The clinical experience gathered throughout the years has raised awareness of primary immunodeficiency diseases (PIDD). T cell receptor excision circles (TREC) and kappa-deleting recombination ...excision circles (KREC) assays for thymic and bone marrow outputs measurement have been widely implemented in newborn screening (NBS) programs for Severe Combined Immunodeficiency. The potential applications of combined TREC and KREC assay in PIDD diagnosis and immune reconstitution monitoring in non-neonatal patients have been suggested. Given that ethnicity, gender, and age can contribute to variations in immunity, defining the reference intervals of TREC and KREC levels in the local population is crucial for setting up cut-offs for PIDD diagnosis. In this retrospective study, 479 healthy Chinese sibling donors (240 males and 239 females; age range: 1 month-74 years) from Hong Kong were tested for TREC and KREC levels using a simultaneous quantitative real-time PCR assay. Age-specific 5
-95
percentile reference intervals of TREC and KREC levels (expressed in copies per μL blood and copies per 10
cells) were established in both pediatric and adult age groups. Significant inverse correlations between age and both TREC and KREC levels were observed in the pediatric age group. A significant higher KREC level was observed in females than males after 9-12 years of age but not for TREC. Low TREC or KREC levels were detected in patients diagnosed with mild or severe PIDD. This assay with the established local reference intervals would allow accurate diagnosis of PIDD, and potentially monitoring immune reconstitution following haematopoietic stem cell transplantation or highly active anti-retroviral therapy in the future.
Persistence of protective immunity for SARS-CoV-2 is important against reinfection. Knowledge on SARS-CoV-2 immunity in pediatric patients is currently lacking. We opted to assess the SARS-CoV-2 ...adaptive immunity in recovered children and adolescents, addressing the pediatrics specific immunity towards COVID-19. Two independent assays were performed to investigate humoral and cellular immunological memory in pediatric convalescent COVID-19 patients. Specifically, RBD IgG, CD4+, and CD8+ T cell responses were identified and quantified in recovered children and adolescents. SARS-CoV-2-specific RBD IgG detected in recovered patients had a half-life of 121.6 days and estimated duration of 7.9 months compared with baseline levels in controls. The specific T cell response was shown to be independent of days after diagnosis. Both CD4+ and CD8+ T cells showed robust responses not only to spike (S) peptides (a main target of vaccine platforms) but were also similarly activated when stimulated by membrane (M) and nuclear (N) peptides. Importantly, we found the differences in the adaptive responses were correlated with the age of the recovered patients. The CD4+ T cell response to SARS-CoV-2 S peptide in children aged <12 years correlated with higher SARS-CoV-2 RBD IgG levels, suggesting the importance of a T cell-dependent humoral response in younger children under 12 years. Both cellular and humoral immunity against SARS-CoV-2 infections can be induced in pediatric patients. Our important findings provide fundamental knowledge on the immune memory responses to SARS-CoV-2 in recovered pediatric patients.
HLA genes are the most polymorphic in the human genome. High resolution HLA typing from 13,870 bone marrow donors in Hong Kong was obtained using Next‐generation sequencing (NGS) technology. Among ...the 67 novel alleles identified, official HLA allele names of 50 novel class I alleles (HLA‐A, ‐B, ‐C) and 8 novel class II alleles (HLA‐DRB1, ‐DQB1) were assigned by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System.
Omicron generally causes milder disease than previous strains of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), especially in fully vaccinated individuals. However, incompletely ...vaccinated children may develop Omicron‐related complications such as those affecting the central nervous system. To characterize the spectrum of clinical manifestations of neuro‐COVID and to identify potential biomarkers associated with clinical outcomes, we recruited 15 children hospitalized for Omicron‐related neurological manifestations in three hospitals in Hong Kong (9 boys and 6 girls aged 1–13 years). All were unvaccinated or incompletely vaccinated. Fourteen (93.3%) were admitted for convulsion, including benign febrile seizure (n = 7), complex febrile seizure (n = 2), seizure with fever (n = 3), and recurrent breakthrough seizure (n = 2), and the remaining nonconvulsive patient developed encephalopathic state with impaired consciousness. None of the seven children with benign febrile seizure and six of eight children with other neurological manifestations had residual deficits at 9‐month follow‐up. SARS‐CoV‐2 RNA was undetectable in the cerebrospinal fluid (CSF) specimens of seven patients who underwent lumbar puncture. Spike‐and‐wave/sharp waves affecting the frontal lobes were detected in four of seven (57.1%) patients who underwent electroencephalogram. Children with Omicron‐related neurological manifestations had significantly higher blood levels of IL‐6 (p < 0.001) and CHI3L1 (p = 0.022) than healthy controls, and higher CSF levels of IL‐6 (p = 0.002) than children with non‐COVID‐19‐related febrile illnesses. Higher CSF‐to‐blood ratios of IL‐8 and CHI3L1 were associated with longer length of stay, whereas higher ratios of IL‐6 and IL‐8 were associated with higher blood tau level. The role of CSF:blood ratio of IL‐6, IL‐8, and CHI3L1 as prognostic markers for neuro–COVID should be further evaluated.
Recent studies showed that ABO‐adjusted calculated panel reactive antibody (ABO‐cPRA) may better reflect the histocompatibility level in a multi‐ethnic population, but such data in Asians is not ...available. We developed an ABO‐adjusted cPRA metric on a cohort of waitlist kidney transplant patients (n = 647, 99% Chinese) in Hong Kong, based on HLA alleles and ABO frequencies of local donors. The concordance between the web‐based ABO‐cPRA calculator and the impact on kidney allocation were evaluated. The blood group distribution for A, B, O and AB among waitlist kidney candidates were 26.2%, 27.5%, 40.1%, and 6.1%, and their chances of encountering incompatible blood group donors were 32.6%, 32.4%, 57.6%, and 0%, respectively. There is poor agreement between web‐based ABO‐cPRA calculator and our locally developed metrics. Over 90% of patients showed an increase in cPRA after ABO adjustment, most notably in those with cPRA between 70% and 79%. Blood group O patients had a much greater increase in cPRA scores after adjustment while patients of blood group A and B had similar increment. 10.6% of non‐AB blood group waitlist patients had ABO‐cPRA elevated to ≥80%. A local ABO‐adjusted cPRA metric is required for Asian populations and may improve equity in kidney distribution for patients with disadvantageous blood groups. The result from the current study potentially helps other countries/localities in establishing their own unified ABO‐cPRA metrics and predict the impact on kidney allocation.
Background
HLA‐B*15:11 is associated with carbamazepine (CBZ)‐induced severe cutaneous adverse drug reactions (SCARs) in Japanese and some Asian populations, but such data remains relatively limited ...in Chinese. Routine HLA‐B*15:02 screening is mandatory before CBZ commencement, however, SCARs related to CBZ were still observed in non‐HLA*B‐15:02 carriers.
Objective
We aimed to find out the prevalence of HLA‐B*15:11 in Chinese patients and its associations with CBZ‐induced SCARs.
Method
We screened 8,328 blood samples collected for HLA allele typing before CBZ commencement during the period of January 2014 to December 2019. In HLA‐B*15:02 negative Chinese patients, HLA‐B*15:11 status were further screened, and the incidence of SCARs in the CBZ group was compared with the control group without CBZ use.
Result
In this cohort, 1416 out of 8328 patients (17%) tested HLA‐B*15:02 positive and were advised to avoid CBZ, while 80 (0.96%) were found to be HLA‐B*15:11 positive. In 6911 (83%) patients who tested HLA‐B*15:02 negative, 70 (1.01%) were HLA‐B*15:11 positive. Five out of 70 (7.14%) patients had SCARs. The incidence of SCARs in HLA‐B*15:11 carriers who received CBZ was significantly higher than those without CBZ (17.4% 4/23 vs. 2.13% 1/47, P = 0.037*). The odds ratio was 9.68 (95% CI 1.02–92.4, P = 0.048*). These included: one Stevens‐Johnson syndrome (SJS), two DRESS, and one MPE after CBZ use, while one developed MPE after phenytoin use in control.
Conclusion
HLA‐B*15:11 is a potential risk factor of CBZ‐induced SCARs in HLA‐B*15:02 negative Chinese patients. Further screening of HLA‐B*15:11 status in those HLA‐B*15:02 negative patients is recommended to avoid undesirable SCARs.
Human leukocyte antigen (HLA)-B*58:01 allele is a significant risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs) which is potentially fatal. In some studies, chronic ...kidney disease (CKD) was also implicated to compound the risk of SCARs. We aim to investigate if pre-treatment HLA-B*58:01 screening can prevent allopurinol-induced SCARs in Chinese patients with CKD and its cost-effectiveness. We prospectively recruited Chinese CKD patients who required allopurinol during 2011–2015 and performed pre-treatment HLA testing (HLA screening group). Patients tested positive for HLA-B*58:01 were refrained from allopurinol while those tested negative were prescribed allopurinol. The incidence of SCARs in the HLA screening group was compared with the historical control in previous 5 years and the cost-effectiveness of HLA testing was analyzed. In the historical control (2006–2010), 3605 patients on allopurinol were screened, 22 out of 1027 (2.14%) CKD Chinese patients newly started on allopurinol developed SCARs, including 6 SJS/TEN. In the HLA screening group, 28 out of 192 patients (14.6%) tested HLA-B*58:01 positive were advised to avoid allopurinol; 156 out of 164 HLA-B*58:01-negative patients received allopurinol and none developed SCARs. The incidence rate of SCARs was significantly lower in the HLA screening group compared with controls (0% vs 2.14% respectively,
p
= 0.037*). The targeted HLA screening approach was associated with lower healthcare costs compared with no HLA screening (US$ 92,430 vs US$ 281,226). Pre-treatment HLA-B*58:01 screening is cost-effective to target on patients with CKD in Chinese to prevent allopurinol-induced SCARs.
Our study (NCT04800133) aimed to determine the safety and immunogenicity in patients with IEIs receiving a 3-dose primary series of mRNA vaccine BNT162b2 (age 12+) or inactivated whole-virion vaccine ...CoronaVac (age 3+) in Hong Kong, including Omicron BA.1 neutralization, in a nonrandomized manner. Intradermal vaccination was also studied. Thirty-nine patients were vaccinated, including 16 with homologous intramuscular 0.3ml BNT162b2 and 17 with homologous intramuscular 0.5ml CoronaVac. Two patients received 3 doses of intradermal 0.5ml CoronaVac, and 4 patients received 2 doses of intramuscular BNT162b2 and the third dose with intradermal BNT162b2. No safety concerns were identified. Inadequate S-RBD IgG and surrogate virus neutralization responses were found after 2 doses in patients with humoral immunodeficiencies and especially so against BA.1. Dose 3 of either vaccine increased S-RBD IgG response. T cell responses against SARS-CoV-2 antigens were detected in vaccinated IEI patients by intracellular cytokine staining on flow cytometry. Intradermal third dose vaccine led to high antibody response in 4 patients. The primary vaccination series of BNT162b2 and CoronaVac in adults and children with IEIs should include 3 doses for optimal immunogenicity.
Allogeneic hematopoietic stem cell transplantation is curative for transfusion‐dependent thalassemia, but mixed chimerism (MC) may herald graft rejection. We report a child who failed bone marrow ...transplant (BMT) from matched unrelated donor (MUD) successfully salvaged with haploidentical peripheral blood stem cell transplant (PBSCT), but had MC in T‐lymphocyte compartment despite near‐complete donor chimerism in myeloid compartment. MC was successfully improved by repeated CD45RA‐depleted donor lymphocyte infusion (DLI). A 2‐year‐old Chinese girl with beta‐thalassemia major underwent 12/12‐MUD BMT with HU/AZA/Cy/Flu/Bu/TT conditioning resulted in graft rejection. As donor refused second donation, rescue haploidentical PBSCT was performed with alemtuzumab/fludarabine/treosulfan conditioning. Harvest product was CD3/CD45RA depleted with extra products cryopreserved. Split cell chimerism performed 1‐month after haplo‐transplant showed 97% mother, 3% MUD, and 0% host for granulocytes but 38% mother, 62% MUD, and 0% host for CD3 + T cells. In view of low haploidentical donor chimerism in T‐lymphocyte compartment, CD45RA‐depleted DLI using cryopreserved product was performed on day + 38, after thymoglobulin 3 mg/kg given as T‐cell depletion 3 days beforehand. T‐cell chimerism improved to 51% mother and 49% MUD post‐DLI. Second cryopreserved CD45RA‐depleted DLI was given 17 days after the first DLI (day + 55), and 100% full chimerism of mother's T cells was gradually established without significant graft‐versus‐host disease (GVHD) or viral reactivation. To conclude, split lineage chimerism determination is beneficial to guide management strategy. For MC in T‐cell compartment, CD45RA‐depleted DLI is a potential alternative to unselected T cells as it carries lower risk of GVHD and infection.
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