ABSTRACTBackgroundPatients with kidney diseases are at risk of severe complications from COVID-19, yet little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases.MethodsWe investigated the immunogenicity and safety of an accelerated, 3-dose primary series of COVID-19 vaccines among 64 pediatric chronic kidney disease patients (mean age 12.2; 32 male) with or without immunosuppression, dialysis, or kidney transplant. CoronaVac was given to those aged <5 years, 0.1ml BNT162b2 to those aged 5-11 years, and 0.3ml BNT162b2 to those aged 11-18 years.ResultsAntibody responses including S-RBD IgG (90.9-100% seropositive) and surrogate virus neutralization (geometric mean sVNT% level, 78.6-94.0%) were significantly elicited by 3 doses of any vaccine. T cell responses were also elicited. Weaker neutralization responses were observed among kidney transplant recipients and non-dialysis children receiving rituximab for glomerular diseases. Neutralization was reduced against Omicron BA.1 compared to wild-type (post-dose 3 sVNT% level; 84% vs 27.2%; p<0.0001). However, T cell response against Omicron BA.1 was preserved, which likely confer protection against severe COVID-19. Hybrid immunity was observed after vaccination in infected patients, as evidenced by higher Omicron BA.1 neutralization response among infected patients receiving 2 doses than those uninfected. Generally mild or moderate adverse reactions following vaccines were reported.ConclusionsOur findings support that an accelerated 3-dose primary series with CoronaVac and BNT162b2 is safe and immunogenic in young children and adolescents with kidney diseases.TRIAL REGISTRATIONClinicaltrials.govNCT04800133SIGNIFICANCE STATEMENTLittle is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. This paper describes the antibody and T cell responses of 3 doses of CoronaVac or BNT162b2, the top 2 COVID-19 vaccines distributed worldwide, by an accelerated regimen in patients with kidney diseases aged 1-18 years. Antibody and T cell responses were significantly elicited by either vaccine. Neutralization was reduced against Omicron while T cell response was preserved, which likely confer protection against severe COVID-19. Rate of severe adverse reactions was low in the study. Results confirm that accelerated 3-dose primary series with CoronaVac and BNT162b2 is safe and immunogenic in young children and adolescents with kidney diseases.

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.

There is no available data pertaining to humoral and cellular response against COVID-19 among young children with kidney diseases following inactivated vaccine.1Han B. Song Y. Li C. Yang W. Ma Q. Jiang Z. Li M. Lian X. Jiao W. Wang L. et al.Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial.Lancet Infect Dis. 2021; 21: 1645-1653https://doi.org/10.1016/S1473-3099(21)00319-4Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar We therefore evaluated the immunogenicity and safety of 3-dose CoronaVac at an accelerated schedule (0.5ml; day 0, 14, 28) in a prospective study in Hong Kong (COVAC; NCT04800133) (Supplementary Methods).2Ma A.L.-T. Leung D. Chan E.Y.-H. Chim S. Cheng S. Ho F.T.-W. Lai W.-M. Tong P.-C. Lee M.H.-L. Wong W.H.-S. et al.Antibody responses to 2 doses of mRNA COVID-19 vaccine in pediatric patients with kidney diseases.Kidney International. 2022; 101: 1069-1072Abstract Full Text Full Text PDF Scopus (6) Google Scholar Sixty-four children were enrolled and five young children (median age 3.3 years, IQR 3.1-3.6; 3 females; 3 Chinese) were analyzed (glomerular disease on immunosuppression, n=2; aCKD, n=2; kidney failure, n=1). (Table S1) We tracked antibody responses in our patients against wild-type (WT) SARS-CoV-2, including S-RBD IgG for binding antibody and surrogate virus neutralization test (sVNT) for neutralization longitudinally from pre-vaccine baseline to post-dose 3 (Fig. 1A and 1B).3Rosa Duque J.S. Wang X. Leung D. Cheng S.M.S. Cohen C.A. Mu X. Hachim A. Zhang Y. Chan S.M. Chaothai S. et al.Immunogenicity and reactogenicity of SARS-CoV-2 vaccines BNT162b2 and CoronaVac in healthy adolescents.Nat Commun. 2022; 13: 3700https://doi.org/10.1038/s41467-022-31485-zCrossref PubMed Scopus (18) Google Scholar After 3 doses, all were seropositive for S-RBD IgG and had a high geometric mean sVNT% level of 94.0%, with increases in titers following successive doses. We also studied IFN-γ+ antiviral CD4+ helper and CD8+ cytotoxic T-cell responses against SARS-CoV-2 S, N and M proteins (Fig. 2). We detected a significant increase of SNM-specific IFN-γ+ CD4+ T-cell response in all 5 patients (Fig. 2B). Other T-cell responses such as IL-2 also showed an increasing trend (Fig. S1A-D). Importantly, all demonstrated S-specific or SNM-specific IFN-γ+ CD4+ and CD8+ T-cell responses. When compared with WT antibody response, we found a significantly lower sVNT% level against Omicron BA.1 (post-dose 3, 94.0% vs 17.9%, P=0.0012) (Fig. S2A), indicating partial neutralization escape. Nonetheless, IFN-γ+ T-cell responses were similar between Omicron BA.1 and WT (Fig. S2B-D).4Leung D. Cohen C.A. Mu X. Rosa Duque J.S. Cheng S.M.S. Wang X. Wang M. Zhang W. Zhang Y. Tam I.Y.S. et al.Immunogenicity against wild-type and Omicron SARS-CoV-2 after a third dose of inactivated COVID-19 vaccine in healthy adolescents.Front Immunol. 2023; 141106837https://doi.org/10.3389/fimmu.2023.1106837Crossref Scopus (0) Google Scholar In addition, we noticed comparable antibody responses between these 5 patients and healthy subjects aged 3-5 who were recruited in another subgroup of the same prospective study (Fig. S3A-B). We also found that CoronaVac was safe and tolerable in our patients, and no breakthrough infections were reported following a median of 118 days (IQR 111-132 days) after dose 3 (Supplemental text 1 and Fig. S4). In conclusion, we demonstrated that accelerated, 3-dose CoronaVac vaccination was safe, and elicited satisfactory antibody and T-cell responses in young children with kidney diseases. T-cell responses appeared preserved against Omicron BA.1, which prevent severe COVID-19. The authors declare no conflicts of interest. Y.L. Lau conceptualized the study. Y.L. Lau, M. Peiris, W. Tu, D. Leung, J.S. Rosa Duque, and X. Mu designed the study. Y.L. Lau led the acquisition of funding. Y.L. Lau, W. Tu, and M. Peiris supervised the project. S.M. Chan, D. Leung, X. Mu, S.M.S. Cheng, I.Y.S. Tam, and J.H.Y. Lam led the study administrative procedures. A.L.T. Ma, Y.L. Lau, J.S. Rosa Duque, E.Y.H. Chan, S. Chim, F.T.W. Ho, P.C. Tong, W.M. Lai, and M.H.L. Lee provided study-related clinical assessments and follow-up. D. Leung, S.M. Chan, S.T.K. Sze, J.H.Y. Lam, J.S. Rosa Duque, and Y.L. Lau collected clinical safety data. S.M.S. Cheng, L.C.H. Tsang, K.K.H. Kwan, and M. Peiris developed and performed S-RBD IgG and sVNT. X. Mu, Y. Chung, H.H.W. Wong, A.M.T. Lee, W.Y. Li, and W. Tu developed and performed the T cell assays. D. Leung, D.H.L. Lee, and J.H.Y. Lam curated, analyzed, and visualized the data. D. Leung, X. Mu, S.M.S. Cheng, J.S. Rosa Duque, D.H.L. Lee, J.H.Y. Lam, and S.M. Chan validated the data. D. Leung and E.Y.H. Chan drafted the manuscript and were supervised by A.L.T. Ma, J.S. Rosa Duque, and Y.L. Lau, with input from X. Mu, and S.M.S. Cheng. All authors reviewed and approved the final manuscript. We thank the staff at Community Vaccination Centers at Ap Lei Chau Sports Centre, Gleneagles Hospital Hong Kong, and Sun Yat-Sen Memorial Park Sports Centre, and the University of Hong Kong Health System. The investigators are grateful to all clinical research team members and laboratory staff of the Department of Pediatrics and Adolescent Medicine at the University of Hong Kong for their research support. We are most thankful to the study participants, as well as clinicians and laboratory staff who have provided clinical care and testing to the patients. FUNDING This study was supported by the research grants COVID19F02, COVID19F10, and COVID19F12 from the Hong Kong SAR Government, which was not involved in the study design, performance, interpretation, or publication of this project. DATA SHARING All requests to share the pseudonymized data underlying the conclusions of this paper from researchers will be facilitated by the authors, subject to ethics approval. Enquiries should be addressed to [email protected]. Download .pdf (2.33 MB) Help with pdf files

Studies in adult patients with kidney diseases have shown an attenuated immune response to natural coronavirus disease 2019 (COVID-19) and COVID-19 vaccination.1Ikizler T.A. Coates P.T. Rovin B.H. Ronco P. Immune response to SARS-CoV-2 infection and vaccination in patients receiving kidney replacement therapy.Kidney Int. 2021; 99: 1275-1279Google Scholar The pivotal trial of BNT162b2 demonstrated a far higher neutralizing antibody titer in adolescents than in adults.2Frenck Jr., R.W. Klein N.P. Kitchin N. et al.Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents.N Engl J Med. 2021; 385: 239-250Google Scholar Yet, the immunogenicity of COVID-19 vaccines in adolescent patients receiving kidney replacement therapy or those who are on immunosuppression remains unknown. One of our aims in the Covid-19 Vaccination in Adolescents and Children study (ClinicalTrials.gov trial registration number NCT04800133) was to determine the reactogenicity and immunogenicity of the mRNA COVID-19 vaccine BNT162b2 (tozinameran, Fosun-BioNTech) in adolescent patients with kidney diseases and those who are immunocompromised and to compare their immune responses against healthy adolescents naive to COVID-19. The study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW21-157). Twenty patients aged 12 to 18 years were enrolled from 2 tertiary pediatric nephrology units in Hong Kong, and their characteristics are summarized in Table 1. At diagnosis, 11 patients had glomerulopathy, 5 patients had hereditary nephropathy such as Alport syndrome and cystic kidney diseases, 3 patients had congenital anomalies of the kidney and urinary tract, and 1 patient had ischemic nephropathy due to perinatal asphyxia. Treatment-wise, 6 participants were on dialysis, with 4 on peritoneal dialysis and 2 on hemodialysis. Six patients received a kidney transplant from deceased donors, and 8 patients with glomerulopathy did not require kidney replacement therapy and were on immunosuppressive therapy only. All other patients were on immunosuppressive therapy except for 4 of the 6 participants on dialysis.Table 1Participant profileCharacteristicAny kidney diseasesDialysisPost-kidney transplantImmunosuppression onlyNumber of participants20668Age, yr, median (range)16 (12–18)16.5 (15–18)17 (15–18)14.5 (12–18)Sex: male:female9:112:44:23:5Type of kidney disease, nGlomerulonephropathy11218Hereditary nephropathy5320Congenital anomalies of the kidney and urinary tract3120Ischemic nephropathy1010Current immunosuppression, nMycophenolate mofetil10145Prednisolone14266Azathioprine2011Cyclosporine A1010Tacrolimus7052Everolimus1010Hydroxychloroquine4103None4400Immunosuppression within 1 yr, n (%)Rituximab2 (10)0 (0)0 (0)2 (25)Kidney function, median (range)Estimated glomerular filtration rate, ml/min per 1.73 m2 aEstimated glomerular filtration rate is estimated using the modified Schwartz equation for participants younger than 18 yr and the Chronic Kidney Disease Epidemiology Collaboration formula for those older than 18 yr.74.5 (25–138)NA61.5 (29–77)102.5 (25–138)Urine protein-to-creatinine ratio, SI unit26 (0–108)NA23 (0–74)28 (0–108)End-stage kidney disease vintage, yr3.75 (1–18)2.5 (1–5)7 (3–18)NABlood count and comorbiditiesHypertension, n (%)13 (65)5 (83)4 (67)4 (50)Absolute lymphocyte count, ×106/ml, median (range)1.99 (1.57–2.97)1.76 (1.65–2.29)2.25 (1.67–2.97)2.18 (1.57–2.45)NA, not applicable.a Estimated glomerular filtration rate is estimated using the modified Schwartz equation for participants younger than 18 yr and the Chronic Kidney Disease Epidemiology Collaboration formula for those older than 18 yr. Open table in a new tab NA, not applicable. For safety, adverse reactions such as injection site pain and fatigue were solicited with an electronic diary 7 days after each dose. Adverse reactions solicited were mostly mild (grade 1) or moderate (grade 2). One participant with hereditary nephropathy on chronic dialysis was admitted for conservative management of diarrhea 1 day after dose 1, but his condition resolved spontaneously, and he was discharged within 2 days. No disease relapse or graft rejection episodes were recorded in our participants. For immunogenicity, anti–severe acute respiratory syndrome coronavirus 2 spike receptor–binding domain (anti–S-RBD) IgG was evaluated using an in-house enzyme-linked immunosorbent assay and neutralizing antibodies were determined using the surrogate virus neutralization test after both doses (Supplementary Methods) in the World Health Organization severe acute respiratory syndrome coronavirus 2 reference laboratory in the School of Public Health of the University of Hong Kong.3Perera R.A. Mok C.K. Tsang O.T. et al.Serological assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), March 2020.Euro Surveill. 2020; 25: 2000421Google Scholar,4Perera R. Ko R. Tsang O.T.Y. et al.Evaluation of a SARS-CoV-2 surrogate virus neutralization test for detection of antibody in human, canine, cat, and hamster sera.J Clin Microbiol. 2021; 59: e02504-e02520Google Scholar Participants had no history of COVID-19. After a single dose of BNT162b2, 10 of the 17 patients tested (59%) failed to seroconvert on anti–S-RBD IgG enzyme-linked immunosorbent assay, all of whom were on immunosuppressive therapy, as shown in Figure 1. These 10 nonresponders included 4 kidney transplant recipients, 2 patients on dialysis, and 4 patients with glomerulopathy who were on immunosuppression alone. Neutralizing activity was positive in all who seroconverted. The mean anti–S-RBD IgG optical density 450 (OD450) values and neutralizing antibody inhibition percentages in patients with kidney diseases overall and each treatment subgroup were all significantly lower than those in 116 healthy adolescents aged 11 to 17 years determined using 1-way analysis of variance with the Dunnett post hoc test. After the second dose, only 2 of the 17 patients (12%) remained seronegative, and similarly, neutralizing activity was detected in all those who seroconverted; yet the mean anti–S-RBD IgG level and inhibition percentages remained lower than those in healthy adolescents, which were significant except in patients on dialysis in analysis of variance. The only 4 patients without immunosuppression in our study seroconverted after the first dose, but all had a lower anti–S-RBD IgG level than the mean in healthy adolescents. Interestingly, 2 patients who received rituximab 12 months before COVID-19 vaccination in our study for nephrotic syndrome and lupus nephritis were seronegative after dose 1, and only the patient with lupus nephritis seroconverted after dose 2 but with an IgG level below the range in healthy adolescents; these 2 patients were on mycophenolate mofetil and prednisolone, and in the patient with lupus nephritis, hydroxychloroquine as well. B cell analysis at 12 months after rituximab treatment before vaccination was available for the patient with nephrotic syndrome and revealed incompletely repleted B cells with CD19+ cell percentage at 5.67% (reference interval 7.73%–16.84%) and an absolute count of 124 cells/μL (reference interval 177–416 cells/μL) as well as a low CD19+ CD27+ memory B cell percentage of 0.12% among total lymphocytes, suggesting that incomplete B cell recovery contributed to vaccine failure.5Colucci M. Carsetti R. Cascioli S. et al.B cell reconstitution after rituximab treatment in idiopathic nephrotic syndrome.J Am Soc Nephrol. 2016; 27: 1811-1822Google Scholar,6Ding Y. Zhou L. Xia Y. et al.Reference values for peripheral blood lymphocyte subsets of healthy children in China.J Allergy Clin Immunol. 2018; 142: 970-973.e8Google Scholar The other nonresponder to the second dose in our study was a transplant recipient, who was on triple maintenance immunosuppression with prednisolone, tacrolimus, and mycophenolate mofetil. Our results showed that adolescents with kidney diseases who are receiving immunosuppression or kidney replacement therapy could respond to 2 doses of BNT162b2 reasonably, but their antibody level was lower than that in healthy adolescents. As these patients are at an increased risk of mortality from COVID-19, it is important to protect them with a robust antibody response from vaccination.7Ng J.H. Hirsch J.S. Wanchoo R. et al.Outcomes of patients with end-stage kidney disease hospitalized with COVID-19.Kidney Int. 2020; 98: 1530-1539Google Scholar mRNA vaccines were found to be associated with myocarditis and pericarditis in adolescents; therefore, Hong Kong and the United Kingdom, among other places, previously recommended a single dose of BNT162b2 for adolescents.8Marshall M. Ferguson I.D. Lewis P. et al.Symptomatic acute myocarditis in 7 adolescents after Pfizer-BioNTech COVID-19 vaccination.Pediatrics. 2021; 148e2021052478Google Scholar,9Zimmermann P. Pittet L.F. Finn A. et al.Should children be vaccinated against COVID-19?.Arch Dis Child. 2021; 107: e1Google Scholar Our results support that immune response to a third dose of the COVID-19 vaccine should be studied in pediatric patients with kidney diseases on kidney replacement therapy or immunosuppression to better protect them from severe COVID-19. All the authors declared no competing interests. This work was supported by the Food and Health Bureau of the Hong Kong Government ( COVID19F02 ). AL-TM, DL, EY-HC, SChi, FT-WH, W-ML, P-CT, MH-LL, SMC, JRD, and YLL were involved in the recruitment of participants. AL-TM, EY-HC, SChi, FT-WH, W-ML, P-CT, and MHLL provided clinical care. DL, WH-SW, S-MC, JRD, and YLL organized the trial. SChe and JSMP performed antibody testing. WH-SW provided statistical support. AL-TM, DL, WH-SW, SChe, JRD, JSMP, and YLL interpreted results. DL drafted the manuscript, critically revised by AL-TM, EY-HC, JRD, JSMP, and YLL. All authors reviewed and approved the final manuscript. Download .doc (.07 MB) Help with doc files Supplementary File (Word)

OBJECTIVES:Intrathecal baclofen pump associated central nervous system (CNS) infection and meningitis is a rare but serious complication and may have dire consequences. Due to bacterial biofilm formation, the optimal treatment strategy is usually for removal of the pump, followed by systemic antibiotics for treatment of local and CNS infection. We describe this case of a patient with recurrent Staphylococcus aureus pump site empyema and meningitis leading to status dystonicus, who was successfully managed with radical debridement and intrareservoir baclofen-vancomycin co-infusion.MATERIALS AND METHODS:We retrospectively report a case of infected intrathecal baclofen pump with meningitis and provide a full review of literature.CONCLUSIONS:To the best of our knowledge, this is the first reported case of intrathecal baclofen (ITB)-associated pump site empyema and meningitis successfully treated with this technique. In selected cases where surgical explantation is deemed not feasible, this method can provide clinicians with an additional option for pump salvage and retention, while eradicating CNS infection and maintaining optimal control of spasticity and dystonia.

American Journal of Medical Genetics Part AVolume 176, Issue 11 p. 2523-2527 RESEARCH LETTER Mosaic KRAS mutation in a patient with encephalocraniocutaneous lipomatosis and renovascular hypertension Laura M. McDonell, Laura M. McDonell orcid.org/0000-0001-9375-4423 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, CanadaSearch for more papers by this authorGordon Ka-Chun Leung, Gordon Ka-Chun Leung Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong KongSearch for more papers by this authorHussein Daoud, Hussein Daoud Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, CanadaSearch for more papers by this authorJanice Ip, Janice Ip Department of Radiology, Queen Mary Hospital, Hong KongSearch for more papers by this authorStella Chim, Stella Chim Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong KongSearch for more papers by this authorHo Ming Luk, Ho Ming Luk orcid.org/0000-0003-4066-4066 Department of Health, Clinical Genetic Service, Hong KongSearch for more papers by this authorLawrence Lan, Lawrence Lan Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, Hong KongSearch for more papers by this authorCare4Rare Canada Consortium, Care4Rare Canada ConsortiumSearch for more papers by this authorKym M. Boycott, Corresponding Author Kym M. Boycott kboycott@cheo.on.ca Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada Correspondence Brian Hon-Yin Chung, Department of Paediatrics and Adolescent Medicine, 102 Pokfulam Road, Hong Kong. Email: bhychung@hku.hk and Kym M. Boycott, Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada K1H 8L1. Email: kboycott@cheo.on.caSearch for more papers by this authorBrian Hon-Yin Chung, Corresponding Author Brian Hon-Yin Chung bhychung@hku.hk Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Correspondence Brian Hon-Yin Chung, Department of Paediatrics and Adolescent Medicine, 102 Pokfulam Road, Hong Kong. Email: bhychung@hku.hk and Kym M. Boycott, Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada K1H 8L1. Email: kboycott@cheo.on.caSearch for more papers by this author Laura M. McDonell, Laura M. McDonell orcid.org/0000-0001-9375-4423 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, CanadaSearch for more papers by this authorGordon Ka-Chun Leung, Gordon Ka-Chun Leung Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong KongSearch for more papers by this authorHussein Daoud, Hussein Daoud Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, CanadaSearch for more papers by this authorJanice Ip, Janice Ip Department of Radiology, Queen Mary Hospital, Hong KongSearch for more papers by this authorStella Chim, Stella Chim Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong KongSearch for more papers by this authorHo Ming Luk, Ho Ming Luk orcid.org/0000-0003-4066-4066 Department of Health, Clinical Genetic Service, Hong KongSearch for more papers by this authorLawrence Lan, Lawrence Lan Division of Paediatric Surgery, Department of Surgery, The University of Hong Kong, Hong KongSearch for more papers by this authorCare4Rare Canada Consortium, Care4Rare Canada ConsortiumSearch for more papers by this authorKym M. Boycott, Corresponding Author Kym M. Boycott kboycott@cheo.on.ca Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada Correspondence Brian Hon-Yin Chung, Department of Paediatrics and Adolescent Medicine, 102 Pokfulam Road, Hong Kong. Email: bhychung@hku.hk and Kym M. Boycott, Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada K1H 8L1. Email: kboycott@cheo.on.caSearch for more papers by this authorBrian Hon-Yin Chung, Corresponding Author Brian Hon-Yin Chung bhychung@hku.hk Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Correspondence Brian Hon-Yin Chung, Department of Paediatrics and Adolescent Medicine, 102 Pokfulam Road, Hong Kong. Email: bhychung@hku.hk and Kym M. Boycott, Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada K1H 8L1. Email: kboycott@cheo.on.caSearch for more papers by this author First published: 05 October 2018 https://doi.org/10.1002/ajmg.a.40349Citations: 6 Funding information Baxter and Alma Ricard Foundation, Grant/Award Number: Doctoral Research Award; Canadian Institutes of Health Research; Care4Rare Canada Consortium; Children's Hospital of Eastern Ontario Foundation; Genome Canada; Génome Québec; Ontario Genomics Institute; Ontario Research Fund; The Hong Kong Society for the Relief of Disabled Children Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume176, Issue11November 2018Pages 2523-2527 RelatedInformation

Haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy characterised by haemolysis, platelet consumption and renal injury. Eculizumab is monoclonal anti-C5 antibody that is proven to be useful in its management.

Objectives: Tyrosinemia type I is an autosomal recessive disorder in tyrosine metabolism. In areas without expanded newborn screening, patients present with acute hepatorenal failure in early infancy. Diagnosis can be elusive when clinical presentation is non-specific and biochemical abnormalities are masked by secondary changes. This is the first Hong Kong Chinese report.Design and methods: A two-month-old Chinese male infant with unremarkable antenatal and postnatal history presented with progressive abdominal distension for three days. He suffered from end-stage liver failure, hypoglycemia and hepatic encephalopathy. Diagnostic work-up was complicated starting from rule-out sepsis, intestinal obstruction, volvulus, peritonitis, septic ileus, poisoning to metabolic diseases. Clinical, biochemical and genetic data was described.Results: The patient showed increases in multiple plasma amino acids including tyrosine, phenylalanine and methionine, and hyper-excretions of 4-hydroxyphenyl-acetate, -pyruvate, and -lactate, as well as N-acetyltyrosine which could be seen in liver failure due to both tyrosinemia type I and non-metabolic conditions. Because of the volatile nature, succinylacetone was almost undetectable. The diagnosis was confirmed by genetic analysis of FAH with two novel mutations, viz. NM_000137.2:c.1063-1G>A and NM_000137.2:c.1035_1037del. Living-related liver transplantation was done. However, the patient still suffered many complications after the severe metabolic insult with hypoxic ischemic encephalopathy, cerebral atrophy, global developmental delay and cortical visual impairment.Conclusions: Because of the lack of expanded newborn screening in Hong Kong, this child unfortunately presented in the most severe form of tyrosinemia type I. Expanded newborn screening can save life and reduce the burden of diagnostic complexity. This illustrates the need for expanded newborn screening in Hong Kong. (C) 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

PURPOSE:To determine the prevalence, risk factors for and patterns of hypertension in Chinese adolescents based on a territory-wide school based screening programme in Hong Kong.METHODS:Cross-sectional anthropometric and oscillometric blood pressure (BP) measurements and lifestyle information were obtained as part of a growth survey of students from randomly selected secondary schools in Hong Kong. Those with blood pressure ≥ 95th centile were screened a second or third time. Hypertension is defined as elevated blood pressure on three separate occasions. The independent effects of age, sex, body mass index, high waist circumference (≥ 85th centile), sleep duration, family history of hypertension and frequency of exercise on hypertension were explored by multivariate analysis.RESULTS:Among the 6193 students screened, the prevalence of elevated blood pressure on the first, second and third screens was 9.54%, 2.77% and 1.44% respectively. Hypertension was more likely to be systolic. High waist circumference (≥ 85th centile) was independently associated with a higher risk of hypertension (adjusted OR 2.4), while exercising twice or more per week was protective (adjusted OR 0.28).CONCLUSIONS:The prevalence of hypertension in Hong Kong Chinese adolescents is 1.44%. The current study shows high waist circumference is a predictor of hypertension in adolescents, while increased physical activity is a protective factor. Incorporating waist circumference into screening protocols may increase the sensitivity of cardiovascular risk stratification. Healthcare providers should be strong advocates helping to prevent obesity and promote physical activity in adolescents and children.

Haemolytic uraemic syndrome is an important cause of acute renal impairment in childhood. We review the incidence, and clinical and laboratory features of haemolytic uraemic syndrome in a Chinese population. Five patients were identified from 2006 to 2008. All patients were young children with associated invasive Streptococcus pneumoniae pulmonary infection. Serotypes 3, 14, and 19A were confirmed in four patients. The classical post-diarrhoeal form associated with Escherichia coli (O157:H7) infection was not seen. One patient died of acute respiratory failure. Streptococcus pneumoniae infection, as an associated condition in haemolytic uraemic syndrome, is important and relatively common in Chinese patients, especially among children. The acute clinical picture is similar to that reported in the western literature, except for an uncommon association with meningitis. The medium-term renal outcome of the Chinese population appears to be more favourable than the Caucasians. Widespread vaccination against Streptococcus pneumoniae may have resulted in changes in bacterial epidemiology and clinicians should be continuously aware of this severe disease. The use of washed blood components for transfusion in the acute stage requires further study.

Gastric pneumatosis is extremely rare during infancy. It has been reported in association with necrotizing enterocolitis or congenital abnormalities such as pyloric stenosis. Here, we report a case of gastric pneumatosis in a premature neonate on synchronized nasal intermittent positive pressure ventilation. No pneumatosis was noted in the rest of the bowel or esophagus. There could have been mild damage in the gastric mucosa, either related to the placement of the feeding tube or secondary to the use of indomethacin or both. The condition was further aggravated by noninvasive ventilation. An increase in intragastric pressure resulted in the submucosal dissection of air followed by the development of gastric pneumatosis. Conservative management strategies, including the use of a nasogastric tube for decompression and the withholding of feeding, successfully managed the gastric pneumatosis in our patient. An uneventful recovery was made after conservative management. Prompt recognition and evaluation of this condition were essential for making the diagnosis.

We conducted a retrospective multicenter review to estimate the prevalence of urological abnormalities in Chinese children with first febrile urinary tract infection (UTI) and to evaluate the selective imaging strategy recommended by the NICE guideline for detecting underlying abnormalities. Atypical UTI was defined as in the NICE UTI guideline. Overall, 576 boys and 244 girls aged below 24 months were reviewed. All underwent ultrasound (US) and micturating cystourethrogram (MCUG) and 612 underwent DMSA scans. US was abnormal in 73 (8.9%) and vesicoureteral reflux was shown in 195 patients (23.8%). A total of 126 patients were considered to have remediable urological abnormalities requiring additional surgical or medical interventions. The NICE guideline yielded excellent negative predictive values (NPV) of 100–94.4% in girls but 91% in boys. If all boys underwent US and DMSA and only those with atypical UTI or abnormal US or DMSA proceeded to MCUG, then the NPV increased to 95.2% and 97.4% for boys aged below and above 6 months, respectively. These revised strategies would substantially save invasive studies—DMSA and MCUG in 27 and 74% of girls aged below and above 6 months, respectively, or MCUG in 23 and 59% of boys aged below and above 6 months, respectively.

We retrospectively reviewed the cases of 13 lupus nephritis children with pure membranous glomerulonephritis (MGN; Group A) and ten children with mixed proliferative and membranous nephritis (Group B). The children were identified through a territory-wide survey of patients between 1990 and 2003. All were ethnic Chinese. Age at diagnosis ranged from 3.7 to 18.6 years (Group A) and from 9.6 to 22.1 years (Group B). Female-to-male ratios were 12:1 (Group A) and 9:1 (Group B). Group A patients were more often nephrotic than Group B patients (11/13 vs. 5/10, p = 0.17). The glomerular filtration rate (GFR) at presentation was normal in all but two patients (one from each group). For induction, Group B patients consistently received prednisolone and cyclophosphamide; in contrast, the cytotoxic regimens in Group A patients varied from cyclophosphamide (five patients), mycophenolate mofetil (two patients), azathiorpine plus cyclosporine (one patient), and azathioprine alone (one patient). After a median follow-up of 7.6-7.8 years, one Group A patient had died of fulminant lupus. One survivor in Group B had a GFR < 90 ml/min per 1.73 m(2). Proteinuria persisted in five Group A patients and two Group B patients. In conclusion, Group B patients had good prognosis in terms of survival and proteinuria control. The only death occurred in Group A, and five of the 12 survivors in this group had persistent proteinuria. Further studies are needed to define the best treatment for pure lupus MGN.

Aim: The ever-growing number and increasing survival of haematopoietic stem cell transplantation (HSCT) allow better recognition of its associated renal injuries. We aimed to study the clinicopathologic features of renal biopsies after HSCT by reviewing 13 percutaneous renal biopsies in our institute (Queen Mary Hospital).Methods: A retrospective clinicopathologic study of all renal biopsies archived to the Department of Pathology, Queen Mary Hospital during the period January 1999 to December 2006 was performed. Biopsies from patients with HSCT were selected. Clinical data on presentation and follow up were retrieved from hospital records and physicians.Results: In the 8-year period, a total of 2233 native renal biopsies were archived. Thirteen renal biopsies were selected from 12 patients with HSCT (11 allogeneic, one autologous). All but one patient were male. The age at renal biopsy ranged from 7 to 63 years (median: 32 years). The median interval of renal biopsy after HSCT was 24 months (range 1-134 months). Evidence of graft-versus-host disease was found in nine patients. The most common presentation was significant proteinuria (10 cases) and renal impairment (eight cases). The predominant histological changes were membranous glomerulonephritis (n = 4) and thrombotic microangiopathy (n = 4). One case of focal segmental glomerulosclerosis, IgA nephropathy, minimal change disease, acute tubular necrosis and hypertensive nephrosclerosis were also recorded. Four of our patients died at 0-11 months after renal biopsy. Of the remaining eight patients with a mean follow up of 43.6 months (range, 10-98 months), chronic renal impairment were found in three (37.5%) patients and significant proteinuria also persisted in three. One patient had cytogenetic evidence of relapse of underlying haematological malignancy after HSCT.Conclusion: Among the various renal lesions after HSCT, membranous glomerulonephritis and thrombotic microangiopathy were the most common. Mechanisms of renal injury varied from graft-versus-host disease-associated immune complex deposition to non-immune complex injury on endothelial cells, glomerular epithelial cells and tubular epithelium. Pathologists and clinicians should attend to the histological and temporal heterogeneity of renal injury when managing patients after HSCT.

We report a multicenter study of Chinese children in Hong Kong with systemic lupus erythematosus (SLE) nephritis. Children were included if: they fulfilled the ACR criteria, had significant proteinuria or casturia, were Chinese and younger than 19 years and had been diagnosed with SLE between January 1990 and December 2003. Investigators in each center retrieved data on clinical features, biopsy reports, treatment and outcome of these patients. There were 128 patients (eight boys, 120 girls; mean age: 11.9+/-2.8 years). About 50% presented with multisystem illness and 40% with nephritic/nephrotic symptoms. Negative anti-dsDNA antibodies were found in 6% of the patients. Renal biopsy revealed WHO Class II, III, IV and V nephritis in 13 (10%), 22 (17%), 69 (54%) and 13 (10%) patients, respectively. The clinical severity of the nephritis did not accurately predict renal biopsy findings. The follow-up period ranged from 1 to 16.5 years (mean+/-SD: 5.76+/-3.61 years). During the study five patients died (two from lupus flare, one from cardiomyopathy, two from infections). Four patients had endstage renal failure (ESRF) (one died during a lupus flare). All deaths and end-stage renal failure occurred in the Class IV nephritis group. Chronic organ damage was infrequent in the survivors. The actuarial patient survival rates at 5, 10 and 15 years of age were 95.3, 91.8, and 91.8%, respectively. For Class IV nephritis patients, the survival rates without ESRF at 5, 10, and 15 years were 91.5, 82.3 and 76%, respectively. The survival and chronic morbidity rates of the Chinese SLE children in the present study are comparable to those of other published studies.

Heavy proteinuria after bone marrow transplantation (BMT) is rare. Pathology shows membranous glomerulonephritis (MGN) in most cases. After BMT, focal segmental glomerulosclerosis (FSGS) after resolution of MGN has not been reported. We describe a 13-year-old boy who had matched unrelated donor allogeneic BMT for relapsed acute lymphoblastic leukemia, complicated by chronic graft-versus-host disease. Nephrotic syndrome developed 1 year after BMT and renal biopsy revealed MGN. Immunosuppressive therapy achieved good clinical remission, and treatment was stopped after 15 months. He developed significant proteinuria 55 months later. The second renal biopsy showed FSGS without changes of MGN. This distinctive disease evolution gives inspiring implications. Complete morphological resolution of graft-versus-host disease–associated MGN, achieved in our case, has not been previously documented. Recurrent significant proteinuria after BMT is not necessarily due to previous renal lesion, and a repeat renal biopsy is indicated. The pathogenesis of MGN and FSGS are different, and different mechanisms of glomerular injury can interplay in a single patient after BMT. This case helps to expand our knowledge of the temporal morphological spectrum of renal lesions associated with BMT.

Primary nocturnal enuresis (PNE) is a common childhood problem. Knowledge of the child's attitudes and his parents' perceptions to enuresis will help in effective counselling of the family and improve their commitment to therapy, which contributes to the success of treatment. In a prospective questionnaire survey by the Hong Kong Childhood Enuresis Study Group, 105 Chinese children aged 9.5±1.8 years (68 boys, 37 girls) with severe PNE were recruited from nine public hospitals in Hong Kong. After informed consent, both patients and parents were interviewed by the attending doctor according to a structured questionnaire. The results showed that bedwetting embarrassed our enuretic children as they avoided talking about bedwetting problem (89.5%), avoided sleeping out (25.7%) and denied having wetting episodes (18.1%). The majority of parents (86%) thought that PNE was abnormal and was caused by renal, psychological, or brain problems. Arousal difficulties occurred in 88% of the children. Parents felt troublesome (71.4%), angry (19%), and ashamed (11.4%) of their children. Although 77% of the parent praised their children for being dry, 57% still punished their children for enuretic episodes. In conclusion, Hong Kong children with PNE were embarrassed by bedwetting while their parents had mixed-feeling of being worried (about organic illness), troublesome, angry and ashamed. A punitive attitude was still common in our local community and this may adversely affect the parent-child relationship and their commitment to treatment.