and PD-1.5 C/T and found that the GT haplotype was overrepresented in patients with RA (31%) compared with controls (23%) (P = 0.001, odds ratio [OR] 1.54, 95% confidence interval [95% CI] 1.18-1.99). Among GT double homozygotes the risk of RA was increased even further (OR 2.31, 95% CI 1.31-4.08, P = 0.006). We also observed that the AA genotype of SNP PD-1.1 was associated with a decreased risk for developing RA (OR 0.38, 95% CI 0.15-0.99, P = 0.034). No association for SNP PD-1.5 in RA was found, and SNP PD-1.3 was nonpolymorphic in the Chinese population., Conclusion: Our results support the involvement of PDCD1 as a susceptibility gene for RA in the Chinese population., ((c) 2005, American College of Rheumatology.)

Purposes: Clinical course and treatment outcome of childhood chronic ITP are quite variable in the literature. We report in the current paper our observation on the clinical behavior of chronic ITP in Chinese children., Patients and Methods: We performed a retrospective review (Jan. 1990 to Dec. 2000) of children having low platelet count (plt <150 x 10(9)/L) for more than 6 months without identifiable cause. The indication for treatment was plt < or =20 x 10(9)/L. Remission is defined as plt > or =150 x 10(9)/L., Results: Thirty-four children were identified within these 11 years. Their median age at diagnosis was 6.7 years (range from 0.4 to 16.8 years). The M:F ratio was 16:18. Bone marrow aspiration was performed in 30/34 cases. The median plt count at presentation was 24 x 10(9)/L (range 2 to 135 x 10(9)/L). Fourteen of 34 (41%) children eventually achieved durable remission. The chance of remission at 5 years was 66.62% with a median follow-up time of 5.86 years (range 0.72 to 10.41 years). Concerning therapy, 17/34 (50%) required no treatment while for the remaining 17, treatment included steroid (n = 16), IVIG (n = 7) or splenectomy (n = 3). In spite of temporary improvement in most, treatment induced prolonged complete remission (plt >150 x 10(9)/L) in only 2 patients. Twenty of 31 tested had abnormal immune marker(s) at presentation but none evolved into specific autoimmune disease later on. There was no correlation between the remission status, response to treatment, and the presence of autoimmune markers., Conclusion: About half of our chronic ITP patients achieved remission within 5 years. Medical treatment does not seem to alter the natural course of the disease but induced a transient response in most cases. Positive autoimmune markers are common among chronic ITP patients and have no significance in predicting outcome.

After the 1988 measles outbreak, annual notification rates for measles in Hong Kong SAR between 1989 and 1999 were 0.4-4.9 per 100 000, with peaks in 1992, 1994 and 1997. The first half-year incidence rates per 100 000 were 2.3 in 1997, 0.5 in 1995 and 1.2 in 1996. Monthly notification rates increased from a baseline of <10 cases to 59 in May 1997. Serological surveillance showed only 85.5% of children aged 1-19 years had measles antibodies. An epidemic, mainly because of failure of the first dose to produce immunity, seemed imminent in mid-1997. A mass immunization campaign targeted children aged 1-19 from July to November 1997. The overall coverage was 77%. The rate of adverse events was low. After the campaign, measles notification fell to 0.9 per 100 000 in 1998. A two-dose strategy and supplementary campaigns will maintain measles susceptibility at levels low enough to make measles elimination our goal.